Is GNAS p.Pro53Arg (c.158C>G) pathogenic?

GNAS p.Pro53Arg (c.158C>G) is classified Uncertain significance in GNAS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-09-02). AlphaMissense: likely benign (0.1086); Ultra-rare (popmax 0.0225%, amr); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Pro53Arg (c.158C>G)?

GNAS p.Pro53Arg (c.158C>G) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Pro53Arg (c.158C>G) in the general population?

GNAS p.Pro53Arg (c.158C>G) is ultra-rare (popmax 0.0225%, amr) (gnomAD).

What do computational predictors say about GNAS p.Pro53Arg (c.158C>G)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

GNAS p.Pro53Arg

c.158C>G · rs763257494 · VCV3029940

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0225%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -7.97	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.8, phastCons 1
Overall
CADD	22.5	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 0.0225% Admixed American · 13/57,780 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.00169% 27/1,596,500 alleles · ultra-rare exomes 24/1,444,358 · genomes 3/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0225%	4,445
Middle Eastern	0.0165%	6,066
Remaining individualsnot grpmax-eligible	0.00808%	12,371
South Asian	0.00338%	29,552
African / African-American	0.00269%	37,149
European (non-Finnish)	0.000256%	390,721

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.Pro53Arg
Coding: c.158C>G
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs763257494
Type: single nucleotide variant
Location: chr20:58853423 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 53: a binding site; the g-alpha domain; the 'g1 motif' region; an α-helix; 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.Lys53= Likely benign ★★ same residue
GNAS p.Lys53Glu Pathogenic ★ same residue
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

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-pro53arg (accessed [today's date]).

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