About GNAQ
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GNAQ c.627A>C, p.(Gln209His)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PM1Moderate
PM1 · moderate
The variant is located at codon 209 (p.Gln209His) within the GTPase domain of GNAQ, a well-established functional hotspot. Codon 209 is a statistically significant hotspot at cancerhotspots.org, and substitutions at this residue (p.Gln209Leu, p.Gln209Pro) are known activating mutations that disrupt GTP hydrolysis, leading to constitutive Gαq signaling.
PM2Moderate
PM2 · moderate
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant (allele frequency <0.1% threshold for non-VCEP assessment).
PM5Moderate
PM5 · moderate
p.Gln209His is a novel missense change at codon 209 where a different missense change, p.Gln209Leu (c.626A>T), has been established as pathogenic. p.Gln209Leu is a well-characterized gain-of-function mutation in uveal melanoma and was experimentally confirmed to activate MAPK signaling in functional studies (PMID:23656586).
PP5Supporting
PP5 · supporting
This variant has been reported as Pathogenic in ClinVar (Variation ID 1172601) by two clinical laboratories, though the evidence supporting the classification is not available for independent evaluation.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PM5 moderate, PP5 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
9 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54109650, n = 9 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 4 met · 14 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant is located at codon 209 within the GTPase domain of GNAQ, a well-established functional hotspot (PM1).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).
A different pathogenic missense change at the same codon, p.Gln209Leu, has been established as a gain-of-function activating mutation in functional studies (PM5).
This variant has been reported as Pathogenic in ClinVar by two clinical laboratories (PP5).
Three moderate criteria (PM1, PM2, PM5) and one supporting criterion (PP5) are met, reaching the Likely Pathogenic threshold per ACMG/AMP 2015 generic combination rules (3 moderate criteria).
No criteria match.
Met · 4
PM1 ModerateThe variant is located at codon 209 (p.Gln209His) within the GTPase domain of GNAQ, a well-established functional hotspot. Codon 209 is a statistically significant hotspot at cancerhotspots.org, and substitutions at this residue (p.Gln209Leu, p.Gln209Pro) are known activating mutations that disrupt GTP hydrolysis, leading to constitutive Gαq signaling. Details ▾Hide ▴
Evidence considered
- Residue 209 is a statistically significant hotspot at cancerhotspots.org
- Codon 209 lies within the GTPase domain critical for G-protein inactivation
- PMID:23656586 demonstrates p.Gln209Leu strongly activates MAPK and SRE signaling
- COSMIC reports 9 somatic observations at this codon
- OncoKB curates codon 209 variants as gain-of-function
Sources
PM2 ModerateThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant (allele frequency <0.1% threshold for non-VCEP assessment). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
PM5 Moderatep.Gln209His is a novel missense change at codon 209 where a different missense change, p.Gln209Leu (c.626A>T), has been established as pathogenic. p.Gln209Leu is a well-characterized gain-of-function mutation in uveal melanoma and was experimentally confirmed to activate MAPK signaling in functional studies (PMID:23656586). Details ▾Hide ▴
Evidence considered
- p.Gln209Leu (c.626A>T) is an established pathogenic missense at the same codon
- PMID:23656586 confirms p.Gln209Leu as gain-of-function via ERK activation and luciferase reporter assays in HEK293T cells
- OncoKB reports codon 209 variants as oncogenic/gain-of-function
Sources
PP5 SupportingThis variant has been reported as Pathogenic in ClinVar (Variation ID 1172601) by two clinical laboratories, though the evidence supporting the classification is not available for independent evaluation. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 1172601: Pathogenic
- 2 clinical laboratory submissions
- Review status: criteria provided
- single submitter
- no expert panel review
Still missing
- ClinVar classification not from expert panel
- underlying evidence not independently verified
Sources
Not met · 14 · evaluated, threshold not reached
PS3 No variant-specific functional data for c.627A>C (p.Gln209His) was identified in the literature. Functional studies have characterized other substitutions at codon 209 (p.Gln209Leu, p.Gln209Pro) as gain-of-function, but the exact variant has not been directly tested. Per PS3 calibration rules, domain-level inference from a single tested residue at the same codon without systematic range characterization does not satisfy variant-specific PS3 requirements. Details ▾Hide ▴
Evidence considered
- PMID:23656586 demonstrates p.Gln209Leu (c.626A>T) is gain-of-function via MAPK activation and luciferase reporter assays in HEK293T cells
