Is ACTN2 p.Leu424Phe (c.1272G>C) pathogenic?

ACTN2 p.Leu424Phe (c.1272G>C) is classified Uncertain significance in ACTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-09). AlphaMissense: likely pathogenic (0.9385); Absent from gnomAD v4.1.

How common is ACTN2 p.Leu424Phe (c.1272G>C) in the general population?

ACTN2 p.Leu424Phe (c.1272G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACTN2 p.Leu424Phe (c.1272G>C)?

AlphaMissense predicts likely pathogenic (score 0.9385) — an in-silico prediction, not a clinical call.

ACTN2 p.Leu424Phe

c.1272G>C · VCV4074676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9385 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9385	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -13.92	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 3.4	GERP -0.75, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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.Leu424Phe
Coding: c.1272G>C
MANE Select: NM_001103
Type: single nucleotide variant
Location: chr1:236744642 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 424: an α-helix

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

Similar variants

ACTN2 p.Leu424= Likely benign ★★ same residue
ACTN2 p.Leu424Ser Uncertain significance ★ ⚠ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same type
ACTN2 p.Leu727Arg Pathogenic/Likely pathogenic ★★ same type
ACTN2 p.Thr247Met Likely pathogenic ★★ same type
ACTN2 c.1107+3G>A Uncertain significance ★★ same type
ACTN2 c.1108-10A>G Uncertain significance ★★ same type
ACTN2 c.1255+1G>C Uncertain significance ★★ same type

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-leu424phe (accessed [today's date]).

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