Is PKP2 p.Ala751= (c.2253C>A) pathogenic?

PKP2 p.Ala751= (c.2253C>A) is classified Likely benign in PKP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular dysplasia 9.

What condition is associated with PKP2 p.Ala751= (c.2253C>A)?

PKP2 p.Ala751= (c.2253C>A) is associated with arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Ala751= (c.2253C>A) in the general population?

PKP2 p.Ala751= (c.2253C>A) is absent from gnomAD v4.1 (gnomAD).

PKP2 p.Ala751=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2253C>A · VCV3640426

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

arrhythmogenic right ventricular dysplasia 9

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 4.3	phastCons 1
Overall
CADD	9.286	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PKP2
Protein: p.Ala751=
Coding: c.2253C>A
MANE Select: NM_001005242
Type: single nucleotide variant
Location: chr12:32796213 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 751: a UniProt-annotated variant site (in arvd9; uncertain significance)

Full PKP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arrhythmogenic right ventricular dysplasia 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

PKP2 p.Ala751Pro Uncertain significance ★ ⚠ same residue
PKP2 p.Ala751Ser Uncertain significance ★ ⚠ same residue
PKP2 p.Ala751Thr Uncertain significance ★ ⚠ same residue
PKP2 c.1034+1G>C Likely pathogenic ★★ same condition
PKP2 c.1034+1G>T Likely pathogenic ★★ same condition
PKP2 c.1035-2A>G Likely pathogenic ★★ same condition
PKP2 c.1170+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.1170+1G>C Pathogenic ★★ 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/pkp2-p-ala751 (accessed [today's date]).

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