The CYP2C9 NM_000771.4:c.1075A>C (NP_000762.2:p.(Ile359Leu)) missense variant has previously been reported in somatic cancers (COSMIC; COSV53247682, n = 3 times). Based on available guidelines, this variant is considered to be Benign.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CYP2C9 encodes a cytochrome P450 enzyme in the endoplasmic reticulum that helps metabolize many medicines and other foreign compounds, including phenytoin, tolbutamide, ibuprofen, and S-warfarin. Inherited differences in CYP2C9 activity can affect how quickly people process certain drugs, including causing poor metabolism. CYP2C9 has no established 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.
No pathogenic criterion marked as applied in the recorded assessment.
Met: gnomAD v4.1 grpmax FAF is 10.8302%, exceeding the >=5% BA1 threshold with 10,029 observed South Asian alleles.
Met: gnomAD v4.1 grpmax FAF is 10.8302%, above the generic BS1 threshold of 1%, based on 10,029 observed alleles.
Met at supporting strength: missense REVEL score 0.07 is below the BP4 supporting cutoff of 0.29.
Benign: BA1 (stand-alone), BS1 (strong), and BP4 (supporting) meet generic ACMG/AMP fallback rules, with BA1 alone sufficient for a benign call.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 102,334 / 1,613,890 alleles. Recorded AF 0.0634083. Recorded homozygote count 3705.
This variant is present in gnomAD v2.1 (AF= 0.061539; MAF= 6.15390%, 17386/282520 alleles, homozygotes = 700) and has highest observed frequency in the South Asian population (AF= 0.109558; MAF= 10.95577%, 3354/30614 alleles, homozygotes = 216); grpmax FAF= 0.106464.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
1 drug response.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV53247682, n = 3 times).
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: 3 met · 9 not met · 12 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The assessed criteria do not support PS1, PM1, or PP2; PM5 and BP1 remain unassessed because the required disease-specific comparator and mechanism evidence are unavailable.
No proband, parental, pedigree, meiosis, segregation, or non-segregation evidence was available for these four criteria; all are not assessed rather than inferred from unrelated pharmacogenetic literature.
No VCEP covers CYP2C9 in this case; generic ACMG/AMP definitions govern.
The reviewed literature supports CYP2C9*3 pharmacogenetic drug-response effects, but does not provide qualifying phenotype-specific disease evidence, case-control enrichment, alternate molecular basis, or exact-variant benign/pathogenic expert-panel classification for these five criteria.
Population evidence supports benign classification: BA1 and BS1 are met because the required gnomAD grpmax FAF exceeds 5% and 1%, respectively, with adequate observed-allele counts.
PM2 is not met because the variant is common and has thousands of observed homozygotes.
BS2 is not assessed because the case does not establish the early-onset, fully penetrant disorder and phenotype-confirmed healthy-adult observations required by the criterion.
No criteria match.
BA1 is met. Under the generic ACMG/AMP rule, the relevant filtering frequency is the gnomAD grpmax FAF rather than the highest population point estimate. gnomAD v2.1 reports grpmax FAF 0.106464 (10.6464%) with the South Asian population contributing 3,354 observed alleles, and gnomAD v4.1 reports grpmax FAF 0.108302 (10.8302%) with 10,029 observed alleles; both exceed the generic BA1 threshold of >=0.05 and the contributing population has at least 2,000 observed alleles. The variant is a common CYP2C9 pharmacogenetic allele, and the available ClinVar record is a drug-response record without a pathogenic disease consensus that would create the prompt's specified frequency-versus-pathogenicity conflict. Therefore the stand-alone benign frequency criterion is met.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is met on the available population-frequency evidence. The generic rule concerns an allele frequency greater than expected for the disorder; the supplied generic default threshold is >=0.01, while the required filtering metric is grpmax FAF. gnomAD v2.1 grpmax FAF is 0.106464 and gnomAD v4.1 grpmax FAF is 0.108302, both well above 0.01, with the relevant South Asian groups contributing 3,354 and 10,029 observed alleles respectively. The elevation is not a small-isolate artifact, and no governing disease-specific maximum credible allele-frequency calculation or reduced-penetrance/founder-disease exception is available for CYP2C9 in this generic case. Therefore BS1 is met using the supplied generic default.
