The GNAQ NM_002072.5:c.626A>C (NP_002063.2:p.(Gln209Pro)) missense variant has previously been reported in somatic cancers (COSMIC; COSV54105903, n = 302 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Purified Q209P showed diminished GTPase activity, and cell assays showed downstream signaling comparable to oncogenic Q209L. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic 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.GNAQ encodes a G-protein alpha subunit that relays signals from cell-surface receptors to enzymes controlling calcium release and other processes such as cell growth and differentiation. Changes in GNAQ have been associated with abnormal platelet activation and aggregation. In cancer, acquired GNAQ changes can drive uveal melanoma and, less often, cutaneous melanoma by keeping growth-signaling pathways abnormally active.
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 strength: purified Q209P showed diminished GTPase activity, and cell assays showed downstream signaling comparable to oncogenic Q209L.
Met, moderate: GNAQ codon 209 is a statistically significant recurrent hotspot, with mutations reported exclusively at this codon in the cited cohort.
Met at supporting strength: the variant was absent from every reported gnomAD dataset, corresponding to AF 0 versus the PM2 threshold of <=0.0001.
Met, strong: REVEL 0.956 exceeds the generic PP3 strong threshold of 0.932 for missense variants.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 supporting, PM1 moderate, PM2 supporting, and PP3 strong satisfy the generic ACMG/AMP combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.956. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV54105903, n = 302 times).
This variant lies 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: 4 met · 6 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
GNAQ p.Gln209Pro is located at codon 209, a recurrent statistically significant hotspot, supporting PM1 at moderate strength.
PS1 and PM5 are not assessed because the required established pathogenic comparator evidence is not documented.
PP2 and BP1 are not assessed because the necessary gene-wide benign-missense and truncating-variant spectrum evidence is incomplete.
PS2, PM6, PP1, and BS4 are not assessed because the available case evidence contains no qualifying proband-parent de novo data or family segregation data.
Under generic ACMG/AMP rules, PS4 is not met because the available tumor cohorts do not provide unaffected or population controls and no qualifying OR/RR with 95% CI is available.
PP4 is not assessed because the individual patient's phenotype and family history are not supplied.
PP5 and BP6 are not met because the exact ClinVar record lacks an expert-panel classification and contains only single-submitter somatic oncology data.
BP5 is not assessed because no case-level alternate molecular basis for the same disease is established.
Neither PM3 nor BP2 is assessable because the case contains no documented pathogenic partner allele, affected-proband allelic observation, or phase testing.
Generic ACMG/AMP rules govern because no VCEP covers GNAQ.
The variant is missense, so PP3 and BP4 use REVEL only; SpliceAI and BayesDel are not counted for these criteria.
PP3 is met at strong strength from REVEL 0.956 versus the supplied >= 0.932 threshold; BP4 is not met because 0.956 is not <= 0.29.
No criteria match.
PS3 is met at supporting strength. Maziarz et al. directly studied GNAQ p.Gln209Pro using purified-protein biochemical assays and cell-based assays, with wild-type GNAQ and the established activating Q209L mutant as comparators. Q209P showed diminished GTPase activity, constitutive dissociation from Gβγ, altered binding to multiple effectors and RGS proteins, and downstream signaling in cells comparable to Q209L, including SRE reporter activation and ERK1/2 phosphorylation. The experiments included orthogonal functional readouts and were reported across at least three independent experiments. This is direct, biologically relevant evidence of an altered/damaging GNAQ protein effect, but the available evidence does not establish reproducibility in a clinical diagnostic laboratory or provide the broader validation needed to justify a stronger level under the supplied generic rules.
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.
GNAQ p.Gln209Pro affects codon 209, a recurrent mutational hotspot. The Cancer Hotspots result states that the variant lies in a statistically significant hotspot, and Kusters-Vandevelde et al. reported that GNAQ mutations occurred exclusively at codon 209 in the studied melanocytic neoplasms. The review by Silva-Rodríguez et al. also identifies codon Q209 as a recurrent activating hotspot and describes loss of GTPase activity from mutations affecting this codon. No benign variation at this hotspot was supplied in the evidence.
