Is ACTN2 p.Pro6= (c.18C>A) pathogenic?

ACTN2 p.Pro6= (c.18C>A) is classified Benign/Likely benign in ACTN2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-15). Rare (popmax 0.49%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Pro6= (c.18C>A)?

ACTN2 p.Pro6= (c.18C>A) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Pro6= (c.18C>A) in the general population?

ACTN2 p.Pro6= (c.18C>A) is rare (popmax 0.49%, sas) (gnomAD).

ACTN2 p.Pro6=

c.18C>A · rs368367224 · VCV162724

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.49%, sas)

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 0.71	GERP 0.72, phastCons 1
Overall
CADD	14.37	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.49% South Asian · 425/86,724 alleles

Filtering AF 0.452% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.436%

Overall 0.0284% 444/1,564,076 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.49%	204
Remaining individualsnot grpmax-eligible	0.0318%	3,147

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.Pro6=
Coding: c.18C>A
MANE Select: NM_001103
dbSNP: rs368367224
Type: single nucleotide variant
Location: chr1:236686691 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 6: the 'actin-binding' region

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.Pro6Ala Uncertain significance ★ ⚠ same residue
ACTN2 p.Pro6Arg Uncertain significance ★ ⚠ same residue
ACTN2 p.Pro6Ser 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

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-pro6 (accessed [today's date]).

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