Is ACTN2 p.Ile686del (c.2054TCA[1]) pathogenic?

ACTN2 p.Ile686del (c.2054TCA[1]) is classified Uncertain significance in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-17). Very rare (popmax 0.00167%, amr); Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Ile686del (c.2054TCA[1])?

ACTN2 p.Ile686del (c.2054TCA[1]) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Ile686del (c.2054TCA[1]) in the general population?

ACTN2 p.Ile686del (c.2054TCA[1]) is very rare (popmax 0.00167%, amr) (gnomAD).

ACTN2 p.Ile686del

c.2054TCA[1] · rs749678360 · VCV1428050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP -0.6, phastCons 1
Region caveats
Repeat context	tandem	(ACA)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,026 alleles

Overall 6.84e-05% 1/1,461,888 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.Ile686del
Coding: c.2054TCA[1]
MANE Select: NM_001103
dbSNP: rs749678360
Type: Microsatellite
Location: chr1:236755096 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 686: an α-helix

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.Ile686Leu Uncertain significance ★★ ⚠ same residue
ACTN2 p.Ile686Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Asn691del Uncertain significance ★★ same condition
ACTN2 c.361+8GT[3] Uncertain significance ★ same condition
ACTN2 p.Asn590del Uncertain significance ★ same condition
ACTN2 p.Trp47_Cys48insTer Uncertain significance ★ same condition
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Thr247Met Likely pathogenic ★★ 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-ile686del (accessed [today's date]).

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