Is ACTN2 p.Asp893Asn (c.2677G>A) pathogenic?

ACTN2 p.Asp893Asn (c.2677G>A) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-23). AlphaMissense: ambiguous (0.4707); Ultra-rare (popmax 0.0137%, nfe); Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Asp893Asn (c.2677G>A)?

ACTN2 p.Asp893Asn (c.2677G>A) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Asp893Asn (c.2677G>A) in the general population?

ACTN2 p.Asp893Asn (c.2677G>A) is ultra-rare (popmax 0.0137%, nfe) (gnomAD).

What do computational predictors say about ACTN2 p.Asp893Asn (c.2677G>A)?

AlphaMissense predicts ambiguous (score 0.4707) — an in-silico prediction, not a clinical call.

ACTN2 p.Asp893Asn

c.2677G>A · rs142646143 · VCV463208

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4707 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, nfe)

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
AlphaMissense	0.4707	ambiguous
REVEL	0.431	indeterminate
SaProt	LLR -11.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	27.6	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 0.0137% European (non-Finnish) · 162/1,179,956 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0113%

Overall 0.0108% 175/1,613,832 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0137%	7,284
African / African-American	0.00668%	14,980
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Finnishnot grpmax-eligible	0.00313%	31,995
East Asian	0.00223%	44,878
South Asian	0.0011%	91,058

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.Asp893Asn
Coding: c.2677G>A
MANE Select: NM_001103
dbSNP: rs142646143
Type: single nucleotide variant
Location: chr1:236762611 (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

Similar variants

ACTN2 p.Asp893Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Asp893Val 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

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-asp893asn (accessed [today's date]).

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