DSP

Summary

DSP (desmoplakin, HGNC:3052) is a protein-coding gene on chromosome 6p24.3, encoding Desmoplakin (P15924). A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1832 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arrhythmogenic cardiomyopathy with wooly hair and keratoderma (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 33
• Clinical variants (ClinVar): 6,050 total — 517 pathogenic, 194 likely-pathogenic
• Phenotypes (HPO): 110
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3052
Approved symbol	DSP
Name	desmoplakin
Location	6p24.3
Locus type	gene with protein product
Status	Approved
Aliases	KPPS2, PPKS2, DPI, DPII, DP
Ensembl gene	ENSG00000096696
Ensembl biotype	protein_coding
OMIM	125647
Entrez	1832

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 6 nonsense_mediated_decay, 4 retained_intron

ENST00000379802, ENST00000418664, ENST00000506617, ENST00000682228, ENST00000683563, ENST00000683682, ENST00000684395, ENST00000710359, ENST00000713869, ENST00000713903, ENST00000713904, ENST00000713909, ENST00000713910, ENST00000713911, ENST00000713912, ENST00000713913, ENST00000713918, ENST00000713924

RefSeq mRNA: 4 — MANE Select: NM_004415 NM_001008844, NM_001319034, NM_001406591, NM_004415

CCDS: CCDS4501, CCDS47368

Canonical transcript exons

ENST00000379802 — 24 exons

Exon	Start	End
ENSE00001154944	7578464	7578562
ENSE00001154954	7577779	7577886
ENSE00001154962	7576959	7577042
ENSE00001154968	7576294	7576456
ENSE00001154975	7575295	7575488
ENSE00001154978	7574657	7574795
ENSE00001154981	7574086	7574252
ENSE00001154985	7571842	7572068
ENSE00001154992	7571383	7571584
ENSE00001154996	7570437	7570563
ENSE00001155002	7569186	7569340
ENSE00001155008	7568437	7568589
ENSE00001155013	7567781	7567906
ENSE00001155018	7567354	7567449
ENSE00001155330	7566377	7566481
ENSE00001155338	7565359	7565520
ENSE00001155357	7559226	7559400
ENSE00001155361	7558116	7558264
ENSE00001155370	7555718	7555820
ENSE00003488058	7562652	7562780
ENSE00003691486	7563736	7563786
ENSE00004021647	7579275	7581569
ENSE00004021766	7541671	7542085
ENSE00004021782	7582642	7586714

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.5201 / max 7657.2682, expressed in 1325 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65658	33.2920	1053
65657	16.9911	1031
65656	3.3531	607
65653	2.8164	798
65678	2.2549	541
65679	2.0247	512
65703	1.6463	496
65655	1.5381	642
65677	0.8801	341
65681	0.7223	288

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of hip	UBERON:0001554	99.86	gold quality
upper leg skin	UBERON:0004262	99.84	gold quality
hair follicle	UBERON:0002073	99.83	gold quality
penis	UBERON:0000989	99.80	gold quality
gingival epithelium	UBERON:0001949	99.80	gold quality
gingiva	UBERON:0001828	99.79	gold quality
cervix squamous epithelium	UBERON:0006922	99.78	gold quality
mammalian vulva	UBERON:0000997	99.77	gold quality
squamous epithelium	UBERON:0006914	99.76	gold quality
upper arm skin	UBERON:0004263	99.75	gold quality
esophagus squamous epithelium	UBERON:0006920	99.73	gold quality
oral cavity	UBERON:0000167	99.72	gold quality
tongue squamous epithelium	UBERON:0006919	99.70	gold quality
nipple	UBERON:0002030	99.68	gold quality
pharyngeal mucosa	UBERON:0000355	99.63	gold quality
cervix epithelium	UBERON:0004801	99.53	gold quality
skin of abdomen	UBERON:0001416	99.39	gold quality
epithelium of nasopharynx	UBERON:0001951	99.36	gold quality
zone of skin	UBERON:0000014	99.34	gold quality
body of tongue	UBERON:0011876	99.29	gold quality
heart right ventricle	UBERON:0002080	99.19	gold quality
jejunal mucosa	UBERON:0000399	99.18	gold quality
skin of leg	UBERON:0001511	99.16	gold quality
left ventricle myocardium	UBERON:0006566	99.01	gold quality
lower esophagus mucosa	UBERON:0035834	98.93	gold quality
epithelium of esophagus	UBERON:0001976	98.83	gold quality
tongue	UBERON:0001723	98.81	gold quality
myocardium	UBERON:0002349	98.76	gold quality
esophagus mucosa	UBERON:0002469	98.76	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.63	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	2121.08
E-HCAD-23	yes	1248.30
E-CURD-79	yes	884.17
E-MTAB-10662	yes	425.70
E-HCAD-1	yes	285.73
E-GEOD-124472	yes	217.11
E-MTAB-6701	yes	119.83
E-CURD-114	yes	56.30
E-MTAB-10287	yes	44.82
E-HCAD-31	yes	26.63
E-HCAD-10	yes	25.26
E-MTAB-6678	yes	16.98
E-MTAB-9388	yes	7.82
E-GEOD-130148	yes	5.23
E-MTAB-10596	no	3981.02

