Is GNAS p.Ser299Arg (c.897C>A) pathogenic?

GNAS p.Ser299Arg (c.897C>A) is classified Conflicting classifications of pathogenicity in GNAS (ClinVar, No assertion criteria, 3 submitters; last evaluated 2024-04-23). AlphaMissense: ambiguous (0.3626); Ultra-rare (popmax 0.0311%, nfe); Associated with GNAS-related disorder.

What condition is associated with GNAS p.Ser299Arg (c.897C>A)?

GNAS p.Ser299Arg (c.897C>A) is associated with GNAS-related disorder (ClinVar).

How common is GNAS p.Ser299Arg (c.897C>A) in the general population?

GNAS p.Ser299Arg (c.897C>A) is ultra-rare (popmax 0.0311%, nfe) (gnomAD).

What do computational predictors say about GNAS p.Ser299Arg (c.897C>A)?

AlphaMissense predicts ambiguous (score 0.3626) — an in-silico prediction, not a clinical call.

GNAS p.Ser299Arg

c.897C>A · rs200409817 · VCV1284745

Conflicting classifications of pathogenicity No assertion criteria

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3626 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0311%, nfe)

Conditions

GNAS-related disorder

Computational evidence

Protein change
AlphaMissense	0.3626	ambiguous
REVEL	0.432	indeterminate
SaProt	LLR -6.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.6, phastCons 1
Overall
CADD	15.13	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 0.0311% European (non-Finnish) · 367/1,179,816 alleles

Filtering AF 0.0285% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0274%

Overall 0.0238% 384/1,612,734 alleles · ultra-rare exomes 358/1,460,374 · genomes 26/152,360 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0311%	3,215
Finnishnot grpmax-eligible	0.0159%	6,282
Remaining individualsnot grpmax-eligible	0.008%	12,493
Admixed American	0.00167%	60,030
African / African-American	0.00133%	75,072

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.Ser299Arg
Coding: c.897C>A
MANE Select: NM_000516 · reported on NM_080425
dbSNP: rs200409817
Type: single nucleotide variant
Location: chr20:58854162 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 299: an α-helix; the g-alpha domain; the 'disordered' region

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.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
GNAS p.Arg42His Likely pathogenic ★★ same condition
GNAS p.Gln12Ter Pathogenic ★★ same condition
GNAS p.Gln213Ter Pathogenic ★★ same condition
GNAS p.Gln31Ter 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-ser299arg (accessed [today's date]).

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