Is GNAS p.Arg596Gln (c.1787G>A) pathogenic?

GNAS p.Arg596Gln (c.1787G>A) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.1148); Very rare (popmax 0.00167%, amr); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Arg596Gln (c.1787G>A)?

GNAS p.Arg596Gln (c.1787G>A) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Arg596Gln (c.1787G>A) in the general population?

GNAS p.Arg596Gln (c.1787G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GNAS p.Arg596Gln (c.1787G>A)?

AlphaMissense predicts likely benign (score 0.1148) — an in-silico prediction, not a clinical call.

GNAS p.Arg596Gln

c.1787G>A · rs764411331 · VCV2634976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.1148	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP -0.016, phastCons 0.46
Overall
CADD	15.76	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,612,904 alleles · very rare exomes 10/1,460,638 · genomes 1/152,266 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
European (non-Finnish)	0.000848%	117,990

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GNAS
Protein: p.Arg596Gln
Coding: c.1787G>A
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs764411331
Type: single nucleotide variant
Location: chr20:58855052 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 596: the 'disordered' region

Full GNAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GNAS-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAS p.Ala102Val Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg165His Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg201Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg258Gln Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg42His Likely pathogenic ★★ same condition
GNAS p.Gln12Ter Pathogenic ★★ same condition
GNAS p.Gln213Ter Pathogenic ★★ same condition
GNAS p.Gln31Ter Pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gnas-p-arg596gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown