Is ACTN2 c.615+15C>T pathogenic?

ACTN2 c.615+15C>T is classified Benign/Likely benign in ACTN2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0221%, nfe); Associated with familial hypertrophic cardiomyopathy.

What condition is associated with ACTN2 c.615+15C>T?

ACTN2 c.615+15C>T is associated with familial hypertrophic cardiomyopathy, dilated cardiomyopathy 1AA (ClinVar).

How common is ACTN2 c.615+15C>T in the general population?

ACTN2 c.615+15C>T is ultra-rare (popmax 0.0221%, nfe) (gnomAD).

ACTN2 c.615+15C>T

rs369293885 · VCV178003

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0221%, nfe)

Conditions

familial hypertrophic cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +15	near-intronic (+15 nt from the splice site)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.15	GERP 1
Non-coding constraint	Z 3.85	1 kb window · o/e 0.75 · regional · uncalibrated
Overall
CADD	5.503	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0221% European (non-Finnish) · 261/1,179,710 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.017% 275/1,613,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0221%	4,520
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00533%	18,753
Finnishnot grpmax-eligible	0.00469%	21,343
Admixed American	0.00333%	30,008

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
Coding: c.615+15C>T
MANE Select: NM_001103
dbSNP: rs369293885
Type: single nucleotide variant
Location: chr1:236727771 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB

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

Disease context

familial hypertrophic cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA

Similar variants

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
ACTN2 c.127-3C>A Uncertain significance ★★ same condition
ACTN2 c.1974+4A>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-c-615-plus-15c-t (accessed [today's date]).

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