Is ACTN2 p.Asn804Lys (c.2412C>G) pathogenic?

ACTN2 p.Asn804Lys (c.2412C>G) is classified Uncertain significance in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: likely benign (0.3021); Absent from gnomAD v4.1; Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Asn804Lys (c.2412C>G)?

ACTN2 p.Asn804Lys (c.2412C>G) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Asn804Lys (c.2412C>G) in the general population?

ACTN2 p.Asn804Lys (c.2412C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN2 p.Asn804Lys (c.2412C>G)?

AlphaMissense predicts likely benign (score 0.3021) — an in-silico prediction, not a clinical call.

ACTN2 p.Asn804Lys

c.2412C>G · VCV4794040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3021 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
AlphaMissense	0.3021	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4.7
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	0.121	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACTN2
Protein: p.Asn804Lys
Coding: c.2412C>G
MANE Select: NM_001103
Type: single nucleotide variant
Location: chr1:236761059 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 804: a binding site; the ef-hand 2 domain

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.Asn804Ser Uncertain significance ★★ ⚠ same residue
ACTN2 p.Asn804= Likely benign ★★ 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-asn804lys (accessed [today's date]).

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