Is GNAS p.Arg336Pro (c.1007G>C) pathogenic?

GNAS p.Arg336Pro (c.1007G>C) is classified Uncertain significance in GNAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-15). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1; Associated with GNAS-related disorder.

What condition is associated with GNAS p.Arg336Pro (c.1007G>C)?

GNAS p.Arg336Pro (c.1007G>C) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Arg336Pro (c.1007G>C) in the general population?

GNAS p.Arg336Pro (c.1007G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAS p.Arg336Pro (c.1007G>C)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

GNAS p.Arg336Pro

c.1007G>C · rs2146300008 · VCV2006480

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic · top 7% in GNAS
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -16.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 1,269 bp · p 5.6e-36 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R979P vs ClinVar R336P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GNAS
Protein: p.Arg336Pro
Coding: c.1007G>C
MANE Select: NM_000516
dbSNP: rs2146300008
Type: single nucleotide variant
Location: chr20:58910370 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 979 UniProt numbering: the g-alpha domain; an α-helix

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.Arg336Gln Uncertain significance ★★ ⚠ same residue
GNAS p.Arg336Trp Pathogenic/Likely 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-arg336pro (accessed [today's date]).

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