Is ACTN2 p.Ala847Val (c.2540C>T) pathogenic?

ACTN2 p.Ala847Val (c.2540C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0718); Ultra-rare (popmax 0.0227%, afr); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with ACTN2 p.Ala847Val (c.2540C>T)?

ACTN2 p.Ala847Val (c.2540C>T) is associated with familial hypertrophic cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Ala847Val (c.2540C>T) in the general population?

ACTN2 p.Ala847Val (c.2540C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about ACTN2 p.Ala847Val (c.2540C>T)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

ACTN2 p.Ala847Val

c.2540C>T · rs370569935 · VCV575734

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	22.8	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 0.0227% African / African-American · 17/74,940 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0018% 29/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,408
Middle Eastern	0.0165%	6,058
East Asian	0.00445%	22,449
Admixed American	0.00333%	30,007
South Asian	0.0022%	45,545
Finnishnot grpmax-eligible	0.00156%	64,022
European (non-Finnish)	0.000339%	294,998

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.Ala847Val
Coding: c.2540C>T
MANE Select: NM_001103
dbSNP: rs370569935
Type: single nucleotide variant
Location: chr1:236762474 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 847: an α-helix

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

Disease context

familial hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA

Similar variants

ACTN2 p.Ala847= Benign/Likely benign ★★ same residue
ACTN2 p.Ala847Pro Uncertain significance ★★ same residue
ACTN2 p.Ala847Thr Conflicting classifications of pathogenicity ★ ⚠ 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

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-ala847val (accessed [today's date]).

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