Is GNAL p.Val431Met (c.1291G>A) pathogenic?

GNAL p.Val431Met (c.1291G>A) is classified Uncertain significance in GNAL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-28). AlphaMissense: likely pathogenic (0.9633); Absent from gnomAD v4.1.

How common is GNAL p.Val431Met (c.1291G>A) in the general population?

GNAL p.Val431Met (c.1291G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GNAL p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely pathogenic (score 0.9633) — an in-silico prediction, not a clinical call.

GNAL p.Val431Met

c.1291G>A · rs1064794741 · VCV420850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9633 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9633	likely pathogenic
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -11.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 8,803 bp · p 2e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V354M vs ClinVar V431M) — 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: GNAL
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_182978
dbSNP: rs1064794741
Type: single nucleotide variant
Location: chr18:11881049 (GRCh38)
Gene constraint: LOEUF 1.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.46 · 10 PDB
Residue 354 UniProt numbering: the g-alpha domain; the 'g5 motif' region

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

Similar variants

GNAL p.Val431Ala Pathogenic ★ same residue
GNAL p.Arg322Ter Pathogenic ★★ same type
GNAL p.Arg400Lys Uncertain significance ★★ ⚠ same type
GNAL p.Arg437His Uncertain significance ★★ ⚠ same type
GNAL p.Arg65Trp Uncertain significance ★★ same type
GNAL p.Asp220Asn Uncertain significance ★★ ⚠ same type
GNAL p.Gly417Ser Uncertain significance ★★ ⚠ same type
GNAL p.Ile351Thr Uncertain significance ★★ ⚠ 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/gnal-p-val431met (accessed [today's date]).

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