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, LEF1, PKP1, PKP3, SATB1, TCF12

miRNA regulators (miRDB)

65 targeting DSP, 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-513A-5P	100.00	69.77	2465
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. haploinsufficiency (PMID:11841538)
• non-small cell lung carcinoma subtypes have specific patterns of desmoplakin 1 and 2 and cytokeratin 18 gene expression, protein content and biodistribution (PMID:11955647)
• Mutation (S299R) in exon 7 of desmoplakin causes arrhythmogenic right ventricular cardiomyopathy, unlinked to other causes. (PMID:12373648)
• desmoplakin has a role in capillary formation (PMID:15190119)
• terminal tail is responsible for discerning among binding of factors to the armadillo domain (PMID:15381698)
• Naxos disease is not caused by the desmoplakin gene mutation in an arab family. (PMID:15494820)
• the involvement of desmoplakin (DP), plectin, and periplakin in the destruction of epithelial cell integrity ensures the efficient elimination of cytoskeleton, but also provides specificity for selectively targeting individual adhesion molecules (PMID:15500642)
• dominant mutation in desmoplakin that causes left-sided arrhythmogenic left ventricular cardiomyopathywith arrhythmias of left ventricular origin. (PMID:16061754)
• dramatic phenotype, which we named “lethal acantholytic epidermolysis bullosa,” underscores the paramount role of desmoplakin in epidermal integrity (PMID:16175511)
• Our data are consistent with the idea that DP assembles into nascent junctions from both diffusible and particulate pools in a temporally overlapping series of events triggered by cell-cell contact and regulated by actin and DP-IF interactions. (PMID:16365169)
• This is the first description of a phenotype caused by a mutation affecting only one DSP isoform. (PMID:16467215)
• A novel insertion mutation in desmoplakin is associated with early death from cardiomyopathy in a family with dominant striate palmoplantar keratoderma and wooly hair. (PMID:16628197)
• Mutation analysis of 66 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. A cause and effect relationship between those DSP missense mutations and ARVD/C was extablished. (PMID:16917092)
• Dp may participate in the regulation of keratinocyte cell proliferation by, in part at least, regulating cell cycle progression (PMID:17475244)
• The Ki67+ proliferation index was inversely correlated with desmoplakin and plakophilin-1 during cervical squamous cell carcinogenesis (PMID:17593084)
• Mutations in the desmosome genes were identified in four of the five patients (three with a DSG2 mutation and one with a DSP mutation). Five gene mutations were noted in four patients and all mutations were novel (one patient had a DSG2 double mutation). (PMID:18632414)
• Loss-of-function mutations in the DSP gene can result in a phenotype similar to ectodermal dysplasia-skin fragility syndrome resulting from PKP1 mutations but only DSP pathology is associated with cardiac disease (PMID:19016709)
• Three proteins were significantly elevated in PTB cases: desmoplakin isoform 1, stratifin, and thrombospondin 1 precursor, providing a foundation for further validation in larger patient cohorts. (PMID:19271751)
• Altered DSP expression at transcriptional and protein levels provides prognostic information in human oropharyngeal cancer. (PMID:19386346)
• we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth (PMID:19924139)
• Lethal acantholytic epidermolysis bullosa (LAEB) is an autosomal recessive disorder caused by mutations in the gene encoding the desmosomal protein, desmoplakin (DSP) (PMID:19945626)
• A novel minor isoform of desmoplakin that is also produced by alternative splicing of the desmoplakin gene, is described. (PMID:20524011)
• Full sequencing of the DSP showed a novel homozygous c.7097 G>A (p.R2366H) mutation in all skin fragility-woolly hair syndrome affected family members. (PMID:20738328)
• Studies identified two mutations in DSG2, four in DSC2, two in DSP, four in JUP and seven in PKP2. (PMID:20864495)
• autosomal-dominant mutations in the DSP gene are associated with hypo/oligodontia in the setting of Carvajal/Naxos syndrome (PMID:20940358)
• SERCA2-deficient cells exhibited up to a 60% reduction in border translocation of desmoplakin (DP), the desmosomal cytolinker protein necessary for intermediate filament (IF) anchorage to sites of robust cell-cell adhesion (PMID:21156808)
• We detected a novel mutations: DSP T1373A and it may be associated with a risk for tachycardia (PMID:21397041)
• A novel nonsense mutation in the desmoplakin gene and the truncated protein which it produces caused left dominant arrhythmogenic cardiomyopathy (PMID:21458130)
• intimate intramolecular association of the SH3 domain with the preceding SR is also observed in plectin, another plakin protein suggesting that the SH3 domain of plakins contributes to the stability and rigidity of this subfamily of SR-containing proteins (PMID:21536047)
• Mutations in desmoplakin protein is associated with cardiomyopathy. (PMID:21756917)
• Case Report: desmoplakin mutation responsible for juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma. (PMID:21789513)
• DP Ser2849Gly promotes hyperadhesion (PMID:21993560)
• Palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. (PMID:22132232)
• desmoplakin is a promising candidate for supportive CSF marker to rule out 14-3-3 false positive cases in sporadic Creutzfeldt-Jakob disease differential diagnosis. (PMID:22213780)
• Desmoplakin disease causes connexin mislocalization in the mouse & man preceding overt histological abnormalities resulting in significant alterations in conduction repolarization kinetics prior to morphological changes detectable on cardiac imaging (PMID:22240500)
• desmoplakin I levels, determined within 1-3 months of the first ischemic stroke, could be a biomarker for statin responsiveness against a new vascular event in post-ischemic stroke patients taking statins (PMID:22304020)
• DSP splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes. (PMID:22454510)
• DSP is inactivated in lung cancer by an epigenetic mechanism, increases the sensitivity to anticancer drug-induced apoptosis and has tumor-suppressive function, possibly through inhibition of the Wnt/beta-catenin signaling pathway in NSCLC cells. (PMID:22791817)
• Desmoplakin and pGSK3beta constitute independent good prognostic factors for progression free survival in Ewing Sarcoma patients. (PMID:22898789)
• In two unrelated patients with Naxos-Carvajal syndrome, a single heterozygous de novo mutation in the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile, leading to severe phenotypes was found. (PMID:22949226)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	eppk1	ENSDARG00000096359
mus_musculus	Dsp	ENSMUSG00000054889
rattus_norvegicus	Dsp	ENSRNOG00000013928