Allele frequency is greater than expected for the disorder.
NM_000771.4:c.1075A>C is a missense variant, NP_000762.2:p.(Ile359Leu), so the applicable generic computational path is REVEL only. REVEL is 0.07, below the generic BP4 supporting cutoff of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore BP4 is met at supporting strength. SpliceAI and BayesDel were not used because they are not the governing predictor path for a missense variant, and no generic BayesDel strength calibration is established.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is NM_000771.4:c.1075A>C, p.Ile359Leu (CYP2C9*3). No previously established pathogenic variant with the same p.Ile359Leu amino-acid change is documented in the reviewed evidence. The exact variant is described in a pharmacogenetic guideline as a decreased-function allele, while the available ClinVar record is drug response with no assertion criteria and cannot establish pathogenicity. Therefore PS1 is not met.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No qualifying case-control enrichment evidence was identified for NM_000771.4:c.1075A>C (CYP2C9 p.Ile359Leu). PMID:15805193 studied CYP2C9*3 dose response in 281 phenytoin-treated patients but had no unaffected or population control comparison and did not explicitly name this exact variant. PMID:25099164 discussed CYP2C9*3 pharmacogenetic effects without a variant-specific affected-versus-control prevalence comparison. PMID:28198005 explicitly named c.1075A>C but summarized warfarin pharmacogenetic and bleeding-risk evidence rather than a case-control prevalence study. Therefore, no odds ratio or 95% confidence interval could be computed, and the ACMG PS4 threshold is not met.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... 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.
Residue 359 is discussed as part of substrate-recognition site 5, providing functional-context evidence, but the variant itself is common in population data (gnomAD v4.1 AF 0.0634083; grpmax FAF 0.10830176, with 3,705 homozygotes). This substantial benign-population variation is inconsistent with the required absence of benign variation for PM1, so PM1 is not met.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is not met. The variant is common in population databases: gnomAD v2.1 reports total AF 0.061539 with 17,386/282,520 alleles and gnomAD v4.1 reports total AF 0.0634083 with 102,334/1,613,890 alleles. The filtering grpmax FAF values are 0.106464 and 0.108302, respectively, far above the supplied PM2 supporting threshold of <=0.0001. The presence of 700 and 3,705 homozygotes also directly contradicts absence or extremely low frequency in controls.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PP2 requires both a low rate of benign missense variation and missense variants as a common disease mechanism. CYP2C9 c.1075A>C/p.Ile359Leu alone is present in gnomAD v4.1 at AF 0.0634083, with grpmax FAF 0.10830176 and 3,705 homozygotes, directly undermining the low-benign-missense-variation requirement. PP2 is therefore not met.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
NM_000771.4:c.1075A>C is a missense variant, NP_000762.2:p.(Ile359Leu), so the applicable generic computational path is REVEL only. REVEL is 0.07, below the generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore PP3 is not met. SpliceAI and BayesDel were not used because they are not the governing predictor path for a missense variant, and no generic BayesDel strength calibration is established.
Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PP5 is not met. The exact-variant ClinVar record available for this case contains only a non-expert laboratory drug-response submission with no assertion criteria and no expert-panel classification. The reviewed publications describe CYP2C9 pharmacogenetic effects but do not report NM_000771.4:c.1075A>C as pathogenic for a disease. Thus, no reputable source recently reporting this exact variant as pathogenic was identified.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
No well-established functional study showing no damaging effect on CYP2C9 p.Ile359Leu or its protein function or splicing was identified. The only variant-specific functional summary available instead reports approximately 80–90% impaired S-warfarin metabolism for CYP2C9*3, so BS3 is not supported.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BP6 is not met. The exact-variant ClinVar record has no expert-panel classification and no benign or likely benign assertion; its only submission is a non-expert drug-response classification. The reviewed publications do not report this exact variant as benign. Therefore, no reputable source recently reporting the variant as benign was identified.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-level evidence documents a proband with a relevant disease phenotype, absence of family history, or confirmed maternity and paternity for NM_000771.4:c.1075A>C; therefore de novo status cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
A variant-specific CPIC guideline identifies CYP2C9 c.1075A>C (p.Ile359Leu; CYP2C9*3; rs1057910) and reports that in vitro and in vivo studies suggest approximately 80–90% impairment of S-warfarin metabolism. However, the available source is a secondary guideline summary and does not provide the underlying primary assay methods, assay controls, biological validation details, replicate/reproducibility data, or evidence that the assay was validated in a clinical diagnostic laboratory. The damaging direction is biologically relevant, but the available documentation is insufficient to establish PS3 under the required well-established functional-study standard or to calibrate a PS3 strength reliably.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
PM3 cannot be assessed because the case provides no established recessive disease context, affected-proband observation, pathogenic second allele, parental or offspring testing, or phase result demonstrating that NM_000771.4:c.1075A>C is in trans with a pathogenic variant.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The available PM5 candidate artifact contains no same-residue comparator variants and explicitly states that classic same-residue PM5 semantics could not be confirmed safely. The reviewed literature identifies p.Ile359Leu itself but does not document a different pathogenic missense substitution at residue 359. A comprehensive pathogenic comparator search is therefore still required before PM5 can be adjudicated.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No case-level evidence documents an assumed de novo occurrence of NM_000771.4:c.1075A>C or parental testing showing the variant absent in either parent; therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, informative meioses, variant-positive relatives, or disease-status segregation data are documented, so co-segregation cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The available case materials do not provide a patient phenotype or family history for this variant, and the reviewed literature concerns pharmacokinetic or drug-response traits rather than a highly specific disease phenotype with a single genetic etiology. The required phenotype information is therefore unavailable for a PP4 assessment.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD shows many homozygotes (700 in v2.1 and 3,705 in v4.1), but the generic BS2 definition requires observation in a healthy adult for a recessive homozygous, dominant heterozygous, or X-linked hemizygous disorder with full penetrance expected at an early age. The case provides no established CYP2C9 Mendelian disease model, disease prevalence, penetrance estimate, or phenotype-confirmed healthy-adult observations that would establish that the gnomAD individuals satisfy the criterion. Homozygote counts alone therefore cannot be converted into BS2.
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, their genotypes, or disease-status comparisons are documented; consequently, lack of segregation and the phenocopy or multiple-pathogenic-variant caveats cannot be evaluated.
Lack of segregation in affected members of a family.
The reviewed case evidence does not establish that CYP2C9-related disease is caused primarily by truncating variants, nor does it provide a disease-specific variant spectrum sufficient to evaluate this gene-level criterion. BP1 cannot be adjudicated from the available evidence.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed because the case provides no observation of NM_000771.4:c.1075A>C with a pathogenic variant in trans in a fully penetrant dominant disorder and no cis-phase observation with a pathogenic variant in any inheritance pattern.
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.
No disease case carrying NM_000771.4:c.1075A>C with an independently established alternate molecular basis for that disease was identified in the available evidence. The pharmacogenetic treatment-response studies do not constitute the BP5 case context, so BP5 cannot be assessed from the supplied data.
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_000771.4:c.1075A>C in CYP2C9 is a missense substitution predicted to produce NP_000762.2:p.(Ile359Leu). 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 CYP2C9, 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_000771.4:c.1075A>C in CYP2C9 is a missense substitution predicted to produce NP_000762.2:p.(Ile359Leu). 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 CYP2C9, 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_000771.4:c.1075A>C in CYP2C9 is a missense substitution predicted to produce NP_000762.2:p.(Ile359Leu). 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 CYP2C9, 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_000771.4:c.1075A>C in CYP2C9 is a missense substitution predicted to produce NP_000762.2:p.(Ile359Leu). 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 CYP2C9, 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 CYP2C9, mapped onto the exon structure of NM_000771.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| South Asian10029 / 91,086 | 0.11605 hom |
| Ashkenazi Jewish2463 / 29,596 | 0.083112 hom |
| Middle Eastern441 / 6,058 | 0.07326 hom |
| European (non-Finnish)76626 / 1,179,884 | 0.0652596 hom |
| Remaining individuals3990 / 62,492 | 0.064136 hom |
| European (Finnish)3941 / 64,020 | 0.062143 hom |
| Admixed American2516 / 59,948 | 0.04262 hom |
| East Asian1355 / 44,870 | 0.0319 hom |
| Amish27 / 912 | 0.03 |
| African/African American946 / 75,024 | 0.0136 hom |
| South Asian3354 / 30,614 | 0.11216 hom |
| Ashkenazi Jewish872 / 10,362 | 0.08439 hom |
| European (non-Finnish)8812 / 128,982 | 0.068329 hom |
| European (Finnish)1572 / 25,114 | 0.06355 hom |
| Remaining individuals451 / 7,208 | 0.06311 hom |
| Admixed American1352 / 35,356 | 0.03835 hom |
| East Asian663 / 19,930 | 0.03315 hom |
| African/African American310 / 24,954 | 0.012 |
This variant is present in gnomAD v4.1 (AF= 0.0634083; MAF= 6.34083%, 102334/1613890 alleles, homozygotes = 3705) and has highest observed frequency in the South Asian population (AF= 0.110105; MAF= 11.01047%, 10029/91086 alleles, homozygotes = 605); grpmax FAF= 0.108302.
