The G6PD NM_001360016.2:c.202G>A (NP_001346945.1:p.(Val68Met)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: The 202A allele reduced erythrocyte G6PD activity by approximately 40% in heterozygotes and 80% in hemizygotes or homozygotes. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.G6PD encodes an enzyme that helps cells produce NADPH, which protects against oxidative damage and supports important biosynthetic reactions. Changes that reduce G6PD activity can cause G6PD deficiency, leading to neonatal jaundice, episodes of red blood cell breakdown, or chronic hemolytic anemia. G6PD is not known to have a primary role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting: the 202A allele reduced erythrocyte G6PD activity by approximately 40% in heterozygotes and 80% in hemizygotes or homozygotes.
Met at supporting strength: p.Val68Met was in cis with p.Asn126Asp in a pathogenic haplotype, with LOD=21.03 and D′=0.806.
VUS: PS3 (supporting) and BP2 (supporting) do not meet any generic ACMG/AMP pathogenic, likely pathogenic, likely benign, or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 7,797 / 1,210,144 alleles. Recorded AF 0.00644303. Recorded homozygote count 328.
This variant is present in gnomAD v2.1 (AF= 0.0115349; MAF= 1.15349%, 2365/205030 alleles, homozygotes = 90) and has highest observed frequency in the African/African American population (AF= 0.116407; MAF= 11.64066%, 2208/18968 alleles, homozygotes = 89); grpmax FAF= 0.110833.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009060727624844377, 131/14458 alleles, homozygotes = 9).
Recorded SpliceAI maximum delta score: 0.057. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 8 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All four requested segregation and de novo criteria are not assessed because the available evidence does not document a patient-level trio, family pedigree, affected relatives, or informative segregation results.
The available variant publications describe cohort, haplotype, enzyme-activity, or computational findings and do not supply the family-level evidence required for PS2, PM6, PP1, or BS4.
Generic ACMG/AMP rules govern because the listed G6PD CSPEC has no released criteria.
No criterion in this group has qualifying exact-variant expert-panel ClinVar evidence.
The available literature reports either a combined haplotype or functional/population association data, not the required case-specific phenotype, alternate molecular basis, or exact-variant case-control evidence for these criteria.
The allelic evidence supports BP2 at supporting strength based on cis occurrence of p.Val68Met with p.Asn126Asp in a pathogenic G6PD haplotype; PM3 is not assessed because trans phase with a pathogenic variant in an affected proband is not documented.
Both criteria are evaluated on the missense REVEL path only. The case has no REVEL score; the available SpliceAI and BayesDel results do not establish PP3 or BP4 under the governing generic rules.
No criteria match.
PS3 is met at supporting strength. PMID:25201310 directly evaluated NM_001360016.2:c.202G>A (p.Val68Met; rs1050828) in a large Kenyan infant cohort using a biologically relevant spectrophotometric NADPH-generation assay for erythrocyte G6PD activity. Among 1,828 individuals meeting genotype/activity inclusion criteria, the 202A allele was associated with approximately 40% lower activity in heterozygotes and 80% lower activity in hemizygotes and homozygotes, providing direct evidence of reduced G6PD function. PMID:23006493 independently measured G6PD activity in a clinical cohort and included p.Val68Met in the A-(1–3) haplotype, but the variant was not isolated from p.Asn126Asp, so it is supportive context rather than independent variant-specific functional confirmation. The evidence is biologically relevant and substantial, but the available studies are observational erythrocyte activity studies rather than validated, reproducible diagnostic-laboratory or controlled isogenic assays; therefore the evidence is not calibrated above supporting strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BP2 is met because p.Val68Met, corresponding to NM_001360016.2:c.202G>A, was observed in cis with p.Asn126Asp in the A-(1–3) G6PD haplotype. The study explicitly characterized this as a pathogenic haplotype and described significant linkage disequilibrium between p.Asn126Asp and p.Val68Met (LOD=21.03; D′=0.806), supporting the required cis relationship with a pathogenic variant.