Is ACTN2 p.Ala244Val (c.731C>T) pathogenic?

ACTN2 p.Ala244Val (c.731C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.9335); Very rare (popmax 0.004%, afr); Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Ala244Val (c.731C>T)?

ACTN2 p.Ala244Val (c.731C>T) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Ala244Val (c.731C>T) in the general population?

ACTN2 p.Ala244Val (c.731C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about ACTN2 p.Ala244Val (c.731C>T)?

AlphaMissense predicts likely pathogenic (score 0.9335) — an in-silico prediction, not a clinical call.

ACTN2 p.Ala244Val

c.731C>T · rs938796645 · VCV934241

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
AlphaMissense	0.9335	likely pathogenic
REVEL	0.516	indeterminate
SaProt	LLR -11.05	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	27.4	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 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,614,078 alleles · very rare

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.Ala244Val
Coding: c.731C>T
MANE Select: NM_001103
dbSNP: rs938796645
Type: single nucleotide variant
Location: chr1:236735668 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 244: the calponin-homology (ch) 2 domain; an α-helix; the 'actin-binding' region

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

Similar variants

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
ACTN2 c.127-3C>A Uncertain significance ★★ same condition
ACTN2 c.1974+4A>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-ala244val (accessed [today's date]).

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