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), PLEC (ENSG00000178209), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Desmoplakin — P15924 (reviewed: P15924)

Alternative names: 250/210 kDa paraneoplastic pemphigus antigen

All UniProt accessions (10): P15924, A0A804HL18, A0AAQ5BH17, A0AAQ5BH21, A0AAQ5BH40, A0AAQ5BH43, A0AAQ5BH50, A0AAQ5BH53, A0AAQ5BH65, A0AAQ5BH69

UniProt curated annotations — full annotation on UniProt →

Function. A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. Critical for cell-cell adhesion in early stage blastocysts and progression through proamniotic cavity formation. Not required for preimplantation morphogenic process in blastocysts. Required for keratin filament anchoring at the desmosome junction and subsequent organization of the keratin intermediate filament network within the cytoplasm. Required for anchoring of desmosomes to the microtubule architecture, via its interaction with NIN. Plays a key role in adhesion and organization of the dermal epithelial barrier. Critical for the maintenance of the neural tube structure following formation and organization of the neuroepithelium. Facilitates outgrowth and repair of motor neuron fibers in regenerating axons following injury, probably by promoting recruitment of a complex containing DSP, CDH2, VIM and JUP to the outgrowth tips. Required for the normal formation of the heart, also required for development of vascular capillary structures and intact endothelial cell barriers. Regulates profibrotic gene expression in cardiomyocytes via activation of the MAPK14/p38 MAPK signaling cascade and increase in TGFB1 protein abundance. Maintains cardiac rhythmicity by ensuring correct cell-cell adhesion within the sinoatrial node, via stabilization of protein components of both desmosome and Gap junctions. Involved in maintaining the protein stability and recruitment of GJA1 to functional gap junctions, via inhibition of KRAS-mediated MAPK1/MAPK3 phosphorylation of GJA1. Required for the survival and maintenance of germ cells in the gonads during embryonic development. Binds to telomere DNA (via C-terminus) and acts to prevent telomere damage and maintain telomere length via its interaction with TRF2.

Subunit / interactions. Homodimer. Identified in a complex containing at least DSP, JUP, VIM and CDH2; the complex is more abundant following crush injury in regenerating motor neurons and may promote axon outgrowth and motor fiber repair. Interacts with COL17A1 (via cytoplasmic region). Interacts with DSC2. Interacts with PKP2. Interacts with PKP1. Interacts weakly with TMEM65. Interacts with NIN: the interaction facilitates recruitment of NIN to desmosome cell-cell junctions. Interacts with TRF2 in the nucleus; the interaction is required for DSP telomere binding.

Subcellular location. Cell projection. Axon. Cell junction. Desmosome. Cell membrane. Cytoplasm. Nucleus.

Tissue specificity. Expressed in oral mucosa (at protein level). Expressed in arrector pili muscle (at protein level). Expressed in the heart in the heart (at protein level). Apparently an obligate constituent of all desmosomes. Resides predominantly in tissues and cells of stratified origin.

Post-translational modifications. Methylation by PRMT1 promotes GSK3B-mediated phosphorylation cascade of multiple serine residues at the C-terminus resulting in trafficking to desmosome cell-cell junctions. Phosphorylation by GSK3B occurs sequentially from Ser-2849 along multiple serine residue at the C-terminus. Hyperphosphorylation by GSK3B results in recruitment to desmosome cell-cell junction and promotion of intercellular adhesion. Phosphorylation at Ser-2849 increases association with intermediate filament cytokeratin, potentially facilitating interaction between desmosome junctions and intermediate filament architecture.

