PKP2
protein-codingplakophilin 2, the group of Plakophilins|Armadillo repeat containing
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~106.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018901
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005021
Submitter: ClinGen
PKP2 was originally evaluated for DCM by the ClinGen DCM GCEP on June 26th 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May 29th, 2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. PKP2 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2010 (Elliot et al., 2010, PMID 20716751) and 2011 (Garcia-Pavia et al., 2011, PMID 21859740). PKP2 has also been curated by the Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Gene Curation Expert Panel for ARVC (Definitive, March 8, 2018). Human genetic evidence supporting the relationship of PKP2 with DCM includes case-level data; however, the majority of variants reported are present in control populations (gnomAD) at frequencies incompatible with the prevalence of DCM. This gene-disease relationship has been studied in at least one case-control study at the aggregate variant level (Mazzarrotto et al., 2020, PMID 31983221); however, no significant enrichment of PKP2 variants in DCM was shown. In addition, this gene-disease assertion is supported by expression studies as PKP2 has been shown to be expressed in the cardiac desmosome and is critical for cardiac junction formation and heart morphogenesis (Grossman et al., 2004, PMID 15479741). In summary, the evidence presented for this gene-disease relationship does not provide convincing human genetic evidence in support of or refuting the role of PKP2 and autosomal dominant DCM. The relationship of PKP2 with DCM is unclear and therefore classified as disputed. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 29th, 2025 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0016333
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: ClinGen
PKP2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). Variants in PKP2 (in particular truncating loss of function variants) are associated with arrhythmogenic cardiomyopathy (ACM/ARVC) and it has been classified as a Definitive gene by the ARVC Gene Curation Expert Panel. The evidence for a role of PKP2 variants in CPVT comes from a single study in which PKP2 was sequenced in a cohort of 18 patients that had been diagnosed with CPVT and were negative for variants in established CPVT genes (in addition to 19 sudden cardiac death cases with structurally normal hearts) (Tester et al, 2019, PMID:30678776). Although truncating variants in PKP2 were detected in 6 cases, the expert panel (and indeed the authors of the paper) believed that these patients were likely to have concealed ARVC and had been diagnosed with CPVT due to exercise-associated arrhythmias prior to structural heart changes. Indeed one of these cases was subsequently diagnosed with ARVC and right ventricular structural changes were subsequently observed in two others. A cardiomyocyte-specific PKP2 mouse knockout model displayed similar phenotypes, with isoproterenol triggered polymorphic ventricular arrhythmias mimicking CPVT observed prior to structural changes (Cerrone et al, 2017, PMID:28740174). In conclusion, we believe that PKP2 variants are not associated with CPVT and therefore the expert panel decided to classify PKP2 as disputed for CPVT. However, as a CPVT-like phenotype can be observed in ARVC patients with truncating PKP2 variants (during the concealed cardiomyopathy phase of the disease), it may be beneficial to include this gene in extended arrhythmia genetic testing panels for patients with a CPVT-like phenotype if no causative variants are found when sequencing validated CPVT genes. If truncating variants in PKP2 are detected in such cases, it would suggest a diagnosis of ARVC. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012180
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012180
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011001
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0016587
Submitter: ClinGen
The relationship between PKP2 and arrhythmogenic right ventricular cardiomyopathy (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of September, 2018. Variants in PKP2 were first reported in humans with this disease as early as 2004 (Gerull et al., PMID: 15489853). PKP2 is the major causative gene for ARVC and accounts for 34%-74% of cases (McNAlly et al., 2005; PMID: 20301310). There are over 250 PKP2 variants listed in ClinVar for ARVC (missense, nonsense, frameshift, complex rearrangements, etc) (Novelli et al., 2018; PMID: 30619891). This gene-disease relationship is well-known and therefore a significant amount of case-level data, segregation data and experimental data is available in the literature, therefore the maximum score for both genetic evidence and experimental evidence has been reached. Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship. This gene-disease relationship is supported by animal models, in vitro assays, and protein interactions. In summary, PKP2 is definitively associated with autosomal dominant ARVC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Arrythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel on October, 26, 2018 (SOP Version 6).
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Due to risk of severe sequelae including sudden cardiac death, individuals require ICD placement regardless of classic risk factors related to ICD necessity in clinically similar patients without PKP2 variants
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PKP2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001005242.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 9 | 405 | 13 | 428 | |
| missense | 3 | 8 | 951 | 98 | 9 | 1069 |
| nonsense | 68 | 27 | 95 | |||
| start loss | 1 | 4 | 1 | 6 | ||
| frameshift | 117 | 96 | 5 | 218 | ||
| splice donor/acceptor (+/-2bp) | 17 | 38 | 3 | 1 | 59 | |
| Total | 206 | 174 | 969 | 504 | 22 | 1875 |
Highest pathogenic variant AF is 0.000076840515
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001005242.2 | 13 | MANE Select | |
| Ensembl | ENSP00000342800.5 | 13 | MANE Select | |
| RefSeq | NP_001394084.1 | 12 | Standard | |
| RefSeq | NP_001394085.1 | 12 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pkp2 | Danio rerio | Structure: post-vent region Quality: kinked abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
- Arrhythmogenic Right Ventricular Cardiomyopathy
- EMT transition in Colorectal Cancer
- Keratinization
- Developmental Biology
Biological Process
- desmosome assembly
- cell-cell junction assembly
- heart development
- positive regulation of sodium ion transport
- keratinization
Molecular Function
- protein kinase C binding
- protein binding
- sodium channel regulator activity
- intermediate filament binding
- protein-containing complex scaffold activity
Cellular Component
- cornified envelope
- nucleus
- nucleoplasm
- cytoplasm
- intermediate filament
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000070846
- Coding exons
- 14
- Length
- 106096
- Individuals with no LoFs
- 125638
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 110
- Defined
- 125748
- p
- 0.000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.213 | 513 | 500 | 1.03 | 0.0000303 | 5724 |
| Missense (PolyPhen) | 130 | 135.54 | 0.95909 | 1684 | ||
| Synonymous | 0.216 | 208 | 212 | 0.981 | 0.0000142 | 1778 |
| Loss of Function | 1.25 | 32 | 40.6 | 0.788 | 0.00000233 | 439 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0026 | 0.0024 | notable |
| Latino/Admixed American | 0.00026 | 0.00026 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000093 | 0.000092 | rare |
| European (Non-Finnish) | 0.00041 | 0.00036 | rare |
| South Asian | 0.00036 | 0.00033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May play a role in junctional plaques. {ECO:0000269|PubMed:22781308}.;
Recessive Scores
- pRec
- 0.123
Intolerance Scores
- LoFtool
- 0.399
- RVIS EVS
- 0.65
- RVIS percentile EVS
- 84.18
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.732
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |