PKP2
Chr 12ADplakophilin 2
Also known as: ARVD9
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.
Primary Disease Associations & Inheritance
Disputed — evidence questions this relationship
4 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 22 | 0 | 24 | 0 | 46 |
Likely Pathogenic | 16 | 2 | 11 | 0 | 29 |
VUS | 3 | 246 | 27 | 0 | 276 |
Likely Benign | 0 | 13 | 40 | 79 | 132 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 4 | |||
| Total | 41 | 261 | 103 | 79 | 488 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →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
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Phase 1, Dose Escalation Trial of RP-A601 in Subjects With PKP2 Variant-Mediated Arrhythmogenic Cardiomyopathy (PKP2-ACM)
RECRUITINGNon-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)
RECRUITINGGene Therapy for ACM Due to a PKP2 Pathogenic Variant
ACTIVE NOT RECRUITINGLong-term Follow-up Study of Gene Therapy for Arrhythmogenic Cardiomyopathy Due to a Plakophilin-2 Pathogenic Variant
ENROLLING BY INVITATIONTissue 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
RECRUITINGOpen-label, Dose Escalation Study of Safety and Preliminary Efficacy of TN-401 in Adults With PKP2 Mutation-associated ARVC
RECRUITINGA Study to Assess Real-world Patient Characteristics and Clinical Course for Symptomatic Patients With PKP2-ACM
RECRUITINGExternal Resources
Links to major genomics databases and tools