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 met at supporting strength. NM_002072.5:c.626A>C (GNAQ p.Gln209Pro) was reported absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, gnomAD v3.1 non-cancer, and gnomAD-Canada. The observed population allele frequency is therefore 0 in the available datasets, which is below the supplied PM2 supporting threshold of <=0.0001. Human review remains appropriate because the available clinical context is predominantly somatic cancer evidence and does not establish a specific germline disorder.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense substitution, NM_002072.5:c.626A>C (p.Gln209Pro), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this missense situation. REVEL is 0.956, meeting the supplied generic PP3 strong threshold of >= 0.932. BayesDel is not used because no generic ACMG-strength calibration is established, and the SpliceAI result is not double-counted.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PS4 is not met. The literature packet's PS4 candidates were checked against available full text. Griewank et al. (PMID:29891723) reported c.626A>C/p.Q209P in a cohort of primary leptomeningeal melanocytic tumors and uveal melanomas, including 7/47 primary leptomeningeal tumors and 9/16 uveal melanomas by the table entries, but these are affected tumor groups rather than unaffected or population controls; the paper does not provide a valid ACMG case-control comparison for this variant. Murugan et al. (PMID:21487925) reported no GNAQ hotspot mutation in 40 thyroid cancer samples and no GNAQ mutation in 12 thyroid cancer cell lines, but did not study this variant in a case-control design. Therefore no valid affected-versus-unaffected/population prevalence estimate, OR/RR, or 95% CI meeting the ACMG threshold is available.
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.
PP5 is not met. The exact ClinVar record for NM_002072.5:c.626A>C (p.Gln209Pro) has no extracted submissions, no expert-panel submission, and only a single-submitter somatic record with a Tier I/Tier II oncology classification rather than an expert-panel germline Pathogenic or Likely pathogenic classification. OncoKB labels the variant Likely Oncogenic, not a qualifying ACMG pathogenic classification, and its cited literature is available for independent evaluation. The reviewed papers describe somatic tumor observations or functional biology, not a reputable-source assertion that triggers PP5 under the supplied rule.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. NM_002072.5:c.626A>C (GNAQ p.Gln209Pro) was absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, gnomAD v3.1 non-cancer, and gnomAD-Canada. Therefore no filtering allele frequency or grpmax FAF is available, and the variant does not reach the generic BA1 threshold of >=0.05. The absence of a population frequency also avoids the small-isolate popmax-versus-FAF artifact described in the governing guidance.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The variant was absent from gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer, gnomAD v3.1 non-cancer, and gnomAD-Canada, so there is no filtering allele frequency or grpmax FAF greater than expected for a disorder. The generic 0.01 default is therefore not reached. No disorder-specific prevalence, penetrance, allelic heterogeneity, or maximum-credible-allele-frequency calculation is available, but that limitation does not change the observed absence-based conclusion.
the criterion is 'allele frequency is greater than expected for the disorder'; the 1% figure is only a default.
The variant is a missense substitution, so the governing generic rule selects the REVEL path only; SpliceAI is not used to establish BP4 for a missense variant. REVEL is 0.956, which does not meet any supplied BP4 threshold, including the supporting threshold of <= 0.29. The available SpliceAI max delta of 0.006 is therefore not evidence for BP4 in this missense situation, and BayesDel is not usable because no generic ACMG-strength calibration is established.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP6 is not met. The exact ClinVar record has no expert-panel submission or validated benign assertion, and the available single-submitter record is somatic oncology data rather than an exact-variant expert-panel Benign or Likely benign classification. No reputable benign classification meeting the required source restriction was identified.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is GNAQ p.Gln209Pro. No previously established pathogenic variant producing the same amino-acid change was identified in the available evidence. The available literature explicitly discusses p.Q209P but does not establish a prior pathogenic occurrence of the same amino-acid change, and the ClinVar record is a single-submitter somatic record without extracted criterion-level evidence.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
No case-specific report or clinical record documents that NM_002072.5:c.626A>C (p.Gln209Pro) occurred de novo in a patient with the disease, confirms both maternity and paternity, and establishes no family history. The available literature extracts concern somatic or functional GNAQ findings and provide no qualifying de novo trio evidence.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No affected-proband observations, pathogenic partner variant, parental or offspring testing, or phase information are documented for NM_002072.5:c.626A>C (GNAQ p.Gln209Pro). The available literature concerns somatic GNAQ alterations in tumors and does not establish a recessive disorder or demonstrate this variant in trans with a pathogenic variant; therefore PM3 cannot be assessed.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
A different missense change at the same residue, GNAQ p.Gln209Leu, was reported and functionally studied, but the available evidence describes it as a somatic oncogenic change and does not establish it as a pathogenic variant under the governing ACMG/AMP rule. Therefore the required pathogenic comparator for PM5 is not confirmed.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No case-specific report documents an assumed de novo occurrence of NM_002072.5:c.626A>C (p.Gln209Pro) in an affected patient. The available evidence does not establish a de novo event even without parental confirmation, and no clinical or family-history details are provided.
Assumed de novo, but without confirmation of paternity and maternity.
No affected family members, genotyped relatives, informative meioses, or cosegregation results are reported for NM_002072.5:c.626A>C (p.Gln209Pro). Therefore, the available evidence cannot establish cosegregation in a gene definitively known to cause the disease.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The evidence supports a recurrent activating missense mechanism for GNAQ, including recurrent codon-209 mutations and loss of GTPase activity. However, no gene-level evidence establishing that GNAQ has a low rate of benign missense variation was supplied, so both required components of PP2 are not documented.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
PP4 cannot be assessed from the supplied case evidence. The rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology, but the case bundle provides no patient phenotype, family history, or clinical diagnosis for this individual. Published tumor cohorts establish disease contexts for variant observations but do not establish this patient's phenotype specificity.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. No healthy adult individual carrying this variant in the required inheritance state was identified. The available ClinVar and cancer literature describe somatic tumor findings rather than documented healthy germline carriers, and the case materials do not establish a specific germline disorder, expected full penetrance, or an early-age phenotype against which the BS2 definition can be applied.
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.
BS3 was not assessed because the available functional evidence does not show that GNAQ p.Gln209Pro has no damaging effect on protein function or splicing. The primary study instead reports altered GTPase activity, effector and regulator interactions, and downstream signaling for Q209P. These findings cannot be converted into benign functional evidence, and no well-established benign assay or normal-function result for this variant was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No affected family members who tested negative for NM_002072.5:c.626A>C (p.Gln209Pro) are identified. Thus, lack of segregation cannot be established, and there is no family-level information to evaluate the phenocopy caveat.
Lack of segregation in affected members of a family.
The available gene-level evidence describes GNAQ as recurrently altered through activating missense mutations, particularly at codon 209, rather than establishing that disease is caused primarily by truncating variants. However, a sufficiently comprehensive disease-variant spectrum demonstrating the absence of a primarily truncating mechanism was not supplied, so BP1 cannot be definitively adjudicated.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
No affected-proband observation demonstrates NM_002072.5:c.626A>C (GNAQ p.Gln209Pro) with a pathogenic variant in trans or in cis, and no phase testing is documented. The available sources describe somatic tumor findings rather than a fully penetrant dominant germline disorder; therefore BP2 cannot be assessed.
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.
BP5 cannot be assessed from the supplied evidence. The rule requires the variant to be found in a case with an alternate molecular basis for disease. The available publications document somatic GNAQ p.Q209P in tumor cohorts and, in some contexts, other tumor alterations, but they do not establish that this exact variant was found in a case whose disease was explained by an alternate molecular basis in the clinical context relevant to this interpretation. The case summary does not provide such a case-level alternate molecular diagnosis.