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing ACMG/AMP rule requires significantly increased prevalence in affected individuals versus controls and, under the supplied generic threshold, OR or RR >5.0 with a confidence interval excluding 1. The literature_pass PS4 lead was PMID:7577654, but the available abstract only describes sequencing 11 unrelated Spanish G6PD-deficient males and does not establish an exact c.202G>A case count or a control count. PMID:23006493 reports p.Val68Met only within a combined p.Val68Met+p.Asn126Asp haplotype in 25/163 affected males (15.33%), without a control comparison and without isolating the exact variant. Therefore no valid exact-variant case-control OR/RR or 95% CI is available; the PS4 threshold cannot be met.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PM2 is not met because the variant is common in population databases. Using the default all-comers sources, gnomAD v4.1 reports total AF=0.00644303 (7,797/1,210,144 alleles; 328 homozygotes) and gnomAD v2.1 reports total AF=0.0115349 (2,365/205,030 alleles; 90 homozygotes). Both exceed the generic PM2 supporting threshold of <=0.0001 by a wide margin. No governing G6PD specification requires a non-cancer or exome-only population source.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is missense, NM_001360016.2:c.202G>A (p.Val68Met), so the governing generic rule requires the missense REVEL path only; the available SpliceAI max delta of 0.057 cannot be used for missense PP3, and BayesDel has no established generic ACMG-strength calibration. No REVEL score is available, so the PP3 threshold cannot be met.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The governing rule requires a reputable source to recently report the variant as pathogenic when the evidence is unavailable to the laboratory for independent evaluation. The exact queried variant has no expert-panel ClinVar classification: the retrieved ClinVar record is marked no_exact_match and is a single-submitter record for the compound variant c.[143T>C;202G>A]. PMID:23006493 is an independently available primary study and does not constitute unavailable evidence. Thus the qualifying PP5 condition is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BS3 is not met. The available variant-relevant functional evidence measures reduced G6PD activity associated with the 202A allele and therefore does not show no damaging effect on protein function or splicing. No well-established benign functional study with appropriate controls was identified for p.Val68Met.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. The reviewed G6PD literature instead describes disease-associated missense haplotypes as common findings, including p.Val68Met-containing A-(1–3) and Aures p.Ile48Thr haplotypes, and directly associates the 202A allele with reduced enzyme activity; this does not support a primarily truncating disease mechanism.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is missense, NM_001360016.2:c.202G>A (p.Val68Met), so the governing generic rule requires the missense REVEL path only; the available SpliceAI max delta of 0.057 cannot substitute for REVEL, and BayesDel has no established generic ACMG-strength calibration. No REVEL score is available, so BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The governing rule requires a reputable source to recently report the variant as benign when the evidence is unavailable to the laboratory for independent evaluation. No exact-variant ClinVar expert-panel benign or likely-benign classification is present; the only retrieved ClinVar submission is single-submitter and not an exact match. No qualifying reputable unavailable benign assertion was identified, so BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is NP_001346945.1:p.(Val68Met), and PMID:23006493 reports p.Val68Met within the A-(1–3) haplotype described as pathogenic. However, the report describes a combined haplotype containing p.Val68Met and p.Asn126Asp rather than an independently established pathogenic variant record for the same amino-acid change, so the evidence does not safely satisfy PS1.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No patient-level documentation establishes that NM_001360016.2:c.202G>A (p.Val68Met) is de novo, confirms both maternity and paternity, documents the patient's disease phenotype, or excludes a family history. The available variant literature describes population or cohort observations but does not provide the required trio testing and family-history evidence. Therefore PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The variant is p.Val68Met at residue 68. The authoritative vcep_materials.json domain_tables entry for G6PD is absent because domain_tables is empty, and the available hotspot searches report no Cancer Hotspots or COSMIC result. Therefore, no approved critical-domain or qualifying hotspot route is established, but the generic rule does not permit concluding that no critical functional domain exists from these negative results alone.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM3 cannot be assessed because the available evidence does not document NM_001360016.2:c.202G>A/p.Val68Met in trans with a pathogenic variant in an affected individual, nor does it provide parent or offspring testing establishing trans phase. The available G6PD study reports this variant in cis with p.Asn126Asp within a pathogenic haplotype, which does not satisfy PM3's recessive trans requirement.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
