PKP1

Summary

PKP1 (plakophilin 1, HGNC:9023) is a protein-coding gene on chromosome 1q32.1, encoding Plakophilin-1 (Q13835). A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

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 protein may be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5317 — RefSeq curated summary.

At a glance

• Gene–disease (curated): epidermolysis bullosa simplex due to plakophilin deficiency (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 396 total — 7 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes
• MANE Select transcript: NM_001005337

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9023
Approved symbol	PKP1
Name	plakophilin 1
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	B6P
Ensembl gene	ENSG00000081277
Ensembl biotype	protein_coding
OMIM	601975
Entrez	5317

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000263946, ENST00000352845, ENST00000367324, ENST00000475988, ENST00000477817

RefSeq mRNA: 2 — MANE Select: NM_001005337 NM_000299, NM_001005337

CCDS: CCDS30966, CCDS30967

Canonical transcript exons

ENST00000367324 — 14 exons

Exon	Start	End
ENSE00000000226	201283506	201283904
ENSE00000000227	201330074	201332989
ENSE00000523184	201324428	201324581
ENSE00000523189	201324941	201325127
ENSE00000791344	201293942	201294045
ENSE00000791345	201313166	201313560
ENSE00000791350	201320267	201320381
ENSE00000791351	201321978	201322133
ENSE00000791353	201323013	201323189
ENSE00000791356	201325754	201325838
ENSE00001253428	201328762	201328868
ENSE00003470076	201318618	201318795
ENSE00003577103	201317572	201317779
ENSE00003685946	201316553	201316697

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 99.44.

FANTOM5 (CAGE): breadth broad, TPM avg 14.2001 / max 2390.6366, expressed in 408 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7689	13.5063	394
7688	0.5941	158
7692	0.0997	64

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	99.44	gold quality
skin of abdomen	UBERON:0001416	99.40	gold quality
lower esophagus mucosa	UBERON:0035834	99.16	gold quality
skin of leg	UBERON:0001511	99.09	gold quality
upper leg skin	UBERON:0004262	99.06	gold quality
gingiva	UBERON:0001828	99.00	gold quality
zone of skin	UBERON:0000014	98.99	gold quality
gingival epithelium	UBERON:0001949	98.92	gold quality
tongue squamous epithelium	UBERON:0006919	98.66	gold quality
esophagus mucosa	UBERON:0002469	98.37	gold quality
mammalian vulva	UBERON:0000997	98.20	gold quality
penis	UBERON:0000989	97.93	gold quality
skin of hip	UBERON:0001554	97.93	gold quality
nipple	UBERON:0002030	97.90	gold quality
pharyngeal mucosa	UBERON:0000355	97.47	gold quality
oral cavity	UBERON:0000167	95.55	gold quality
body of tongue	UBERON:0011876	94.98	gold quality
cervix epithelium	UBERON:0004801	94.62	gold quality
squamous epithelium	UBERON:0006914	93.97	gold quality
epithelium of esophagus	UBERON:0001976	93.33	gold quality
esophagus squamous epithelium	UBERON:0006920	93.00	gold quality
vagina	UBERON:0000996	90.45	gold quality
hair follicle	UBERON:0002073	90.02	gold quality
tongue	UBERON:0001723	89.50	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.37	gold quality
cervix squamous epithelium	UBERON:0006922	87.59	silver quality
tonsil	UBERON:0002372	84.73	gold quality
mouth mucosa	UBERON:0003729	84.05	gold quality
prostate gland	UBERON:0002367	83.14	gold quality
minor salivary gland	UBERON:0001830	81.81	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	217.20
E-MTAB-8142	yes	119.74
E-ANND-3	yes	24.09
E-MTAB-10596	no	937.34

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
DSP	Activation
PKP2	Activation
PKP3	Activation

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

117 targeting PKP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698

Literature-anchored findings (GeneRIF, showing 31)

• Genotype-phenotype correlation in skin fragility-ectodermal dysplasia syndrome resulting from mutations in plakophilin 1. Homozygous intron 11 donor splice site mutation in the plakophilin 1 gene, 2021+1 G>A. (PMID:11994137)
• The PKP1 null patients showed poorly developed inner and outer desmosomal plaques and reductions in the lower suprabasal layer desmosome size and number so pkp1 has a recruiting and stabilizing role in desmosome formation (PMID:12839569)
• plakophilin 1 has a key role in increasing desmosomal protein content, in desmosome assembly, and in regulating cell migration (PMID:12840072)
• crystal structure of the arm repeat domain from plakophilin-1 (PKP1), a member of the p120ctn subfamily that is found in desmosomes (PMID:15663951)
• Co-expression of a classical cadherin (N-cadherin) and plakophilin-1/ER in A431D cells resulted in punctate desmoplakin staining at cell-cell borders (PMID:15988759)
• Compound heterozygosity for new splice site mutations in the plakophilin 1 gene (PKP1) in a Chinese case of ectodermal dysplasia-skin fragility syndrome (PMID:16159729)
• the Plakophilin-1 carboxyl terminus recruits it to plasma membrane, whereas amino terminus recruits desmoplakin and promotes desmosome assembly (PMID:16632867)
• The Ki67+ proliferation index was inversely correlated with desmoplakin and plakophilin-1 during cervical squamous cell carcinogenesis (PMID:17593084)
• Loss of plakophilin-1 expression during head and neck squamous cell carcinoma (HNSCC) progression may contribute to an invasive phenotype. (PMID:17668353)
• a homozygous nonsense mutation, p.R672X, in the PKP1 gene is similar to the molecular pathology underlying other cases of ectodermal dysplasia-skin fragility syndrome (PMID:19016709)
• the clinicopathologic features attest to the significant role of PKP1 in stabilization of desmosome structure and function, predominantly in the spinous layers of the epidermis (PMID:19945625)
• These findings identify PKP1 as a regulator of translation and proliferation via modulation of eIF4A1 activity. (PMID:20156963)
• both loss of PKP1 and up-regulation of PKP3 expression are biologically important events in prostate cancer and are associated with a more aggressive phenotype (PMID:20348237)
• in addition to mediating desmosome assembly, the nuclear pool of Pkp can influence cell survival by interactions with DNA (PMID:20613778)
• In breast cancer, compared with normal tissue, PKP1 and PKP2 expressions were indifferent (P > 0.05), but PKP3 expression was significantly increased (PMID:21947748)
• PKP1 loss secondary to promoter methylation, as well as other mechanisms, may promote the progression of Barrett’s esophagus to esophageal adenocarcinoma in a subset of patients via decreased desmosome assembly and increased cell motility (PMID:22170739)
• Data indicate that upon activation of growth factor signaling, plakophilin 1 switches from a desmosome-associated growth-inhibiting to a cytoplasmic proliferation-promoting function. (PMID:23444369)
• Plakophilin-1 has a role in protecting keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes (PMID:24056861)
• cytoplasmic PKP1/3 are components of mRNA ribonucleoprotein particles and act as posttranscriptional regulators of gene expression. (PMID:25225333)
• Collectively, altered expression of PKP1 and SPOCK1 appears to be a frequent and critical event in prostate cancer (PMID:26138584)
• These results implicate the participation of PKP1 in early tooth morphogenesis as an effector of canonical Wnt signaling that controls ameloblast differentiation via regulation of the cell adhesion complex (PMID:27015268)
• 14-3-3gamma associated primarily with cytoplasmic PKP1 phosphorylated at S155 and destabilized intercellular cohesion of keratinocytes by reducing its incorporation into desmosomes. (PMID:29678907)
• In advanced primary lung tumor samples, higher expression of plakophilin 1 (PKP1) was significantly associated with favorable clinical outcome. (PMID:30946843)
• LncRNA APPAT regulated miR-328a/Pkp1 signal pathway to participate in breast cancer. (PMID:32495884)
• Intrinsically disordered protein NUPR1 binds to the armadillo-repeat domain of Plakophilin 1. (PMID:33385445)
• The Prognostic Significance of Plakophilin-1 Expression in Esophageal Cancer. (PMID:34230135)
• PKP1 and MYC create a feedforward loop linking transcription and translation in squamous cell lung cancer. (PMID:35182388)
• The armadillo-repeat domain of Plakophilin 1 binds to human enzyme PADI4. (PMID:36372391)
• Plakophilin 1 deficiency in prostatic tumours is correlated with immune cell recruitment and controls the up-regulation of cytokine expression post-transcriptionally. (PMID:36380691)
• Elucidation of the inhibitory potential of flavonoids against PKP1 protein in non-small cell lung cancer. (PMID:37114302)
• Unveiling the Binding between the Armadillo-Repeat Domain of Plakophilin 1 and the Intrinsically Disordered Transcriptional Repressor RYBP. (PMID:38785968)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pkp1b	ENSDARG00000052705
danio_rerio	pkp1a	ENSDARG00000090598
mus_musculus	Pkp1	ENSMUSG00000026413
rattus_norvegicus	Pkp1	ENSRNOG00000010076
drosophila_melanogaster	p120ctn	FBGN0260799
caenorhabditis_elegans		WBGENE00002175

