Is ACTN2 p.Ala259Val (c.776C>T) pathogenic?

ACTN2 p.Ala259Val (c.776C>T) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-17). AlphaMissense: likely pathogenic (0.5642); Ultra-rare (popmax 0.0165%, mid); Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Ala259Val (c.776C>T)?

ACTN2 p.Ala259Val (c.776C>T) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy, myopathy, congenital, with structured cores and z-line abnormalities (ClinVar).

How common is ACTN2 p.Ala259Val (c.776C>T) in the general population?

ACTN2 p.Ala259Val (c.776C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACTN2 p.Ala259Val (c.776C>T)?

AlphaMissense predicts likely pathogenic (score 0.5642) — an in-silico prediction, not a clinical call.

ACTN2 p.Ala259Val

c.776C>T · rs566552494 · VCV463217

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.5642 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
AlphaMissense	0.5642	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -11.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	28.7	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00155% 25/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00186%	53,636
African / African-American	0.00133%	75,044
South Asian	0.0011%	91,086

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.Ala259Val
Coding: c.776C>T
MANE Select: NM_001103
dbSNP: rs566552494
Type: single nucleotide variant
Location: chr1:236735713 (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

dilated cardiomyopathy 1AA — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial hypertrophic cardiomyopathy myopathy, congenital, with structured cores and z-line abnormalities myopathy, distal, 6, adult-onset, autosomal dominant

Similar variants

ACTN2 p.Ala259Thr Uncertain significance ★★ ⚠ same residue
ACTN2 p.Ala259= Conflicting classifications of pathogenicity ★ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Leu727Arg 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

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-ala259val (accessed [today's date]).

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