Is ACTN2 p.Glu448Gln (c.1342G>C) pathogenic?

ACTN2 p.Glu448Gln (c.1342G>C) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.7809); Very rare (popmax 0.00133%, afr); Associated with dilated cardiomyopathy 1AA.

What condition is associated with ACTN2 p.Glu448Gln (c.1342G>C)?

ACTN2 p.Glu448Gln (c.1342G>C) is associated with dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy, myopathy, congenital, with structured cores and z-line abnormalities (ClinVar).

How common is ACTN2 p.Glu448Gln (c.1342G>C) in the general population?

ACTN2 p.Glu448Gln (c.1342G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ACTN2 p.Glu448Gln (c.1342G>C)?

AlphaMissense predicts likely pathogenic (score 0.7809) — an in-silico prediction, not a clinical call.

ACTN2 p.Glu448Gln

c.1342G>C · rs764031568 · VCV1395077

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1AA

Computational evidence

Protein change
AlphaMissense	0.7809	likely pathogenic
REVEL	0.371	indeterminate
SaProt	LLR -13.38	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic
Overall
CADD	25.8	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 0.00133% African / African-American · 1/75,072 alleles

Overall 0.000205% 3/1,461,846 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
African / African-Americangrpmax	0.00133%	75,072
South Asian	0.0011%	91,090

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu448Gln
Coding: c.1342G>C
MANE Select: NM_001103
dbSNP: rs764031568
Type: single nucleotide variant
Location: chr1:236744712 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 448: 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 myopathy, congenital, with structured cores and z-line abnormalities myopathy, distal, 6, adult-onset, autosomal dominant

Similar variants

ACTN2 p.Glu448Lys Uncertain significance ★★ ⚠ same residue
ACTN2 p.Ala119Thr Pathogenic/Likely pathogenic ★★ same condition
ACTN2 p.Leu727Arg 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-glu448gln (accessed [today's date]).

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