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_002072.5:c.626A>C in GNAQ is a missense substitution predicted to produce NP_002063.2:p.(Gln209Pro). 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 GNAQ, 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_002072.5:c.626A>C in GNAQ is a missense substitution predicted to produce NP_002063.2:p.(Gln209Pro). 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 GNAQ, 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_002072.5:c.626A>C in GNAQ is a missense substitution predicted to produce NP_002063.2:p.(Gln209Pro). 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 GNAQ, 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_002072.5:c.626A>C in GNAQ is a missense substitution predicted to produce NP_002063.2:p.(Gln209Pro). 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 GNAQ, 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 GNAQ, mapped onto the exon structure of NM_002072.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
The variant is a missense substitution, NM_002072.5:c.626A>C (p.Gln209Pro), so the governing generic rule selects the REVEL path only; SpliceAI is not used for PP3/BP4 in this missense situation. REVEL is 0.956, meeting the supplied generic PP3 strong threshold of >= 0.932. BayesDel is not used because no generic ACMG-strength calibration is established, and the SpliceAI result is not double-counted.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense substitution, so the governing generic rule selects the REVEL path only; SpliceAI is not used to establish BP4 for a missense variant. REVEL is 0.956, which does not meet any supplied BP4 threshold, including the supporting threshold of <= 0.29. The available SpliceAI max delta of 0.006 is therefore not evidence for BP4 in this missense situation, and BayesDel is not usable because no generic ACMG-strength calibration is established.
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_002072.5:c.626A>C in GNAQ is a missense substitution predicted to produce NP_002063.2:p.(Gln209Pro). 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 GNAQ, 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 = 0.956. BayesDel score = 0.470779.
7 paper records listed. 3 cited in the classification.
All mutations in GNAQ were somatically acquired as assessed by sequencing DNA from adjacent tissue, and occurred exclusively at codon 209 (Supplementary Information, Table 1).
Location Results, paragraph beginning ‘All mutations in GNAQ were somatically acquired’; functional results for GNAQ-Q209L in Figures 1–3 and Methods
Context Sequencing of 29 blue nevi, 2 malignant blue nevi, 48 uveal melanomas, and 14 nevus-of-Ota cases; functional studies used GNAQ-Q209L expression and GNAQ knockdown in melanocyte and uveal melanoma cell models.
Gαq Q209P has diminished GTPase activity.
Location Figure 3 caption and Figure 2 caption; supporting data in Figures 1, 4, 5, and 6
Context Purified GNAQ protein biochemical assays, GST pulldown and immunoprecipitation assays, BRET assays in HEK293T cells, SRE reporter assays, ERK1/2 phosphorylation, limited proteolysis, and GTPase assays; wild type and Q209L comparators were used, and experiments were reported as repeated independent experiments.
and proline (A > C, p.Q209P), in most cases.
Location Section 2, ‘Mutational Hotspots and Other Less Recurrent Described Mutations in GNAQ and GNA11 Genes,’ paragraph discussing codon 209
Context Review of published molecular and functional studies of GNAQ/GNA11 mutations in uveal melanoma; no variant-specific case or assay for c.626A>C/p.Q209P is presented.
Our sequencing results showed no mutation in and around the hot spot codon 209 in the GNAQ gene in 12 thyroid cancer cell lines and 40 thyroid cancer samples (including 20 FTC and 20 ATC).
Results, paragraph beginning ‘We examined exon 5 of the GNAQ gene’
In 47 primary leptomeningeal tumors, 94% (44/47) tumors harbored activating hotspot mutations in GNAQ (n=26, 55%), GNA11 (n=13, 28%), CYSLTR2 (n=3, 6%) and PLCB4 (n=2, 4%).
Results, ‘Gene mutations detected by targeted NGS’; Table 1; Figure 5
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4530522)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.956. BayesDel score = 0.470779.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54105903, n = 302 times).
This variant lies in a statistically significant hotspot.