Disease relevance. Keratoderma, palmoplantar, striate 2 (SPPK2) [MIM:612908] A dermatological disorder characterized by thickening of the skin on the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities of the nails, the teeth and the hair are rarely present. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, with woolly hair and keratoderma (DCWHK) [MIM:605676] An autosomal recessive cardiocutaneous syndrome characterized by a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and dilated left ventricular cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry. Arrhythmogenic right ventricular dysplasia, familial, 8 (ARVD8) [MIM:607450] A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. The disease is caused by variants affecting the gene represented in this entry. Epidermolysis bullosa, lethal acantholytic (EBLA) [MIM:609638] A form of epidermolysis bullosa characterized by severe fragility of skin and mucous membranes. The phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. Typical features include universal alopecia, neonatal teeth, and nail loss. Histopathology of the skin shows suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, with woolly hair, keratoderma, and tooth agenesis (DCWHKTA) [MIM:615821] A cardiocutaneous syndrome characterized by biventricular dilated cardiomyopathy, hyperkeratosis, woolly hair, palmoplantar keratoderma, and hypo/oligodontia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminal region is required for localization to the desmosomal plaque and interacts with the N-terminal region of PKP1.

Miscellaneous. Minor isoform.

Similarity. Belongs to the plakin or cytolinker family.

Isoforms (3)

UniProt ID	Names	Canonical?
P15924-1	DPI, DP1	yes
P15924-2	DPII, DP2
P15924-3	DSPIa

RefSeq proteins (4): NP_001008844, NP_001305963, NP_001393520, NP_004406* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001101	Plectin_repeat	Repeat
IPR001452	SH3_domain	Domain
IPR018159	Spectrin/alpha-actinin	Repeat
IPR035915	Plakin_repeat_sf	Homologous_superfamily
IPR041573	Desmoplakin_Spectrin-like	Domain
IPR041615	Desmoplakin_SH3	Domain
IPR043197	Plakin	Family

Pfam: PF00681, PF17902, PF18373, PF21019

UniProt features (205 total): helix 51, modified residue 34, strand 33, repeat 24, turn 20, sequence variant 16, region of interest 10, mutagenesis site 5, sequence conflict 3, compositionally biased region 3, splice variant 2, chain 1, coiled-coil region 1, short sequence motif 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1LM5	X-RAY DIFFRACTION	1.8
5DZZ	X-RAY DIFFRACTION	2.6
3R6N	X-RAY DIFFRACTION	2.95
1LM7	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

No AlphaFold model available for P15924 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (34): 22, 53, 56, 61, 165, 166, 176, 1658, 1708, 2024, 2207, 2209, 2225, 2810, 2815, 2817, 2820, 2821, 2825, 2826 …

Mutagenesis-validated functional residues (5):

Position	Phenotype
1122–1126	abolishes localization to the nucleus and binding to telomeres.
2834	decreases interaction with gsk3b resulting in a significant decrease in gsk3b-mediated phosphorylation of multiple downs
2845	abolishes gsk3b phosphorylation of multiple downstream sites within the c-terminus and decreases interaction with gsk3b.
2849	decreases cell-cell adhesion when under mechanical stress.
2853	no effect on gsk3b-mediated phosphorylation of multiple downstream sites within the c-terminus.

Function

Pathways and Gene Ontology

Reactome pathways

6 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
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696273	RND1 GTPase cycle

MSigDB gene sets: 541 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_BUNDLE_OF_HIS_CELL_TO_PURKINJE_MYOCYTE_COMMUNICATION, BROWNE_HCMV_INFECTION_6HR_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, JAEGER_METASTASIS_DN

GO Biological Process (16): desmosome organization (GO:0002934), ventricular compact myocardium morphogenesis (GO:0003223), epidermis development (GO:0008544), peptide cross-linking (GO:0018149), keratinocyte differentiation (GO:0030216), adherens junction organization (GO:0034332), wound healing (GO:0042060), skin development (GO:0043588), intermediate filament cytoskeleton organization (GO:0045104), intermediate filament organization (GO:0045109), bundle of His cell-Purkinje myocyte adhesion involved in cell communication (GO:0086073), regulation of heart rate by cardiac conduction (GO:0086091), epithelial cell-cell adhesion (GO:0090136), cell-cell adhesion (GO:0098609), regulation of ventricular cardiac muscle cell action potential (GO:0098911), protein localization to cell-cell junction (GO:0150105)

GO Molecular Function (7): RNA binding (GO:0003723), protein kinase C binding (GO:0005080), structural molecule activity (GO:0005198), structural constituent of cytoskeleton (GO:0005200), cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication (GO:0086083), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (16): cornified envelope (GO:0001533), nucleus (GO:0005634), cytoplasm (GO:0005737), intermediate filament (GO:0005882), plasma membrane (GO:0005886), adherens junction (GO:0005912), fascia adherens (GO:0005916), intercalated disc (GO:0014704), basolateral plasma membrane (GO:0016323), desmosome (GO:0030057), extracellular exosome (GO:0070062), ficolin-1-rich granule membrane (GO:0101003), cytoskeleton (GO:0005856), cell-cell junction (GO:0005911), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RHO GTPase cycle	2
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
cell-cell junction	3
cell-cell junction organization	2
cytoskeleton organization	2
cellular anatomical structure	2
ventricular cardiac muscle tissue morphogenesis	1
tissue development	1
protein modification process	1
epidermal cell differentiation	1
skin development	1
response to wounding	1
tissue regeneration	1
animal organ development	1
intermediate filament-based process	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
heterotypic cell-cell adhesion	1
cardiac muscle cell-cardiac muscle cell adhesion	1
bundle of His cell to Purkinje myocyte communication	1
regulation of heart rate	1
cardiac conduction	1
cell-cell adhesion	1
cell adhesion	1
regulation of cardiac muscle cell contraction	1
ventricular cardiac muscle cell action potential	1
regulation of cardiac muscle cell action potential	1
protein localization to cell junction	1
nucleic acid binding	1
protein kinase binding	1
molecular_function	1
structural molecule activity	1
cytoskeleton	1
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1
protein binding involved in heterotypic cell-cell adhesion	1
protein binding	1
binding	1
plasma membrane	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
intermediate filament cytoskeleton	1
polymeric cytoskeletal fiber	1

