Is ACTN2 p.Arg394Trp (c.1180C>T) pathogenic?

ACTN2 p.Arg394Trp (c.1180C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-25). AlphaMissense: likely pathogenic (0.7352); Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Arg394Trp (c.1180C>T)?

ACTN2 p.Arg394Trp (c.1180C>T) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 p.Arg394Trp (c.1180C>T) in the general population?

ACTN2 p.Arg394Trp (c.1180C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACTN2 p.Arg394Trp (c.1180C>T)?

AlphaMissense predicts likely pathogenic (score 0.7352) — an in-silico prediction, not a clinical call.

ACTN2 p.Arg394Trp

c.1180C>T · rs559395092 · VCV412273

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7352 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7352	likely pathogenic
REVEL	0.404	indeterminate
SaProt	LLR -13.82	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 3.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	26.2	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00752%

Overall 0.0075% 121/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00949%	10,536
East Asian	0.00446%	22,438
Remaining individualsnot grpmax-eligible	0.0032%	31,253
African / African-American	0.00267%	37,502
South Asian	0.0022%	45,540

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.Arg394Trp
Coding: c.1180C>T
MANE Select: NM_001103
dbSNP: rs559395092
Type: single nucleotide variant
Location: chr1:236742968 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 394: an α-helix

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.Arg394Gln 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
ACTN2 c.127-3C>A 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-arg394trp (accessed [today's date]).

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