Paralogs (6): PKP2 (ENSG00000057294), ARVCF (ENSG00000099889), PKP4 (ENSG00000144283), CTNND2 (ENSG00000169862), PKP3 (ENSG00000184363), CTNND1 (ENSG00000198561)

Protein

Protein identifiers

Plakophilin-1 — Q13835 (reviewed: Q13835)

Alternative names: Band 6 protein

All UniProt accessions (1): Q13835

UniProt curated annotations — full annotation on UniProt →

Function. A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. Plays a role in desmosome protein expression regulation and localization to the desmosomal plaque, thereby maintaining cell sheet integrity and anchorage of desmosomes to intermediate filaments. Required for localization of DSG3 and YAP1 to the cell membrane in keratinocytes in response to mechanical strain, via the formation of an interaction complex composed of DSG3, YAP1, PKP1 and YWHAG. Positively regulates differentiation of keratinocytes, potentially via promoting localization of DSG1 at desmosome cell junctions. Required for calcium-independent development and maturation of desmosome plaques specifically at lateral cell-cell contacts in differentiating keratinocytes. Plays a role in the maintenance of DSG3 protein abundance, DSG3 clustering and localization of these clusters to the cell membrane in keratinocytes. May also promote keratinocyte proliferation and morphogenesis during postnatal development. Required for tight junction inside-out transepidermal barrier function of the skin. Promotes Wnt-mediated proliferation and differentiation of ameloblasts, via facilitating TJP1/ZO-1 localization to tight junctions. Binds single-stranded DNA (ssDNA), and may thereby play a role in sensing DNA damage and promoting cell survival. Positively regulates cap-dependent translation and as a result cell proliferation, via recruitment of EIF4A1 to the initiation complex and promotion of EIF4A1 ATPase activity. Regulates the mRNA stability and protein abundance of desmosome components PKP2, PKP3, DSC2 and DSP, potentially via its interaction with FXR1.

Subunit / interactions. Part of a complex that contains DSG3, PKP1, YAP1 and YWHAG; the complex is required for localization of DSG3 and YAP1 to the cell membrane in keratinocytes. Interacts with DSP. Interacts (via N-terminus) with KRT5/CK5, KRT8/CK8 (via rod domain), KRT15/CK15 and KRT18/CK18 (via rod domain) as part of intermediate filaments. Interacts with VIM (via rod domain). Interacts with DSP. Interacts with DES. Interacts with FXR1; the interaction may facilitate the binding of PKP1 to PKP2, PKP3 and DSP mRNA. Interacts (via N-terminus) with EIF4A1; the interaction promotes EIF4A1 recruitment to the cap-dependent translation complex and EIF4A1 ATPase activity. Interacts with TJP1/ZO-1; the interaction facilitates TJP1/ZO-1 localization to the plasma membrane. Interacts (when phosphorylated) with YWHAG; the interaction results in translocation of PKP1 to the cytoplasm and loss of intercellular adhesion in keratinocytes.

Subcellular location. Cell junction. Desmosome Nucleus Nucleus. Cytoplasm. Perinuclear region. Desmosome. Cell membrane. Stress granule.

Tissue specificity. Expressed in stratified squamous, complex, glandular duct and bladder epithelia (at protein level). Widely expressed (at protein level).

Post-translational modifications. Phosphorylated by AKT2; required for interaction with YWHAG and subsequent localization away from desmosomes to the cytoplasm. Phosphorylation of Ser-118 by AKT2 promotes PKP1-driven cap-dependent mRNA translation and decreases intercellular adhesion, phosphorylation is promoted by insulin. Phosphorylation by RIPK4 at the N-terminus is required for its role in differentiation of keratinocytes and DSG1 localization at cell junctions.

Disease relevance. Ectodermal dysplasia-skin fragility syndrome (EDSFS) [MIM:604536] A form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Characterized by features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the beta-catenin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13835-1	2, 1b	yes
Q13835-2	1, 1a

RefSeq proteins (2): NP_000290, NP_001005337* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR028435	Plakophilin/d_Catenin	Family

Pfam: PF00514

UniProt features (72 total): helix 30, repeat 9, region of interest 6, sequence conflict 6, modified residue 5, sequence variant 5, mutagenesis site 5, strand 3, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1XM9	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13835-F1	68.91	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 4, 118, 119, 121, 142

Mutagenesis-validated functional residues (5):

Position	Phenotype
54	no effect on interaction with ywhag.
118	reduces the interaction with ywhag.
119	reduces the interaction with ywhag.
155	abolishes interaction with ywhag.
171	no effect on interaction with ywhag.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-351906	Apoptotic cleavage of cell adhesion proteins
R-HSA-6798695	Neutrophil degranulation
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope

MSigDB gene sets: 345 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_CYTOPLASMIC_TRANSLATION, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_KERATINOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN

GO Biological Process (16): desmosome assembly (GO:0002159), desmosome maintenance (GO:0002160), cell adhesion (GO:0007155), signal transduction (GO:0007165), positive regulation of gene expression (GO:0010628), positive regulation of cell-cell adhesion (GO:0022409), transepithelial water transport (GO:0035377), ameloblast differentiation (GO:0036305), intermediate filament bundle assembly (GO:0045110), positive regulation of keratinocyte differentiation (GO:0045618), positive regulation of transcription by RNA polymerase II (GO:0045944), cell-cell adhesion (GO:0098609), negative regulation of mRNA catabolic process (GO:1902373), positive regulation of protein localization to plasma membrane (GO:1903078), positive regulation of cap-dependent translational initiation (GO:1903676), positive regulation of protein localization to membrane (GO:1905477)

GO Molecular Function (7): DNA binding (GO:0003677), RNA binding (GO:0003723), lamin binding (GO:0005521), intermediate filament binding (GO:0019215), structural constituent of skin epidermis (GO:0030280), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (14): cornified envelope (GO:0001533), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), intermediate filament (GO:0005882), plasma membrane (GO:0005886), adherens junction (GO:0005912), cytoplasmic stress granule (GO:0010494), desmosome (GO:0030057), perinuclear region of cytoplasm (GO:0048471), nuclear stress granule (GO:0097165), ficolin-1-rich granule membrane (GO:0101003), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Apoptotic cleavage of cellular proteins	1
Innate Immune System	1
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
desmosome organization	2
cellular process	2
nucleic acid binding	2
binding	2
cell-cell junction	2
cell-cell junction assembly	1
cell-cell junction maintenance	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
water transport	1
epithelial fluid transport	1
columnar/cuboidal epithelial cell differentiation	1
cellular component assembly	1
intermediate filament organization	1
keratinocyte differentiation	1
positive regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
positive regulation of multicellular organismal process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell adhesion	1
mRNA catabolic process	1
positive regulation of gene expression	1
regulation of mRNA catabolic process	1
negative regulation of RNA catabolic process	1
negative regulation of mRNA metabolic process	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
positive regulation of protein localization to cell periphery	1
positive regulation of protein localization to membrane	1

Protein interactions and networks

STRING

1096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PKP1	DSP	P15924	982
PKP1	DSG1	Q02413	959
PKP1	JUP	P14923	886
PKP1	DSG3	P32926	835
PKP1	EIF4A1	P04765	820
PKP1	EVPL	Q92817	775
PKP1	DSG2	Q14126	763
PKP1	PPL	O60437	724
PKP1	PLEC	Q15149	708
PKP1	DSC3	Q14574	706
PKP1	SHOC2	Q9UQ13	695
PKP1	DSC2	Q02487	667
PKP1	PKP3	Q9Y446	644
PKP1	KRT5	P13647	624
PKP1	DSG4	Q86SJ6	598

IntAct

97 interactions, top by confidence:

A	B	Type	Score
SMARCB1	ARID1A	psi-mi:“MI:0914”(association)	0.860
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
KIF3A	KIF3C	psi-mi:“MI:0914”(association)	0.730
JADE1	KAT7	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ANXA9	PPL	psi-mi:“MI:0914”(association)	0.660
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
CAPZA2	CNOT1	psi-mi:“MI:0914”(association)	0.640
MYC	ACTL6A	psi-mi:“MI:0914”(association)	0.610
PKP1	TNS2	psi-mi:“MI:0915”(physical association)	0.560
TNS2	PKP1	psi-mi:“MI:0915”(physical association)	0.560
ARAF	BAG2	psi-mi:“MI:0914”(association)	0.530
GOSR1	SEC22B	psi-mi:“MI:0914”(association)	0.530
CA8	IGLL5	psi-mi:“MI:0914”(association)	0.530
NDUFS5	NDUFS4	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
RBM24	PPL	psi-mi:“MI:0914”(association)	0.530
CPLX3	CIAO1	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
TFG	CRYAB	psi-mi:“MI:0914”(association)	0.530
SPICE1	SERPINB2	psi-mi:“MI:0914”(association)	0.530
PKP1	GTF2IRD1	psi-mi:“MI:0915”(physical association)	0.510
GTF2IRD1	PKP1	psi-mi:“MI:0915”(physical association)	0.510
DSG1	PKP1	psi-mi:“MI:0407”(direct interaction)	0.440
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
ARMC8	PKP1	psi-mi:“MI:0915”(physical association)	0.370
FOXI2	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (164): TENC1 (Two-hybrid), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Affinity Capture-MS), PKP1 (Proximity Label-MS), PKP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4K859, A0A644F649, A0JMA8, A1Z7A6, A1Z7L1, A1ZBE8, A5D8W1, A8WTE8, A8X811, A8XBZ8, B0CM26, B0VXE6, E7F187, F4JY37, G5EDY0, G5EEV2, O17237, O17581, P21541, P25054, P38937, P40061, P49816, P70039, P70478, Q10953, Q13835, Q17423, Q18825, Q21106, Q22560, Q24592, Q5U245, Q61037, Q61315, Q61A92, Q61QK6, Q641A2, Q8BH53, Q8IGJ0

Diamond homologs: B0BF33, F1M7L9, O35116, O35927, P97350, Q08DQ0, Q13835, Q28161, Q68FH0, Q99569, Q99959, Q9CQ73, Q9QY23, Q9UQB3, Q9Y446, B4F7F3, O00192, O60716, P30999, P98203, Q8AXM9, Q9U308, Q9C9A6, Q86V71, Q8NHA8, Q96N38

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
AKT2	“up-regulates quantity by stabilization”	PKP1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

396 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	2
Uncertain significance	211
Likely benign	62
Benign	94

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
429879	NM_001005337.3(PKP1):c.1840C>T (p.Gln614Ter)	Pathogenic
7603	NM_001005337.3(PKP1):c.910C>T (p.Gln304Ter)	Pathogenic
7604	NM_001005337.3(PKP1):c.1107_1134dup (p.Val379fs)	Pathogenic
7605	NM_001005337.3(PKP1):c.1233-2A>T	Pathogenic
812568	NM_001005337.3(PKP1):c.2021+1G>A	Pathogenic
812569	NM_001005337.3(PKP1):c.889del (p.Arg297fs)	Pathogenic
812570	NM_001005337.3(PKP1):c.1233-2A>G	Pathogenic
1339041	NM_001005337.3(PKP1):c.203-1G>C	Likely pathogenic
495106	NM_001005337.3(PKP1):c.841C>T (p.Gln281Ter)	Likely pathogenic

SpliceAI

1976 predictions. Top by Δscore:

Variant	Effect	Δscore
1:201283901:CGAG:C	donor_loss	1.0000
1:201283902:GAGGT:G	donor_loss	1.0000
1:201293936:CTCTA:C	acceptor_loss	1.0000
1:201293937:TCTA:T	acceptor_loss	1.0000
1:201293938:CTAG:C	acceptor_loss	1.0000
1:201293939:TAGGT:T	acceptor_loss	1.0000
1:201293940:A:AG	acceptor_gain	1.0000
1:201293940:A:C	acceptor_loss	1.0000
1:201293941:G:GG	acceptor_gain	1.0000
1:201294042:TCCGG:T	donor_loss	1.0000
1:201294044:CGGTA:C	donor_loss	1.0000
1:201294046:G:GG	donor_gain	1.0000
1:201294046:GT:G	donor_loss	1.0000
1:201294047:T:G	donor_loss	1.0000
1:201313159:T:TA	acceptor_gain	1.0000
1:201313165:GATCT:G	acceptor_gain	1.0000
1:201313450:G:GT	donor_gain	1.0000
1:201313558:CAAG:C	donor_loss	1.0000
1:201313559:AAG:A	donor_loss	1.0000
1:201313560:AGTG:A	donor_loss	1.0000
1:201313561:G:A	donor_loss	1.0000
1:201313561:G:GG	donor_gain	1.0000
1:201313562:T:A	donor_loss	1.0000
1:201316551:A:AG	acceptor_gain	1.0000
1:201316551:A:T	acceptor_loss	1.0000
1:201316551:AG:A	acceptor_gain	1.0000
1:201316552:G:GA	acceptor_gain	1.0000
1:201316552:GG:G	acceptor_gain	1.0000
1:201316677:G:GT	donor_gain	1.0000
1:201316693:AACAG:A	donor_loss	1.0000

AlphaMissense

4814 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:201316645:G:A	G265E	1.000
1:201316657:T:A	I269N	1.000
1:201316670:C:G	C273W	1.000
1:201316671:T:C	F274L	1.000
1:201316673:C:A	F274L	1.000
1:201316673:C:G	F274L	1.000
1:201317659:C:A	R312S	1.000
1:201317671:T:C	F316L	1.000
1:201317673:C:A	F316L	1.000
1:201317673:C:G	F316L	1.000
1:201318633:T:C	L357P	1.000
1:201322012:T:C	L482P	1.000
1:201316599:G:C	A250P	0.999
1:201316600:C:A	A250D	0.999
1:201316612:T:C	L254P	0.999
1:201316644:G:A	G265R	0.999
1:201316644:G:C	G265R	0.999
1:201316644:G:T	G265W	0.999
1:201316647:G:C	A266P	0.999
1:201316648:C:A	A266D	0.999
1:201316657:T:G	I269S	0.999
1:201316668:T:C	C273R	0.999
1:201316669:G:A	C273Y	0.999
1:201316672:T:C	F274S	0.999
1:201316691:G:C	K280N	0.999
1:201316691:G:T	K280N	0.999
1:201317600:T:C	L292P	0.999
1:201317657:T:C	L311P	0.999
1:201317660:G:C	R312P	0.999
1:201317662:A:G	N313D	0.999

dbSNP variants (sampled 300 via entrez): RS1000030675 (1:201305402 A>C,G), RS1000249463 (1:201308815 C>T), RS1000266168 (1:201314674 G>A), RS1000310640 (1:201303606 T>G), RS1000398278 (1:201309365 G>A), RS1000699752 (1:201314473 C>A), RS1000787109 (1:201308196 C>G,T), RS1000876770 (1:201292720 G>A), RS1000881414 (1:201287425 T>C,G), RS1000960081 (1:201330256 T>G), RS1001003726 (1:201319449 A>G), RS1001043605 (1:201323872 C>G), RS1001048920 (1:201287572 T>C), RS1001162343 (1:201281884 T>C), RS1001295109 (1:201309314 G>A)

Disease associations

OMIM: gene MIM:601975 | disease phenotypes: MIM:604536

GenCC curated gene-disease

Disease	Classification	Inheritance
epidermolysis bullosa simplex due to plakophilin deficiency	Definitive	Autosomal recessive

Mondo (1): epidermolysis bullosa simplex due to plakophilin deficiency (MONDO:0011472)

Orphanet (1): Ectodermal dysplasia-skin fragility syndrome (Orphanet:158668)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000561	Absent eyelashes
HP:0000670	Carious teeth
HP:0000966	Hypohidrosis
HP:0000968	Ectodermal dysplasia
HP:0000970	Anhidrosis
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001030	Fragile skin
HP:0001288	Gait disturbance
HP:0001508	Failure to thrive
HP:0001581	Recurrent skin infections
HP:0002028	Chronic diarrhea
HP:0002223	Absent eyebrow
HP:0002289	Alopecia universalis
HP:0002293	Alopecia of scalp
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0005218	Anoperineal fistula
HP:0006482	Abnormal dental morphology
HP:0006532	Recurrent pneumonia
HP:0007446	Palmoplantar blistering
HP:0007502	Follicular hyperkeratosis
HP:0008066	Abnormal blistering of the skin
HP:0008070	Sparse hair
HP:0008391	Dystrophic fingernails
HP:0008404	Nail dystrophy
HP:0012227	Urethral stricture

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000320_4	Panic disorder	5.000000e-08
GCST011011_49	Youthful appearance (self-reported)	8.000000e-10

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536183	Ectodermal Dysplasia-Skin Fragility Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295817 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Tetrachlorodibenzodioxin	increases expression	2
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
terbufos	increases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
dibenzo(a,l)pyrene	decreases expression	1
pentanal	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
CGP 52608	affects binding, increases reaction	1
incobotulinumtoxinA	decreases expression	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Air Pollutants	increases abundance, decreases expression	1
Amphotericin B	increases expression	1
Diacetyl	decreases expression	1
Fonofos	increases methylation	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Lasalocid	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Methapyrilene	affects methylation	1
Methotrexate	decreases expression	1
Parathion	increases methylation	1
Ribonucleotides	affects binding	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118585	Binding	Binding affinity to PKP1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.