Is ACTN2 p.Ala265Val (c.794C>T) pathogenic?

ACTN2 p.Ala265Val (c.794C>T) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9501); Very rare (popmax 0.00226%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Ala265Val (c.794C>T)?

ACTN2 p.Ala265Val (c.794C>T) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Ala265Val (c.794C>T) in the general population?

ACTN2 p.Ala265Val (c.794C>T) is very rare (popmax 0.00226%, eas) (gnomAD).

What do computational predictors say about ACTN2 p.Ala265Val (c.794C>T)?

AlphaMissense predicts likely pathogenic (score 0.9501) — an in-silico prediction, not a clinical call.

ACTN2 p.Ala265Val

c.794C>T · rs794728965 · VCV201634

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9501 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00226%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9501	likely pathogenic
REVEL	0.688	pathogenic-leaning
SaProt	LLR -11.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 50 kb · p 1.6e-10 · regional, not allelic
Overall
CADD	31.0	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00226% East Asian · 1/44,282 alleles

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

Overall 0.000313% 5/1,599,074 alleles · very rare exomes 5/1,448,250 · genomes 0/150,824 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00226%	44,282
Admixed American	0.00168%	59,440
African / African-American	0.00134%	74,398
European (non-Finnish)	0.000171%	585,220

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: ACTN2
Protein: p.Ala265Val
Coding: c.794C>T
MANE Select: NM_001103
dbSNP: rs794728965
Type: single nucleotide variant
Location: chr1:236737132 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB

Full ACTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Ala265= Likely benign ★★ same residue
ACTN2 p.Ala265Thr Uncertain significance ★ ⚠ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
ACTN2 p.Thr247Met Likely pathogenic ★★ same condition
ACTN2 c.1107+3G>A Uncertain significance ★★ same condition
ACTN2 c.1108-10A>G Uncertain significance ★★ same condition
ACTN2 c.1255+1G>C Uncertain significance ★★ same condition
ACTN2 c.126+2T>G 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/actn2-p-ala265val (accessed [today's date]).

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