Is ACTN2 p.Lys351Asn (c.1053G>C) pathogenic?

ACTN2 p.Lys351Asn (c.1053G>C) is classified Benign in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-27). AlphaMissense: likely pathogenic (0.9886); Absent from gnomAD v4.1; Associated with myopathy, congenital, with structured cores and z-line abnormalities.

What condition is associated with ACTN2 p.Lys351Asn (c.1053G>C)?

ACTN2 p.Lys351Asn (c.1053G>C) is associated with myopathy, congenital, with structured cores and z-line abnormalities (ClinVar).

How common is ACTN2 p.Lys351Asn (c.1053G>C) in the general population?

ACTN2 p.Lys351Asn (c.1053G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN2 p.Lys351Asn (c.1053G>C)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

ACTN2 p.Lys351Asn

c.1053G>C · VCV3338236

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myopathy, congenital, with structured cores and z-line abnormalities

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic
REVEL	0.21	benign-leaning
SaProt	LLR -16.64	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	21.7	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

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.Lys351Asn
Coding: c.1053G>C
MANE Select: NM_001103
Type: single nucleotide variant
Location: chr1:236739478 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 351: an α-helix

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

Disease context

myopathy, congenital, with structured cores and z-line abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same condition
ACTN2 c.127-3C>A Uncertain significance ★★ same condition
ACTN2 c.536+6C>G Uncertain significance ★★ same condition
ACTN2 c.698-1179G>A Uncertain significance ★★ same condition
ACTN2 c.*1001T>A Uncertain significance ★★ same condition
ACTN2 c.*128G>A Uncertain significance ★★ same condition
ACTN2 c.*1645C>G Uncertain significance ★★ same condition
ACTN2 c.*286T>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-lys351asn (accessed [today's date]).

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