The target variant is p.Val68Met. The case PM5 candidate file contains zero same-residue candidates and no pathogenic alternate missense change at Val68, so a qualifying previously pathogenic different missense change at the same residue has not been established.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No patient-level observation establishes an assumed de novo occurrence of NM_001360016.2:c.202G>A (p.Val68Met). There is no documented affected proband with parental testing that is incomplete, and no evidence indicates whether maternity or paternity was unconfirmed. Therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No family pedigree, affected relatives, variant genotypes, phenotype assessments, or informative meioses are documented for NM_001360016.2:c.202G>A (p.Val68Met). The available cohort and haplotype studies do not establish co-segregation with disease in multiple affected family members. Therefore PP1 cannot be assessed at any strength.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The available literature supports that missense variation is a disease mechanism in G6PD: PMID:23006493 describes common disease-associated missense haplotypes, including p.Val68Met, and PMID:25201310 demonstrates a large enzyme-activity effect for the 202A allele. However, the case evidence does not provide a gene-wide assessment establishing a low rate of benign G6PD missense variation, which is an independent requirement of PP2.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence identifies cohorts referred for or suspected of G6PD deficiency and reports enzyme activity, but it does not provide a case-specific phenotype or family history demonstrating a highly specific presentation with a single genetic etiology. PP4 therefore cannot be assessed from the available evidence.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
The filtering allele frequency criterion is numerically exceeded: gnomAD v4.1 grpmax FAF is 0.120371 (African/African American), with 7,024 observed alleles, above the generic BA1 threshold of 0.05 and the required 2,000 observed alleles. However, this is a well-documented G6PD deficiency allele: gnomAD v4.1 reports 319 homozygotes in females and the Kenyan study reports an approximately 40% activity reduction in heterozygotes and 80% reduction in hemizygotes/homozygotes, with a 17% derived allele frequency. The high ancestry-enriched frequency is therefore not sufficient by itself for a stand-alone benign call, and the available evidence does not establish that the allele is benign rather than a common, variably expressed or trigger-dependent pathogenic G6PD allele. BA1 is not assessed pending human review of disease penetrance and the appropriate maximum credible allele frequency.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The filtering allele frequency is numerically above the generic BS1 default: gnomAD v4.1 grpmax FAF is 0.120371, with 7,024 observed African/African American alleles, exceeding 0.01 and the 2,000-allele reliability requirement. Nevertheless, the frequency is strongly ancestry-enriched and the variant is associated with G6PD deficiency and reduced enzyme activity, including an approximately 17% derived allele frequency in a Kenyan cohort. Because G6PD deficiency has ancestry-dependent frequency and variable clinical expression, the default 1% threshold cannot establish that this allele is more frequent than expected for the disorder. A disease-specific maximum credible allele frequency calculation with prevalence, penetrance, and allelic heterogeneity inputs is unavailable, so BS1 is not assessed.
Allele frequency is greater than expected for the disorder.
The population data show 319 female homozygotes in gnomAD v4.1 and no reported hemizygous homozygote count in the African/African American XY subset, but gnomAD does not establish that these individuals are healthy adults, unaffected by G6PD deficiency, or fully phenotyped for an early-onset, fully penetrant disorder. The available literature describes enzyme activity effects and deficiency-associated cohorts rather than verified healthy adult hemizygotes or homozygotes. Therefore, the BS2 healthy-adult requirement is not established.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No affected family members with tested genotypes are documented, and no family-level observation shows that NM_001360016.2:c.202G>A (p.Val68Met) fails to segregate with disease. Because there is no evaluable family and no information to address phenocopies or multiple pathogenic variants, BS4 cannot be assessed.
