Is ACTN2 p.Gly7= (c.21C>T) pathogenic?

ACTN2 p.Gly7= (c.21C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-12). Very rare (popmax 0.00182%, amr); Associated with myopathy, congenital, with structured cores and z-line abnormalities.

What condition is associated with ACTN2 p.Gly7= (c.21C>T)?

ACTN2 p.Gly7= (c.21C>T) is associated with myopathy, congenital, with structured cores and z-line abnormalities, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Gly7= (c.21C>T) in the general population?

ACTN2 p.Gly7= (c.21C>T) is very rare (popmax 0.00182%, amr) (gnomAD).

ACTN2 p.Gly7=

c.21C>T · rs1387972965 · VCV1042730

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00182%, amr)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	GERP -2.2, phastCons 0.034
Overall
CADD	14.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00182% Admixed American · 1/55,026 alleles

Overall 7.08e-05% 1/1,412,948 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.Gly7=
Coding: c.21C>T
MANE Select: NM_001103
dbSNP: rs1387972965
Type: single nucleotide variant
Location: chr1:236686694 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 7: the 'actin-binding' region

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

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy myopathy, distal, 6, adult-onset, autosomal dominant

Similar variants

ACTN2 p.Gly7Ser 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-gly7 (accessed [today's date]).

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