Is GNAS p.Pro531Ser (c.1591C>T) pathogenic?

GNAS p.Pro531Ser (c.1591C>T) is classified Uncertain significance in GNAS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-24). AlphaMissense: ambiguous (0.5557); Very rare (popmax 0.00748%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GNAS p.Pro531Ser (c.1591C>T)?

GNAS p.Pro531Ser (c.1591C>T) is associated with Inborn genetic diseases, Duane retraction syndrome (ClinVar).

How common is GNAS p.Pro531Ser (c.1591C>T) in the general population?

GNAS p.Pro531Ser (c.1591C>T) is very rare (popmax 0.00748%, nfe) (gnomAD).

What do computational predictors say about GNAS p.Pro531Ser (c.1591C>T)?

AlphaMissense predicts ambiguous (score 0.5557) — an in-silico prediction, not a clinical call.

GNAS p.Pro531Ser

c.1591C>T · rs761504648 · VCV2355015

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5557 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00748%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5557	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -6.75	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.6, phastCons 1
Overall
CADD	20.6	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

Grpmax group 0.00748% European (non-Finnish) · 88/1,176,162 alleles

Filtering AF 0.00617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00575%

Overall 0.00589% 94/1,597,108 alleles · very rare exomes 90/1,444,862 · genomes 4/152,246 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00748%	13,365
Admixed American	0.00507%	19,723
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,380
Remaining individualsnot grpmax-eligible	0.00322%	31,028

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.Pro531Ser
Coding: c.1591C>T
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs761504648
Type: single nucleotide variant
Location: chr20:58854856 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 531: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Duane retraction syndrome

Similar variants

GNAS c.432+1G>A Pathogenic ★★ same condition
GNAS p.Arg265Cys Pathogenic/Likely pathogenic ★★ same condition
GNAS p.Arg385His Pathogenic ★★ same condition
GNAS p.Arg42Cys Pathogenic ★★ same condition
GNAS p.Arg385Cys Uncertain significance ★★ ⚠ same condition
GNAS p.Asn239Ser Uncertain significance ★★ same condition
GNAS p.Asp401Asn Uncertain significance ★★ ⚠ same condition
GNAS p.Val36Ile Uncertain significance ★★ 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-pro531ser (accessed [today's date]).

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