Protein interactions and networks

STRING

2124 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DSP	PKP2	Q99959	999
DSP	DSG2	Q14126	995
DSP	DSG1	Q02413	994
DSP	DSC2	Q02487	993
DSP	JUP	P14923	993
DSP	PKP1	Q13835	982
DSP	CDH17	Q12864	925
DSP	EVPL	Q92817	923
DSP	PPL	O60437	892
DSP	DSC3	Q14574	881
DSP	DSG3	P32926	867
DSP	CTNNB1	P35222	854
DSP	KRT18	P05783	849
DSP	TJP1	Q07157	837
DSP	PKP4	Q99569	837

IntAct

258 interactions, top by confidence:

A	B	Type	Score
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
NCK1	NCK2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAPRE1	DSP	psi-mi:“MI:0915”(physical association)	0.630
DSP	MAPRE1	psi-mi:“MI:2364”(proximity)	0.630
DSP	MAPRE1	psi-mi:“MI:0403”(colocalization)	0.630
PECAM1	JUP	psi-mi:“MI:0914”(association)	0.610
JUP	DSP	psi-mi:“MI:0915”(physical association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
DSP	FES	psi-mi:“MI:0915”(physical association)	0.560
FES	DSP	psi-mi:“MI:0914”(association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
ARAF	BAG2	psi-mi:“MI:0914”(association)	0.530
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530

BioGRID (515): DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), DSP (Affinity Capture-MS), KRT1 (Co-fractionation), KRT16 (Co-fractionation), DSP (Reconstituted Complex), DSP (Affinity Capture-MS), DSP (Proximity Label-MS), DSP (Proximity Label-MS)

ESM2 similar proteins: A0A8M2BID5, A0A8M9PQ61, A1Z7A6, D3ZHV2, E9Q557, F1LMV6, F1M0Z1, G3V7L1, O43150, O60229, O60437, O75962, O97592, O97902, P0CE94, P0CE95, P10911, P11530, P11531, P11532, P11533, P15924, P30427, P33175, P46939, Q03001, Q0KL02, Q15149, Q1AAU6, Q1LUA6, Q5GN48, Q6ZWR6, Q7SIG6, Q8CIS0, Q8NF91, Q8WXH0, Q91ZU6, Q92817, Q95RG8, Q9BXL7

Diamond homologs: A0A8M2BID5, A0A8M9PQ61, D3ZHV2, E9Q557, F1LMV6, P15924, P30427, P58107, Q15149, Q8R0W0, Q92817, Q9D952, Q9JI55, Q9QXS1, O60437, Q9R269, A5D7D1, D3ZEN0, D3ZHA0, D3ZQL6, F1QH17, G3MWR8, G3V7L1, L7UZ85, M9MRD1, O13728, O15020, O43707, O75369, O76329, O88990, O94854, O97592, P05094, P05095, P11277, P11530, P11531, P11532, P11533

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKACA	“down-regulates activity”	DSP	phosphorylation
PKP2	“up-regulates quantity by stabilization”	DSP	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 213 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF-independent MAPK1/3 activation	5	20.6×	4e-04
Loss of Nlp from mitotic centrosomes	12	12.4×	4e-08
Loss of proteins required for interphase microtubule organization from the centrosome	12	12.4×	4e-08
Dengue Virus Genome Translation and Replication	6	12.4×	6e-04
Co-stimulation by CD28	5	12.4×	2e-03
AURKA Activation by TPX2	12	11.9×	5e-08
Recruitment of NuMA to mitotic centrosomes	14	10.6×	3e-08
Recruitment of mitotic centrosome proteins and complexes	12	10.6×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	11.0×	5e-03
endocytosis	10	5.0×	9e-03
negative regulation of apoptotic process	17	3.1×	9e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — NPC.