This variant is present in gnomAD v2.1 (AF= 0.061539; MAF= 6.15390%, 17386/282520 alleles, homozygotes = 700) and has highest observed frequency in the South Asian population (AF= 0.109558; MAF= 10.95577%, 3354/30614 alleles, homozygotes = 216); grpmax FAF= 0.106464.
Not available in gnomAD-Canada v1.0.
NM_000771.4:c.1075A>C is a missense variant, NP_000762.2:p.(Ile359Leu), so the applicable generic computational path is REVEL only. REVEL is 0.07, below the generic BP4 supporting cutoff of <= 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore BP4 is met at supporting strength. SpliceAI and BayesDel were not used because they are not the governing predictor path for a missense variant, and no generic BayesDel strength calibration is established.
Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
NM_000771.4:c.1075A>C is a missense variant, NP_000762.2:p.(Ile359Leu), so the applicable generic computational path is REVEL only. REVEL is 0.07, below the generic PP3 supporting threshold of >= 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); therefore PP3 is not met. SpliceAI and BayesDel were not used because they are not the governing predictor path for a missense variant, and no generic BayesDel strength calibration is established.
Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
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_000771.4:c.1075A>C in CYP2C9 is a missense substitution predicted to produce NP_000762.2:p.(Ile359Leu). 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 CYP2C9, 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 = 0.01). REVEL score = 0.07. BayesDel score = -0.415514.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
For phenytoin, we find that the CYP2C9*3 allele shows significant association with maximum dose, with P = 0.0066 (uncorrected).
Results, paragraph beginning ‘For phenytoin’; Table 1, CYP2C9*3 row
The two most common decreased function alleles among individuals of European ancestry are CYP2C9*2 (c.430C>T; p.Arg144Cys; rs1799853) and CYP2C9*3 (c.1075A>C; p.Ile359Leu; rs1057910) (8). In vitro and in vivo studies suggest CYP2C9*2 and *3 impair metabolism of S-warfarin by ∼30-40% and ∼80-90%, respectively (8).
CYP2C9 and warfarin section, paragraph discussing CYP2C9 star alleles and warfarin metabolism
in vitro data suggest that the degree of reduction of catalytic activity is greater for the CYP2C9*3 variant than for the CYP2C9*2 variant
Therapeutic Recommendations, CYP2C9 recommendations paragraph
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= 0.0634083; MAF= 6.34083%, 102334/1613890 alleles, homozygotes = 3705) and has highest observed frequency in the South Asian population (AF= 0.110105; MAF= 11.01047%, 10029/91086 alleles, homozygotes = 605); grpmax FAF= 0.108302.
This variant is present in gnomAD v2.1 (AF= 0.061539; MAF= 6.15390%, 17386/282520 alleles, homozygotes = 700) and has highest observed frequency in the South Asian population (AF= 0.109558; MAF= 10.95577%, 3354/30614 alleles, homozygotes = 216); grpmax FAF= 0.106464.
Not available in gnomAD-Canada v1.0.
Error retrieving ClinVar entry.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.07. BayesDel score = -0.415514.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53247682, n = 3 times).
This variant does not lie in a statistically significant hotspot.