Is ACTN2 p.Pro867= (c.2601C>T) pathogenic?

ACTN2 p.Pro867= (c.2601C>T) is classified Conflicting classifications of pathogenicity in ACTN2 (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.044%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Pro867= (c.2601C>T)?

ACTN2 p.Pro867= (c.2601C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Pro867= (c.2601C>T) in the general population?

ACTN2 p.Pro867= (c.2601C>T) is ultra-rare (popmax 0.044%, afr) (gnomAD).

ACTN2 p.Pro867=

c.2601C>T · rs147245615 · VCV296510

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.044%, afr)

Conditions

Cardiovascular phenotype

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 -20	GERP -5.7
Overall
CADD	0.945	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.044% African / African-American · 33/75,024 alleles

Filtering AF 0.0321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0281%

Overall 0.018% 290/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.044%	2,273
Finnishnot grpmax-eligible	0.0344%	2,910
Admixed American	0.0267%	3,752
European (non-Finnish)	0.0174%	5,756
East Asian	0.0134%	7,480
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.0011%	91,084

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.Pro867=
Coding: c.2601C>T
MANE Select: NM_001103
dbSNP: rs147245615
Type: single nucleotide variant
Location: chr1:236762535 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1AA familial hypertrophic cardiomyopathy

Similar variants

ACTN2 p.Pro867Leu Uncertain significance ★ ⚠ same residue
ACTN2 p.Pro867Ser 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-pro867 (accessed [today's date]).

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