Clinical variants and AI predictions

ClinVar

6050 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	517
Likely pathogenic	194
Uncertain significance	2641
Likely benign	1586
Benign	116

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012338	NM_004415.4(DSP):c.748C>T (p.Gln250Ter)	Pathogenic
1034083	NM_004415.4(DSP):c.5664_5667del (p.Ser1888fs)	Pathogenic
1068839	NM_004415.4(DSP):c.2832del (p.Glu945fs)	Pathogenic
1069300	NM_004415.4(DSP):c.3494dup (p.Glu1166fs)	Pathogenic
1069659	NM_004415.4(DSP):c.1439del (p.Asp480fs)	Pathogenic
1069787	NM_004415.4(DSP):c.4337_4338insTGCT (p.Gln1446fs)	Pathogenic
1069816	NM_004415.4(DSP):c.7082dup (p.His2363fs)	Pathogenic
1069979	NM_004415.4(DSP):c.2834_2835del (p.Glu945fs)	Pathogenic
1070194	NM_004415.4(DSP):c.4882del (p.Arg1628fs)	Pathogenic
1070495	NM_004415.4(DSP):c.5671_5674del (p.Glu1891fs)	Pathogenic
1070496	NM_004415.4(DSP):c.6562del (p.Glu2188fs)	Pathogenic
1070590	NM_004415.4(DSP):c.4201G>T (p.Glu1401Ter)	Pathogenic
1071031	NM_004415.4(DSP):c.5806C>T (p.Gln1936Ter)	Pathogenic
1071053	NM_004415.4(DSP):c.1339C>T (p.Gln447Ter)	Pathogenic
1071328	NM_004415.4(DSP):c.3465G>A (p.Trp1155Ter)	Pathogenic
1071932	NM_004415.4(DSP):c.4434dup (p.Lys1479Ter)	Pathogenic
1072004	NM_004415.4(DSP):c.5014C>T (p.Gln1672Ter)	Pathogenic
1072032	NM_004415.4(DSP):c.3338del (p.Arg1113fs)	Pathogenic
1072033	NM_004415.4(DSP):c.1656C>G (p.Tyr552Ter)	Pathogenic
1072294	NM_004415.4(DSP):c.2655del (p.Lys886fs)	Pathogenic
1072769	NM_004415.4(DSP):c.1186del (p.Gln396fs)	Pathogenic
1073737	NM_004415.4(DSP):c.894G>A (p.Trp298Ter)	Pathogenic
1073940	NM_004415.4(DSP):c.2903dup (p.Tyr968Ter)	Pathogenic
1074224	NM_004415.4(DSP):c.2223T>G (p.Tyr741Ter)	Pathogenic
1074954	NM_004415.4(DSP):c.3045del (p.Arg1015fs)	Pathogenic
1074955	NM_004415.4(DSP):c.3535C>T (p.Gln1179Ter)	Pathogenic
1075135	NM_004415.4(DSP):c.2185dup (p.Met729fs)	Pathogenic
1075169	NM_004415.4(DSP):c.3094del (p.Thr1032fs)	Pathogenic
1075207	NM_004415.4(DSP):c.3739C>T (p.Arg1247Ter)	Pathogenic
1075228	NC_000006.11:g.(?7565582)(7569583_?)del	Pathogenic

SpliceAI

2148 predictions. Top by Δscore:

Variant	Effect	Δscore
6:7542086:G:GG	donor_gain	1.0000
6:7542087:T:A	donor_loss	1.0000
6:7555703:T:TA	acceptor_gain	1.0000
6:7555707:T:A	acceptor_gain	1.0000
6:7555715:TAGTC:T	acceptor_loss	1.0000
6:7555716:A:AG	acceptor_gain	1.0000
6:7555716:A:G	acceptor_loss	1.0000
6:7555717:G:GA	acceptor_gain	1.0000
6:7555717:GT:G	acceptor_gain	1.0000
6:7555717:GTC:G	acceptor_gain	1.0000
6:7555717:GTCA:G	acceptor_gain	1.0000
6:7555717:GTCAA:G	acceptor_gain	1.0000
6:7555816:AGCCT:A	donor_gain	1.0000
6:7555817:GCCT:G	donor_gain	1.0000
6:7555817:GCCTG:G	donor_gain	1.0000
6:7555818:CCT:C	donor_gain	1.0000
6:7555818:CCTG:C	donor_loss	1.0000
6:7555819:CT:C	donor_gain	1.0000
6:7555819:CTG:C	donor_loss	1.0000
6:7555820:TGT:T	donor_loss	1.0000
6:7555821:G:GG	donor_gain	1.0000
6:7555821:GTAAG:G	donor_loss	1.0000
6:7555822:T:G	donor_loss	1.0000
6:7558111:TTCA:T	acceptor_loss	1.0000
6:7558112:TCAG:T	acceptor_loss	1.0000
6:7558113:CAGG:C	acceptor_loss	1.0000
6:7558114:A:AG	acceptor_gain	1.0000
6:7558114:AGGA:A	acceptor_loss	1.0000
6:7558115:G:GG	acceptor_gain	1.0000
6:7558260:AAAAG:A	donor_loss	1.0000

