Is GNAS p.Pro96Ser (c.286C>T) pathogenic?

GNAS p.Pro96Ser (c.286C>T) is classified Uncertain significance in GNAS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-04). AlphaMissense: likely benign (0.2351); Absent from gnomAD v4.1; Associated with GNAS-related disorder.

What condition is associated with GNAS p.Pro96Ser (c.286C>T)?

GNAS p.Pro96Ser (c.286C>T) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Pro96Ser (c.286C>T) in the general population?

GNAS p.Pro96Ser (c.286C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAS p.Pro96Ser (c.286C>T)?

AlphaMissense predicts likely benign (score 0.2351) — an in-silico prediction, not a clinical call.

GNAS p.Pro96Ser

c.286C>T · VCV3348896

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2351 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.2351	likely benign
REVEL	0.601	indeterminate
SaProt	LLR -10.36	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	23.6	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

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.Pro96Ser
Coding: c.286C>T
MANE Select: NM_000516 · reported on NM_080425
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.Pro96Ala 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-pro96ser (accessed [today's date]).

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