LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-10
Case ID: NM_002072.5_c.548G_A_20260710_050607
Framework: ACMG/AMP 2015
Variant classification summary

NM_002072.5:c.548G>A

GNAQ  · NP_002063.2:p.(Arg183Gln)  · NM_002072.5
GRCh37: chr9:80412493 C>T  ·  GRCh38: chr9:77797577 C>T
Gene: GNAQ Transcript: NM_002072.5
Final call
Pathogenic
PS3 strong PM1 moderate PM2 moderate PP3 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
GNAQ
Transcript
NM_002072.5
Protein
NP_002063.2:p.(Arg183Gln)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 (strong): Two independent publications (PMID:23656586, PMID:24882516) directly tested NM_002072.5:c.548G>A (p.Arg183Gln) and demonstrated gain-of-function activation of downstream signaling pathways (ERK activation, YAP/TAZ activation) in cell-based assays.
2
PM1 (moderate): The variant is located at Arg183 in the GTP-binding pocket/switch I domain of Gαq, a critical functional domain essential for GTP hydrolysis. This residue is a statistically significant cancer hotspot (cancerhotspots.org) with 59 COSMIC entries and no benign variation in gnomAD.
3
PM2 (moderate): The variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the <0.1% threshold for rarity.
4
PP3 (supporting): Multiple in silico predictors support a deleterious effect: REVEL score 0.855 and BayesDel score 0.476.
5
PP5 (supporting): This variant has been reported as Pathogenic by 8 clinical laboratories and Likely pathogenic by 1 clinical laboratory in ClinVar (Variation ID: 50853).
6
Classification: PATHOGENIC. The combination of 1 Strong (PS3), 2 Moderate (PM1, PM2), and 2 Supporting (PP3, PP5) criteria satisfies the ACMG/AMP 2015 pathogenic threshold (1 Strong + 2 Moderate + 2 Supporting → Pathogenic).
7
Note: This variant is a well-characterized somatic gain-of-function mutation causing Sturge-Weber syndrome and port-wine stains in mosaic state (PMID:23656586). Germline classification is supported by ClinVar submissions and functional evidence, though most clinical observations are in somatic rather than constitutional contexts.
Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Missense variant (p.Arg183Gln) does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 framework does not apply.
pvs1_generic_framework
PS1 N/A No prior evidence that the exact same amino acid change (p.Arg183Gln) has been established as pathogenic via a different nucleotide change at this position.
PS2 Not met No de novo observation (maternity and paternity confirmed) has been reported for NM_002072.5:c.548G>A in the reviewed literature.
PS3 Met Two independent publications directly tested NM_002072.5:c.548G>A (p.Arg183Gln) in functional assays and both demonstrate a gain-of-function activating effect. Shirley et al. (PMID:23656586) showed p.Arg183Gln activates ERK phosphorylation and SRE promoter activity in HEK293T cells. Yu et al. (PMID:24882516) showed GqR183Q potently activates YAP/TAZ in HEK293A cells. The functional effect is unequivocal and confirmed across independent laboratories and assay types.
PMID:23656586 PMID:24882516 oncokb
PS4 Not met No germline case-control data or statistically significant enrichment in affected individuals versus controls has been demonstrated for this variant. Reported observations are predominantly somatic mosaic (Sturge-Weber syndrome, port-wine stains) and do not satisfy germline PS4 requirements.
clinvar
PS5 N/A No different pathogenic missense variant at the same residue (Arg183) has been identified as a comparator. PS5 requires an established pathogenic variant at the same position via a different nucleotide change.
PM1 Met The variant is located at Arg183, a residue within the GTP-binding pocket (switch I domain) of Gαq, a critical and well-established functional domain. This position is a statistically significant cancer hotspot (cancerhotspots.org), is reported 59 times in COSMIC, and is completely devoid of benign variation in gnomAD. The domain is characterized in PMID:23656586 and PMID:24882516 as essential for GTP hydrolysis and protein inactivation.
PMID:23656586 PMID:24882516 gnomad_v2 gnomad_v4
PM2 Met The variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Allele frequency of 0% meets the PM2 threshold (<0.1%) for a rare variant absent from population controls.
gnomad_v2 gnomad_v4 gnomad_canada
PM5 Not met No different pathogenic missense variant at residue Arg183 was identified in ClinVar for PM5 comparison. Automatic PM5 candidate harvesting could not identify a same-residue comparator with established pathogenicity.
pm5_candidates
PM6 Not met No de novo observation with confirmed maternity and paternity has been reported for NM_002072.5:c.548G>A.
PP1 Not met No co-segregation data with disease in multiple affected family members has been reported for this variant.
PP2 Not met GNAQ is not established as a gene in which missense variants are a common mechanism of germline disease. The known pathogenic mechanism for this variant is gain-of-function in somatic mosaicism; there is no evidence that missense variants in GNAQ represent a prevalent germline disease mechanism.
PP3 Met Multiple in silico predictors support a deleterious effect: REVEL score 0.855 (deleterious, >0.5 threshold) and BayesDel score 0.476 (>0.27 add threshold). SpliceAI predicts no splicing impact (max delta 0.04), consistent with a missense effect rather than splicing alteration.
revel bayesdel spliceai
PP4 Not met No specific germline phenotype data or detailed clinical information for individual patients harboring this variant in germline context is available. Reported phenotypes are somatic mosaic conditions (Sturge-Weber syndrome, port-wine stains).
clinvar
PP5 Met This variant has been reported in ClinVar as Pathogenic by 8 clinical laboratories and as Likely pathogenic by 1 clinical laboratory (ClinVar ID: 50853). While most submissions pertain to somatic conditions, one clinical testing laboratory (Greenwood Genetic Center, SCV005873972) has classified it as Pathogenic for GNAQ-related disorder in a germline context. Multiple reputable clinical sources support pathogenicity.
clinvar
BA1 Not met The variant is absent from gnomAD (allele frequency 0%). BA1 requires allele frequency >1% in population databases.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met The variant is absent from gnomAD (allele frequency 0%). BS1 requires allele frequency >0.3% in population databases.
gnomad_v2 gnomad_v4
BS2 Not met No evidence that this variant has been observed in healthy adults in a germline context. The variant is absent from population databases.
gnomad_v2 gnomad_v4
BS3 Not met Functional studies (PMID:23656586, PMID:24882516) demonstrate a gain-of-function activating effect, not a benign effect. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
PMID:23656586 PMID:24882516
BS4 Not met No evidence of non-segregation with disease in affected family members has been reported.
BP1 Not met BP1 applies to missense variants in genes where primarily truncating variants cause disease. GNAQ germline disease is not established as primarily caused by loss-of-function truncating variants; the known pathogenic mechanism for this variant is gain-of-function.
PMID:23656586 PMID:24882516
BP2 Not met No evidence that this variant has been observed in trans with a known pathogenic variant in GNAQ.
BP4 Not met Multiple in silico predictors support a deleterious effect (REVEL 0.855, BayesDel 0.476), contradicting a benign interpretation. BP4 requires multiple lines of computational evidence suggesting no impact.
revel bayesdel
BP5 Not met No evidence that this variant has been found in a case with an alternate molecular basis for disease.
BP6 Not met No reputable source reports this variant as benign. ClinVar classification is Pathogenic/Likely pathogenic.
clinvar
BP7 Not met BP7 applies to synonymous variants with no predicted splicing impact. NM_002072.5:c.548G>A is a missense variant (p.Arg183Gln), not synonymous.
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