Is ACTN2 p.Ala847Pro (c.2538_2539delinsTC) pathogenic?

ACTN2 p.Ala847Pro (c.25382539delinsTC) is classified Uncertain significance in ACTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-27). Absent from gnomAD; Associated with Cardiovascular phenotype.

What condition is associated with ACTN2 p.Ala847Pro (c.2538_2539delinsTC)?

ACTN2 p.Ala847Pro (c.2538_2539delinsTC) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1AA, familial hypertrophic cardiomyopathy (ClinVar).

How common is ACTN2 p.Ala847Pro (c.2538_2539delinsTC) in the general population?

ACTN2 p.Ala847Pro (c.2538_2539delinsTC) is absent from gnomAD (gnomAD).

ACTN2 p.Ala847Pro

c.2538_2539delinsTC · rs2102953618 · VCV1056609

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP -1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 25 kb · p 0.0054 · regional, not allelic

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ACTN2
Protein: p.Ala847Pro
Coding: c.2538_2539delinsTC
MANE Select: NM_001103
dbSNP: rs2102953618
Type: Indel
Location: chr1:236762472 (GRCh38)
Gene constraint: LOEUF 0.432 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.88 · 18 PDB
Residue 847: an α-helix

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.Ala847= Benign/Likely benign ★★ same residue
ACTN2 p.Ala847Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Ala847Val Conflicting classifications of pathogenicity ★ ⚠ same residue
ACTN2 p.Asn687Thr Uncertain significance ★★ same condition
ACTN2 p.Pro872Glu Uncertain significance ★★ same condition
ACTN2 p.Ser433Leu Benign/Likely benign ★★ same condition
ACTN2 c.698-11_698-10delinsAA Uncertain significance ★ same condition
ACTN2 p.Glu404Lys 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-ala847pro (accessed [today's date]).

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