PKP2

Chr 12

plakophilin 2

Also known as: ARVD9

NCBI Gene: 5318 ENSG00000057294 UniProt: Q99959

This gene encodes plakophilin-2, a desmosomal protein that maintains cell-cell adhesion in cardiac myocytes and is required for proper cardiac electrical conduction and structural integrity. Mutations cause arrhythmogenic right ventricular dysplasia, an inherited cardiomyopathy that typically presents in adolescence or young adulthood with ventricular arrhythmias and sudden cardiac death risk. The condition follows autosomal dominant inheritance with variable penetrance and expressivity.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtArrhythmogenic right ventricular dysplasia, familial, 9

Clinical highlights

Gene-disease validity (ClinGen)

catecholaminergic polymorphic ventricular tachycardia · ADDisputedevidence questions this relationship4 gene-disease associations curated in total

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.06

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.000

Z-score 1.25

OE 0.79 (0.59–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.21Z-score

OE missense 1.03 (0.95–1.10)

513 obs / 499.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.79 (0.59–1.06)

0≤0.351.4

Missense OE?1.03 (0.95–1.10)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 32 / 40.6Missense obs/exp: 513 / 499.6Syn Z: 0.22

ClinVar

No ClinVar data available.

Protein Context — Lollipop Plot

PKP2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Arrhythmogenic Right Ventricular Cardiomyopathy

Non-interventional Study of Seroprevalence of Pre-existing Antibodies Against Adenovirus-associated Virus Vector (AAV9) and the Progression of Disease in Patients With Plakophilin 2 (PKP2)-Associated Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

RECRUITING

NCT06311708Tenaya TherapeuticsStarted 2023-01-31

Arrhythmogenic CardiomyopathyPKP2-ACMPKP2-ARVC

A Study to Assess Real-world Patient Characteristics and Clinical Course for Symptomatic Patients With PKP2-ACM

RECRUITING

NCT06976606Lexeo TherapeuticsStarted 2024-01-23

Arrhythmogenic Right Ventricular Cardiomyopathy

Open-label, Dose Escalation Study of Safety and Preliminary Efficacy of TN-401 in Adults With PKP2 Mutation-associated ARVC

RECRUITING

NCT06228924Phase PHASE1Tenaya TherapeuticsStarted 2024-03-26

TN-401

PKP2 Arrhythmogenic Cardiomyopathy (PKP2-ACM)

A Phase 1, Dose Escalation Trial of RP-A601 in Subjects With PKP2 Variant-Mediated Arrhythmogenic Cardiomyopathy (PKP2-ACM)

RECRUITING

NCT05885412Phase PHASE1Rocket Pharmaceuticals Inc.Started 2023-08-29

RP-A601

Arrhythmogenic Cardiomyopathies

Tissue and Metabolic Characterization of Arrhythmogenic Cardiomyopathies by Hybrid PET-MRI Imaging, Impact of the Observed Profiles on the Phenotype and on the Evolution of Cardiomyopathy

RECRUITING

NCT05450783Nantes University HospitalStarted 2022-09-01

Biocollection

Arrhythmogenic CardiomyopathyPKP2-ACMPKP2-ARVC

Gene Therapy for ACM Due to a PKP2 Pathogenic Variant

ACTIVE NOT RECRUITING

NCT06109181Phase PHASE1, PHASE2Lexeo TherapeuticsStarted 2024-02-29

LX2020

Arrhythmogenic CardiomyopathyPKP2-ACMPKP2-ARVC

Long-term Follow-up Study of Gene Therapy for Arrhythmogenic Cardiomyopathy Due to a Plakophilin-2 Pathogenic Variant

ENROLLING BY INVITATION

NCT07050160Lexeo TherapeuticsStarted 2025-08-29