Is GNAS p.Ala445Val (c.1334C>T) pathogenic?

GNAS p.Ala445Val (c.1334C>T) is classified Uncertain significance in GNAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). AlphaMissense: likely benign (0.1333); Very rare (popmax 0.00237%, sas).

How common is GNAS p.Ala445Val (c.1334C>T) in the general population?

GNAS p.Ala445Val (c.1334C>T) is very rare (popmax 0.00237%, sas) (gnomAD).

What do computational predictors say about GNAS p.Ala445Val (c.1334C>T)?

AlphaMissense predicts likely benign (score 0.1333) — an in-silico prediction, not a clinical call.

GNAS p.Ala445Val

c.1334C>T · VCV4681730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1333	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -1.2
Overall
CADD	8.343	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 0.00237% South Asian · 2/84,474 alleles

Filtering AF 0.000393% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000147%

Overall 0.000519% 8/1,540,942 alleles · very rare exomes 8/1,390,006 · genomes 0/150,936 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00237%	42,237
African / African-American	0.00138%	72,436
European (non-Finnish)	0.000434%	230,198

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.Ala445Val
Coding: c.1334C>T
MANE Select: NM_000516 · reported on NM_080425
Type: single nucleotide variant
Location: chr20:58854599 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.47 · 200 PDB
Residue 445: the 'disordered' region

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

Similar variants

GNAS p.Ala445= Likely benign same residue
GNAS p.Ala445_Ala446insValProAspAlaProAlaAspProAspSerGlyAla Uncertain significance 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-ala445val (accessed [today's date]).

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