- p.Gln209His is a different amino acid substitution at the same codon
- no direct experimental data for this specific change
- OncoKB classifies c.627A>C as Likely Oncogenic/Likely Gain-of-function based on curated knowledge but this is not primary functional evidence
Still missing
- No direct functional testing of c.627A>C (p.Gln209His) in any publication
Sources
PS4 No case-control or cohort prevalence data are available to establish significantly increased prevalence of this variant in affected individuals compared with controls. Details ▾Hide ▴
Still missing
- No case-control studies or patient cohort data available
PP1 No co-segregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Still missing
- No segregation analysis data available
PP3 Computational evidence is mixed and does not meet the multiple-lines threshold. REVEL score of 0.725 supports a deleterious effect, but BayesDel score of 0.164 does not reach the deleterious threshold (~0.27), and SpliceAI predicts no splicing impact (max delta score = 0.01). Details ▾Hide ▴
Evidence considered
- REVEL: 0.725 (deleterious
- above 0.5 threshold)
- BayesDel: 0.164 (does not reach deleterious threshold ~0.27)
- SpliceAI: max delta score 0.01 (no predicted splice impact)
Sources
PP4 No phenotype or family history data are available for this variant. Patient-specific clinical information is not present in the case materials. Details ▾Hide ▴
Still missing
- No patient phenotype or clinical data available
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >1% allele frequency threshold for BA1. Details ▾Hide ▴
BS1 The variant is absent from gnomAD. Does not meet the >0.3% allele frequency threshold for BS1. Details ▾Hide ▴
BS2 No data are available regarding observation of this variant in healthy adult controls with full penetrance expected. Details ▾Hide ▴
Still missing
- No healthy adult control data available
BS3 No well-established functional studies show a benign effect. Functional data from related substitutions at codon 209 (p.Gln209Leu) demonstrate gain-of-function activation of MAPK signaling, consistent with a damaging rather than benign effect. Details ▾Hide ▴
Evidence considered
- PMID:23656586 shows p.Gln209Leu is gain-of-function
- activating ERK and SRE signaling
- No functional evidence supports a benign effect for this variant or codon 209 substitutions
Sources
BS4 No segregation data are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No segregation analysis data available
BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
- No trans-phase observation data available
BP4 Computational evidence does not support a benign effect. REVEL score of 0.725 is in the deleterious range, and SpliceAI shows no splicing impact. The evidence does not meet the multiple-lines-of-benign threshold. Details ▾Hide ▴
Evidence considered
- REVEL: 0.725 (deleterious range)
- BayesDel: 0.164 (borderline
- does not strongly support benign)
- SpliceAI: max delta 0.01 (no splice impact)
Sources
BP5 No evidence is available that this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
BP6 This variant is not reported as benign by any reputable source. ClinVar reports it as Pathogenic. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PP2 HCI prior score is not available for GNAQ, and gene-level missense constraint data are insufficient to determine whether GNAQ has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- HCI prior not found for GNAQ
Still missing
- No HCI prior score or gene-level missense constraint metric available for GNAQ
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002072.5:c.627A>C is a missense variant (p.Gln209His). It does not fall into the generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a predicted null variant
- Generic PVS1 framework (PMC6185798) does not apply to missense variants
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo known pathogenic variant with the same amino acid change (p.Gln209His) arising from a different nucleotide change has been identified. Details ▾Hide ▴
No further detail was recorded.
PS2 N/ANo de novo data are available for this variant. Both maternity and paternity confirmation would be required. Details ▾Hide ▴
Still missing
- No de novo testing data available
PM6 N/ANo de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available
BP1 N/AGNAQ disease mechanism includes gain-of-function missense variants (e.g., p.Gln209Leu, p.Arg183Gln). The gene is not limited to a truncating-only disease mechanism. Details ▾Hide ▴
Evidence considered
- GNAQ pathogenic variants include gain-of-function missense changes
- not solely truncating variants
Sources
BP7 N/AThis is a missense variant (c.627A>C, p.Gln209His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 generic framework (Richards et al., PMID:25741868). The same-codon pathogenic missense evidence is captured under PM5. Details ▾Hide ▴
Sources
Identifiers
- Gene
- GNAQ
- Transcript
- NM_002072.5
- Coding (HGVS c.)
