Is GJA5 p.Val91Ala (c.272T>C) pathogenic?

GJA5 p.Val91Ala (c.272T>C) is classified Uncertain significance in GJA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-13). AlphaMissense: likely benign (0.2699); Very rare (popmax 0.000169%, nfe); Associated with atrial fibrillation, familial, 11.

What condition is associated with GJA5 p.Val91Ala (c.272T>C)?

GJA5 p.Val91Ala (c.272T>C) is associated with atrial fibrillation, familial, 11, atrial standstill 1 (ClinVar).

How common is GJA5 p.Val91Ala (c.272T>C) in the general population?

GJA5 p.Val91Ala (c.272T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Hereditary atrial fibrillation inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GJA5 p.Val91Ala (c.272T>C)?

AlphaMissense predicts likely benign (score 0.2699) — an in-silico prediction, not a clinical call.

GJA5 p.Val91Ala

c.272T>C · rs1018708274 · VCV2943176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrial fibrillation, familial, 11

Computational evidence

Protein change
AlphaMissense	0.2699	likely benign
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -10.49	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 863 bp · p 0.38 · regional, not allelic
Overall
CADD	23.9	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 0.000169% European (non-Finnish) · 2/1,180,020 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,172 alleles · very rare exomes 2/1,461,878 · genomes 0/152,294 · joint denominator

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: GJA5
Protein: p.Val91Ala
Coding: c.272T>C
MANE Select: NM_181703
dbSNP: rs1018708274
Type: single nucleotide variant
Location: chr1:147758967 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.50 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 70.35

Full GJA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atrial fibrillation, familial, 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atrial standstill 1

For Hereditary atrial fibrillation (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

GJA5 p.Val91Leu Uncertain significance ★ ⚠ same residue
GJA5 c.*22G>A Uncertain significance ★★ same condition
GJA5 p.Ala216Thr Uncertain significance ★★ ⚠ same condition
GJA5 p.Ala347Pro Uncertain significance ★★ ⚠ same condition
GJA5 p.Ala96Ser Uncertain significance ★★ ⚠ same condition
GJA5 p.Ala96Val Uncertain significance ★★ ⚠ same condition
GJA5 p.Arg101His Uncertain significance ★★ ⚠ same condition
GJA5 p.Arg106Leu 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/gja5-p-val91ala (accessed [today's date]).

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