Is ACTN2 p.Met20Val (c.58A>G) pathogenic?

ACTN2 p.Met20Val (c.58A>G) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-12). AlphaMissense: likely benign (0.1883); Very rare (popmax 0.00116%, sas); Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Met20Val (c.58A>G)?

ACTN2 p.Met20Val (c.58A>G) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Met20Val (c.58A>G) in the general population?

ACTN2 p.Met20Val (c.58A>G) is very rare (popmax 0.00116%, sas) (gnomAD).

What do computational predictors say about ACTN2 p.Met20Val (c.58A>G)?

AlphaMissense predicts likely benign (score 0.1883) — an in-silico prediction, not a clinical call.

ACTN2 p.Met20Val

c.58A>G · rs1203291298 · VCV1750372

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00116%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
AlphaMissense	0.1883	likely benign
REVEL	0.28	benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	donor gain · deltas
Constraint at this position
Conservation	phyloP 7.5	GERP -0.56, phastCons 1
Regional constraint	o/e 1.44	unconstrained · MANE · 58 bp · p 0.028 · regional, not allelic
Overall
CADD	26.8	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

Grpmax group 0.00116% South Asian · 1/86,288 alleles

Filtering AF 0.000438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000319%

Overall 0.000704% 11/1,562,496 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00116%	86,288
European (non-Finnish)	0.000866%	115,418

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.Met20Val
Coding: c.58A>G
MANE Select: NM_001103
dbSNP: rs1203291298
Type: single nucleotide variant
Location: chr1:236686731 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 20: the 'actin-binding' region

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.Met20Leu Uncertain significance ★★ ⚠ same residue
ACTN2 p.Met20Thr 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-met20val (accessed [today's date]).

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