Lack of segregation in affected members of a family.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The available records do not document an exact queried-variant case with a separate molecular diagnosis or alternate molecular basis. BP5 cannot be assessed because the required case-level evidence is absent.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001360016.2:c.202G>A in G6PD is a missense substitution predicted to produce NP_001346945.1:p.(Val68Met). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for G6PD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001360016.2:c.202G>A in G6PD is a missense substitution predicted to produce NP_001346945.1:p.(Val68Met). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for G6PD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001360016.2:c.202G>A in G6PD is a missense substitution predicted to produce NP_001346945.1:p.(Val68Met). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for G6PD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001360016.2:c.202G>A in G6PD is a missense substitution predicted to produce NP_001346945.1:p.(Val68Met). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for G6PD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in G6PD, mapped onto the exon structure of NM_001360016.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American7024 / 57,212 | 0.12319 hom |
| Remaining individuals370 / 47,618 | 0.00786 hom |
| Admixed American301 / 45,849 | 0.00663 hom |
| Middle Eastern19 / 4,354 | 0.0044 |
| South Asian17 / 56,849 | 0.0003 |
| European (non-Finnish)66 / 895,137 | 7.4e-05 |
| African/African American2208 / 18,968 | 0.1289 hom |
| Admixed American116 / 28,041 | 0.0041 |
| Remaining individuals16 / 5,325 | 0.0031 hom |
| South Asian7 / 19,076 | 0.00037 |
| European (non-Finnish)18 / 92,499 | 0.00019 |
This variant is present in gnomAD v4.1 (AF= 0.00644303; MAF= 0.64430%, 7797/1210144 alleles, homozygotes = 328) and has highest observed frequency in the African/African American population (AF= 0.122771; MAF= 12.27714%, 7024/57212 alleles, homozygotes = 319); grpmax FAF= 0.120371.
This variant is present in gnomAD v2.1 (AF= 0.0115349; MAF= 1.15349%, 2365/205030 alleles, homozygotes = 90) and has highest observed frequency in the African/African American population (AF= 0.116407; MAF= 11.64066%, 2208/18968 alleles, homozygotes = 89); grpmax FAF= 0.110833.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009060727624844377, 131/14458 alleles, homozygotes = 9).
The variant is missense, NM_001360016.2:c.202G>A (p.Val68Met), so the governing generic rule requires the missense REVEL path only; the available SpliceAI max delta of 0.057 cannot be used for missense PP3, and BayesDel has no established generic ACMG-strength calibration. No REVEL score is available, so the PP3 threshold cannot be met.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is missense, NM_001360016.2:c.202G>A (p.Val68Met), so the governing generic rule requires the missense REVEL path only; the available SpliceAI max delta of 0.057 cannot substitute for REVEL, and BayesDel has no established generic ACMG-strength calibration. No REVEL score is available, so BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001360016.2:c.202G>A in G6PD is a missense substitution predicted to produce NP_001346945.1:p.(Val68Met). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for G6PD, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). BayesDel score = 0.406482.
7 paper records listed. 2 cited in the classification.
In males, the three most common pathogenic 6-locus haplotypes observed in order of frequency were Aures, characterised by a single p.Ile48Thr mutation (49/163, 30.06%), Mediterranean, characterised by a single p.Ser188Phe mutation (29/164, 17.79%) and variant of A- designated A-(1–3) [15] characterised by a combination of p.Val68Met and p.Asn126Asp mutations (25/163, 15.33%).
Location Results, paragraph describing 6-locus haplotypes; Table 3 and Table 5
Context Saudi cohort of 249 individuals with suspected G6PD deficiency (163 male and 86 female); G6PD enzyme activity was quantitatively measured using a UV/kinetic spectrophotometric assay, and G6PD exons and intron-exon boundaries were sequenced for haplotype analysis.
The effect size for the 202A allele corresponds to a roughly 40% reduction in enzyme activity for heterozygotes, and 80% for hemizygotes and homozygotes
Location Results, sections 3.1, 3.2, and 3.4
Context Association study of erythrocyte G6PD enzyme activity in predominantly Mijikenda infants recruited in Kilifi, Kenya; 2,100 healthy infants were enrolled, with 1,828 individuals and 30 SNPs meeting final genotype/activity inclusion criteria. Activity was measured by a spectrophotometric NADPH-generation assay, and associations were tested by linear regression with sex as a covariate.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00644303; MAF= 0.64430%, 7797/1210144 alleles, homozygotes = 328) and has highest observed frequency in the African/African American population (AF= 0.122771; MAF= 12.27714%, 7024/57212 alleles, homozygotes = 319); grpmax FAF= 0.120371.
This variant is present in gnomAD v2.1 (AF= 0.0115349; MAF= 1.15349%, 2365/205030 alleles, homozygotes = 90) and has highest observed frequency in the African/African American population (AF= 0.116407; MAF= 11.64066%, 2208/18968 alleles, homozygotes = 89); grpmax FAF= 0.110833.
This variant is present in gnomAD-Canada v1.0 (AF= 0.009060727624844377, 131/14458 alleles, homozygotes = 9).
Error retrieving ClinVar entry.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). BayesDel score = 0.406482.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.