Is GNAS p.Ala426Pro (c.1276G>C) pathogenic?

GNAS p.Ala426Pro (c.1276G>C) is classified Conflicting classifications of pathogenicity in GNAS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2023-07-27). AlphaMissense: likely benign (0.0557); Very rare (popmax 0.00866%, nfe); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Ala426Pro (c.1276G>C)?

GNAS p.Ala426Pro (c.1276G>C) is associated with GNAS-related disorder, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia (ClinVar).

How common is GNAS p.Ala426Pro (c.1276G>C) in the general population?

GNAS p.Ala426Pro (c.1276G>C) is very rare (popmax 0.00866%, nfe) (gnomAD).

What do computational predictors say about GNAS p.Ala426Pro (c.1276G>C)?

AlphaMissense predicts likely benign (score 0.0557) — an in-silico prediction, not a clinical call.

GNAS p.Ala426Pro

c.1276G>C · rs767104257 · VCV931358

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0557 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00866%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.0557	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -1.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -2.5
Overall
CADD	2.428	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 0.00866% European (non-Finnish) · 101/1,166,266 alleles

Filtering AF 0.00724% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00676%

Overall 0.00691% 108/1,563,346 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00866%	11,547
Admixed American	0.00535%	18,680
Remaining individualsnot grpmax-eligible	0.00491%	20,349
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,230

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.Ala426Pro
Coding: c.1276G>C
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs767104257
Type: single nucleotide variant
Location: chr20:58854541 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 426: the 'disordered' region

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

Disease context

Also linked: pseudohypoparathyroidism type 1A progressive osseous heteroplasia pseudohypoparathyroidism type 1B pseudohypoparathyroidism type 1C pseudopseudohypoparathyroidism McCune-Albright syndrome ACTH-independent macronodular adrenal hyperplasia 1 pituitary adenoma 3, multiple types

Similar variants

GNAS p.Ala426Gly Uncertain significance ⚠ same residue
GNAS p.Ala426Thr Likely benign ★ same residue
GNAS c.139+1G>C Pathogenic ★★ same condition
GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS c.433-2A>C Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Ala102Val Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg165Cys Pathogenic ★★ same condition
GNAS p.Arg165His 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-ala426pro (accessed [today's date]).

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