Is GNAS p.Ala366Ser (c.1096G>T) pathogenic?

GNAS p.Ala366Ser (c.1096G>T) is classified Pathogenic in GNAS (ClinVar, No assertion criteria, 1 submitter; last evaluated 1994-09-08). AlphaMissense: likely pathogenic (0.9163); Absent from gnomAD v4.1; Associated with PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS.

What condition is associated with GNAS p.Ala366Ser (c.1096G>T)?

GNAS p.Ala366Ser (c.1096G>T) is associated with PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS (ClinVar).

How common is GNAS p.Ala366Ser (c.1096G>T) in the general population?

GNAS p.Ala366Ser (c.1096G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAS p.Ala366Ser (c.1096G>T)?

AlphaMissense predicts likely pathogenic (score 0.9163) — an in-silico prediction, not a clinical call.

GNAS p.Ala366Ser

c.1096G>T · rs137854537 · VCV15944

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9163 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS

Computational evidence

Protein change
AlphaMissense	0.9163	likely pathogenic ✓ concordant with ClinVar
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -10.41	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 1.9, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 1,269 bp · p 5.6e-36 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A1009S vs ClinVar A366S) — 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.Ala366Ser
Coding: c.1096G>T
MANE Select: NM_000516
dbSNP: rs137854537
Type: single nucleotide variant
Location: chr20:58910740 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 1009 UniProt numbering: the g-alpha domain; the 'g5 motif' region; a binding site

Full GNAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PSEUDOHYPOPARATHYROIDISM, TYPE IA, WITH TESTOTOXICOSIS — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GNAS p.Ala366= Likely benign ★★ same residue
GNAS p.Ala366Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
GNAS c.139+1G>C Pathogenic ★★ same type
GNAS c.139+2T>C Pathogenic ★★ same type
GNAS c.312+5G>A Pathogenic ★★ same type
GNAS c.432+1G>A Pathogenic ★★ same type
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same type
GNAS p.Ala102Thr Pathogenic/Likely pathogenic ★★ same type

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-ala366ser (accessed [today's date]).

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