Is GNAS p.Arg511Pro (c.1532G>C) pathogenic?

GNAS p.Arg511Pro (c.1532G>C) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-28). AlphaMissense: likely benign (0.0638); Very rare (popmax 0.0046%, eas); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Arg511Pro (c.1532G>C)?

GNAS p.Arg511Pro (c.1532G>C) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Arg511Pro (c.1532G>C) in the general population?

GNAS p.Arg511Pro (c.1532G>C) is very rare (popmax 0.0046%, eas) (gnomAD).

What do computational predictors say about GNAS p.Arg511Pro (c.1532G>C)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

GNAS p.Arg511Pro

c.1532G>C · rs763548981 · VCV2630380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0046%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -4.34	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 -0.008	GERP -2.2, phastCons 0.043
Overall
CADD	6.822	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 0.0046% East Asian · 2/43,522 alleles

Filtering AF 0.000762% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000285%

Overall 0.000127% 2/1,578,874 alleles · very rare exomes 1/1,427,302 · genomes 1/151,572 · joint denominator

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.Arg511Pro
Coding: c.1532G>C
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs763548981
Type: single nucleotide variant
Location: chr20:58854797 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 511: 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-arg511pro (accessed [today's date]).

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