AlphaMissense

19069 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:7565387:T:C	L269P	1.000
6:7565396:T:C	L272P	1.000
6:7565473:T:A	W298R	1.000
6:7565473:T:C	W298R	1.000
6:7565475:G:C	W298C	1.000
6:7565475:G:T	W298C	1.000
6:7566393:T:C	L319P	1.000
6:7566414:T:C	L326P	1.000
6:7567370:T:C	L354P	1.000
6:7567381:T:A	W358R	1.000
6:7567381:T:C	W358R	1.000
6:7567387:T:A	W360R	1.000
6:7567387:T:C	W360R	1.000
6:7567394:T:C	L362P	1.000
6:7567424:T:C	L372P	1.000
6:7567815:T:C	L392P	1.000
6:7568521:C:A	R451S	1.000
6:7569243:T:A	W493R	1.000
6:7569243:T:C	W493R	1.000
6:7569245:G:C	W493C	1.000
6:7569245:G:T	W493C	1.000
6:7584041:T:A	I2260K	1.000
6:7584046:G:C	G2262R	1.000
6:7584047:G:A	G2262D	1.000
6:7584134:T:C	L2291S	1.000
6:7584137:T:C	L2292P	1.000
6:7584141:A:C	E2293D	1.000
6:7584141:A:T	E2293D	1.000
6:7584142:G:C	A2294P	1.000
6:7584148:G:C	A2296P	1.000

dbSNP variants (sampled 300 via entrez): RS1000100688 (6:7546964 A>G), RS1000350779 (6:7564501 G>A,C,T), RS1000403043 (6:7564766 A>G), RS1000455163 (6:7563925 A>T), RS1000555925 (6:7547298 T>G), RS1000659723 (6:7573543 A>C,G), RS1000671849 (6:7577390 G>T), RS1000743733 (6:7570859 T>C), RS1000760058 (6:7552644 C>T), RS1000765149 (6:7577537 A>G), RS1000961554 (6:7584871 G>C), RS1000993007 (6:7543172 T>A,C), RS1000994852 (6:7541495 G>A,C), RS1001014984 (6:7554498 T>C), RS1001053553 (6:7541270 C>G,T)

Disease associations

OMIM: gene MIM:125647 | disease phenotypes: MIM:605676, MIM:607450, MIM:609638, MIM:612908, MIM:615821, MIM:620415, MIM:107970, MIM:192600, MIM:607655, MIM:115195, MIM:603829, MIM:613426, MIM:609040, MIM:115210, MIM:115200, MIM:615508, MIM:600996, MIM:604772, MIM:604145, MIM:601144, MIM:192500, MIM:113900, MIM:194200, MIM:604169, MIM:606963, MIM:178500

GenCC curated gene-disease

Disease	Classification	Inheritance
arrhythmogenic cardiomyopathy with wooly hair and keratoderma	Definitive	Autosomal dominant
skin fragility-woolly hair-palmoplantar keratoderma syndrome	Definitive	Autosomal recessive
keratosis palmoplantaris striata 2	Definitive	Autosomal dominant
arrhythmogenic right ventricular dysplasia 8	Definitive	Autosomal dominant
lethal acantholytic epidermolysis bullosa	Strong	Autosomal recessive
cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	Strong	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
severe dermatitis-multiple allergies-metabolic wasting syndrome	Supportive	Autosomal recessive
striate palmoplantar keratoderma	Supportive	Autosomal dominant
hypertrophic cardiomyopathy	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Disputed	AD
arrhythmogenic cardiomyopathy with wooly hair and keratoderma	Definitive	AD

Mondo (49): cardiomyopathy (MONDO:0004994), arrhythmogenic cardiomyopathy with wooly hair and keratoderma (MONDO:0011581), arrhythmogenic right ventricular dysplasia 8 (MONDO:0011831), lethal acantholytic epidermolysis bullosa (MONDO:0012323), keratosis palmoplantaris striata 2 (MONDO:0013034), cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (MONDO:0014355), woolly hair-skin fragility syndrome (MONDO:0957307), familial isolated arrhythmogenic right ventricular dysplasia (MONDO:0016342), long QT syndrome (MONDO:0002442), hypertrophic cardiomyopathy (MONDO:0005045), ventricular tachycardia (MONDO:0005477), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), dilated cardiomyopathy (MONDO:0005021), familial hypertrophic cardiomyopathy (MONDO:0024573), skin fragility-woolly hair-palmoplantar keratoderma syndrome (MONDO:0011882)

Orphanet (30): Rare cardiomyopathy (Orphanet:167848), Carvajal syndrome (Orphanet:65282), Lethal acantholytic erosive disorder (Orphanet:158687), Skin fragility-woolly hair-palmoplantar keratoderma syndrome (Orphanet:293165), Erythrokeratodermia-cardiomyopathy syndrome (Orphanet:476096), Inherited isolated arrhythmogenic cardiomyopathy (Orphanet:217656), Rare hypertrophic cardiomyopathy (Orphanet:217569), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Dilated cardiomyopathy (Orphanet:217604), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Idiopathic ventricular fibrillation (Orphanet:228140), Restrictive cardiomyopathy (Orphanet:217632), Uhl anomaly (Orphanet:3403), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260)

HPO phenotypes

110 total (30 of 110 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000377	Abnormal pinna morphology
HP:0000407	Sensorineural hearing impairment
HP:0000561	Absent eyelashes
HP:0000653	Sparse eyelashes
HP:0000695	Natal tooth
HP:0000924	Abnormality of the skeletal system
HP:0000962	Hyperkeratosis
HP:0000969	Edema
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001030	Fragile skin
HP:0001036	Parakeratosis
HP:0001057	Aplasia cutis congenita
HP:0001063	Acrocyanosis
HP:0001159	Syndactyly
HP:0001233	2-3 finger cutaneous syndactyly
HP:0001279	Syncope
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001562	Oligohydramnios
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001626	Abnormality of the cardiovascular system
HP:0001635	Congestive heart failure

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST001968_3	Interstitial lung disease	1.000000e-19
GCST003488_12	Response to fenofibrate (triglyceride levels)	3.000000e-06
GCST003818_47	Resting heart rate	2.000000e-07
GCST004147_28	Chronic obstructive pulmonary disease	4.000000e-09
GCST004986_3	Idiopathic pulmonary fibrosis	8.000000e-28
GCST007429_13	Lung function (FVC)	2.000000e-08
GCST007431_138	Lung function (FEV1/FVC)	7.000000e-23
GCST007692_47	Chronic obstructive pulmonary disease	2.000000e-07
GCST009322_3	Numerical cognitive ability	2.000000e-06
GCST009758_16	Idiopathic pulmonary fibrosis	3.000000e-30
GCST010320_112	PR interval	1.000000e-15
GCST010321_7	PR interval	3.000000e-16
GCST010796_403	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-10
GCST010796_404	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-10
GCST010796_405	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-10
GCST010796_406	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-10
GCST010796_407	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-10
GCST010796_408	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_409	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_410	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_411	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_412	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_413	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_414	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-09
GCST010796_416	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST010796_417	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_418	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_419	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_420	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_421	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007681	triglyceride change measurement
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0004312	vital capacity
EFO:0004713	FEV/FVC ratio
EFO:0008354	cognitive function measurement
EFO:0004462	PR interval
EFO:0004327	electrocardiography

MeSH disease descriptors (31)

Descriptor	Name	Tree numbers
D000686	Amyloidosis	C18.452.845.500
D001020	Aortic Stenosis, Subvalvular	C14.280.484.048.750.070; C14.280.955.249.070
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D002313	Cardiomyopathy, Restrictive	C14.280.238.160
D006323	Heart Arrest	C14.280.383
D054143	Heart Failure, Systolic	C14.280.434.676
D006429	Hemiplegia	C10.597.622.295; C23.888.592.636.312
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008881	Migraine Disorders	C10.228.140.546.399.750
D009205	Myocarditis	C14.280.238.625
D029424	Pulmonary Disease, Chronic Obstructive	C08.381.495.389; C23.550.291.500.875
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C564400	Arrhythmogenic Right Ventricular Dysplasia, Familial, 8 (supp.)
C563808	Arrhythmogenic Right Ventricular Dysplasia, Familial, 9 (supp.)
C535581	Cardiomyopathy dilated with woolly hair and keratoderma (supp.)
C565824	Cardiomyopathy, Dilated, 1g (supp.)
C563538	Cardiomyopathy, Dilated, 1s (supp.)
C566171	Cardiomyopathy, Familial Hypertrophic, 2 (supp.)
C535493	Epidermolysis bullosa, lethal acantholytic (supp.)
C565102	Keratosis Palmoplantaris Striata II (supp.)
C564359	Skin Fragility-Woolly Hair Syndrome (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4742273 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066953 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2076295	DSP		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.54	Kd	287.7	nM	CHEMBL5653589
6.54	ED50	287.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148265: Binding affinity to human DSP incubated for 45 mins by Kinobead based pull down assay	kd	0.2877	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	7
trichostatin A	increases expression, affects cotreatment	4
sodium arsenite	affects methylation, affects binding, decreases reaction, decreases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
bisphenol A	decreases expression, increases expression	3
methylmercuric chloride	decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Cadmium	increases abundance, increases palmitoylation, affects binding, decreases reaction	2
Doxorubicin	increases expression, affects response to substance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, decreases reaction, increases abundance, increases palmitoylation	2
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
lead acetate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
IMOL S-140	increases expression	1
butyraldehyde	decreases expression	1
16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	decreases expression	1
cupric chloride	decreases expression	1
coumarin	decreases phosphorylation	1
triadimefon	decreases expression	1
artenimol	affects binding	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713764	Binding	Protac activity at CRBN/DSP in human BxPC-3 cells assessed as DSP degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Cellosaurus cell lines

10 cell lines: 10 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2EJ	HUBUi001-A	Induced pluripotent stem cell	Female
CVCL_A2EK	HUBUi002-A	Induced pluripotent stem cell	Male
CVCL_A2EL	HUBUi003-A	Induced pluripotent stem cell	Female
CVCL_A8KR	EHTJUi004-A	Induced pluripotent stem cell	Female
CVCL_C6Q1	ISCRMi001-A	Induced pluripotent stem cell	Female
CVCL_D0MM	UGENTi002-A	Induced pluripotent stem cell	Male
CVCL_D0MN	UGENTi002-A-1	Induced pluripotent stem cell	Male
CVCL_WP82	FAMRCi004-A	Induced pluripotent stem cell	Male
CVCL_WP83	FAMRCi004-B	Induced pluripotent stem cell	Male
CVCL_XD52	IBMS-iPSC-045-02	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy