Is GNAS p.Pro96Ala (c.286C>G) pathogenic?

GNAS p.Pro96Ala (c.286C>G) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-26). AlphaMissense: likely benign (0.1396); Ultra-rare (popmax 0.0178%, eas); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Pro96Ala (c.286C>G)?

GNAS p.Pro96Ala (c.286C>G) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Pro96Ala (c.286C>G) in the general population?

GNAS p.Pro96Ala (c.286C>G) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about GNAS p.Pro96Ala (c.286C>G)?

AlphaMissense predicts likely benign (score 0.1396) — an in-silico prediction, not a clinical call.

GNAS p.Pro96Ala

c.286C>G · rs531835243 · VCV2635855

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1396 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.1396	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 1.8, phastCons 1
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,884 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00149% 24/1,613,286 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,611
European (non-Finnish)	0.00136%	73,741

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.Pro96Ala
Coding: c.286C>G
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs531835243
Type: single nucleotide variant
Location: chr20:58853551 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 96: the 'disordered' region; 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.Pro96Ser Uncertain significance ⚠ same residue
GNAS p.Ser96Ala Uncertain significance same residue
GNAS p.Ser96= Likely benign same residue
GNAS p.Lys96Glu 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

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-pro96ala (accessed [today's date]).

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