- NM_002072.5:c.627A>C
- Protein (HGVS p.)
- NP_002063.2:p.(Gln209His)
- GRCh38
- chr9:77794571 T>G
- GRCh37
- chr9:80409487 T>G
- ClinVar
- 1172601
- COSMIC
- COSV54109650
Gene diagram
Every interpreted variant in GNAQ, mapped onto the exon structure of NM_002072.5. Select a row to find it on the plot.
GNAQNM_002072.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GNAQ
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.725
- BayesDel
- 0.164
How the predictions were used
PP3 Computational evidence is mixed and does not meet the multiple-lines threshold. REVEL score of 0.725 supports a deleterious effect, but BayesDel score of 0.164 does not reach the deleterious threshold (~0.27), and SpliceAI predicts no splicing impact (max delta score = 0.01). Details ▾Hide ▴
Evidence considered
- REVEL: 0.725 (deleterious
- above 0.5 threshold)
- BayesDel: 0.164 (does not reach deleterious threshold ~0.27)
- SpliceAI: max delta score 0.01 (no predicted splice impact)
Sources
BP4 Computational evidence does not support a benign effect. REVEL score of 0.725 is in the deleterious range, and SpliceAI shows no splicing impact. The evidence does not meet the multiple-lines-of-benign threshold. Details ▾Hide ▴
Evidence considered
- REVEL: 0.725 (deleterious range)
- BayesDel: 0.164 (borderline
- does not strongly support benign)
- SpliceAI: max delta 0.01 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.627A>C, p.Gln209His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.725. BayesDel score = 0.163625.
6 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 23656586 ↗Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ.Shirley MD et al. · 2013 May 23Shirley et al. identified somatic mosaic c.548G>A (p.Arg183Gln) in GNAQ as the cause of Sturge-Weber syndrome and nonsyndromic port-wine stains. The study tested p.Gln209Leu (c.626A>T) as a positive control in functional experiments, demonstrating gain-of-function activation of MAPK signaling (ERK, p38, JNK) and SRE promoter activity in HEK293T cells. NM_002072.5:c.627A>C (p.Gln209His) was not studied or mentioned.→ PM1 → PM5 Does not name this variant
Source detail
Two specific mutations, c.548G→A (encoding p.Arg183Gln) and c.626A→T (encoding p.Gln209 Leu), were introduced separately into GNAQ with the use of primers for site-directed mutagenesis.
Location Methods (Plasmids section); Results (Effect of Mutation on MAPK Signaling Pathway, Figure 2); Discussion
Context HEK293T cells; luciferase reporter assay (pSRE-Luc); Western blotting for ERK, p38, JNK activation
Other recorded publications
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015Richards et al. present the ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a framework paper that does not discuss any specific GNAQ variant. NM_002072.5:c.627A>C was not mentioned.Does not name this variant
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PMID 38917801 ↗GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.Ren J et al. · 2024Ren et al. report GNA14 and GNAQ somatic mutations in spinal and intracranial extra-axial cavernous hemangiomas. The abstract discusses GNAQ mutations generally; NM_002072.5:c.627A>C was not confirmed in the available abstract.Does not name this variant
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PMID 31189994 ↗High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms.Liau JY et al. · 2019Liau et al. report high frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma. The abstract discusses GNAQ mutations generally; NM_002072.5:c.627A>C was not confirmed in the available abstract.Does not name this variant
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PMID 39367533 ↗Genotypes and phenotypes of capillary malformation-arteriovenous malformation: characterization and correlation analysis.Chen Y et al. · 2025Chen et al. characterize genotypes and phenotypes of capillary malformation-arteriovenous malformation (CM-AVM) associated with RASA1 and EPHB4 pathogenic variants. GNAQ is not the focus of this study; NM_002072.5:c.627A>C was not confirmed in the available abstract.Does not name this variant
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PMID 27993330 ↗Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.Li MM et al. · 2017Li et al. present standards and guidelines for the interpretation and reporting of sequence variants in cancer (AMP/ASCO/CAP). This is a framework paper that does not discuss any specific GNAQ variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
2 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1172601/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-80409487-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-77794571-T-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-77794571-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002072.5%3Ac.627A…
- OncoKB ↗www.oncokb.org/gene/GNAQ/Q209H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121978697
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 1172601)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.725. BayesDel score = 0.163625.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54109650, n = 9 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.