DSP

Chr 6ADAR

desmoplakin

A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:25733715). Critical for cell-cell adhesion in early stage blastocysts and progression through proamniotic cavity formation (By similarity). Not required for preimplantation morphogenic process in blastocysts (By similarity). Required for keratin filament anchoring at the desmosome junction and subsequent organization of the keratin intermediate filament network within the cytoplasm (By similarity). Required for anchoring of desmosomes to the microtubule architecture, via its interaction with NIN (By similarity). Plays a key role in adhesion and organization of the dermal epithelial barrier (By similarity). Critical for the maintenance of the neural tube structure following formation and organization of the neuroepithelium (By similarity). 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 (By similarity). Required for the normal formation of the heart, also required for development of vascular capillary structures and intact endothelial cell barriers (By similarity). Regulates profibrotic gene expression in cardiomyocytes via activation of the MAPK14/p38 MAPK signaling cascade and increase in TGFB1 protein abundance (By similarity). Maintains cardiac rhythmicity by ensuring correct cell-cell adhesion within the sinoatrial node, via stabilization of protein components of both desmosome and Gap junctions (By similarity). Involved in maintaining the protein stability and recruitment of GJA1 to functional gap junctions, via inhibition of KRAS-mediated MAPK1/MAPK3 phosphorylation of GJA1 (By similarity). Required for the survival and maintenance of germ cells in the gonads during embryonic development (By similarity). Binds to telomere DNA (via C-terminus) and acts to prevent telomere damage and maintain telomere length via its interaction with TRF2 (PubMed:31595153)

Primary Disease Associations & Inheritance

Arrhythmogenic right ventricular dysplasia 8MIM #607450
AD
Cardiomyopathy, dilated, with woolly hair and keratodermaMIM #605676
AR
Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesisMIM #615821
AD
Epidermolysis bullosa, lethal acantholyticMIM #609638
AR
Keratosis palmoplantaris striata IIMIM #612908
AD
UniProtKeratoderma, palmoplantar, striate 2
578
ClinVar variants
82
Pathogenic / LP
1.00
pLI score· haploinsufficient
7
Active trials
Clinical SummaryDSP
🧬
Gene-Disease Validity (ClinGen)
hypertrophic cardiomyopathy · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
82 Pathogenic / Likely Pathogenic· 334 VUS of 578 total submissions
💊
Clinical Trials
7 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.26LOEUF
pLI 1.000
Z-score 8.61
OE 0.18 (0.130.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.60Z-score
OE missense 0.96 (0.921.00)
1446 obs / 1511.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.18 (0.130.26)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.96 (0.921.00)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
01.21.6
LoF obs/exp: 24 / 129.9Missense obs/exp: 1446 / 1511.1Syn Z: -0.95

ClinVar Variant Classifications

578 submitted variants in ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic20
VUS334
Likely Benign159
Conflicting3
62
Pathogenic
20
Likely Pathogenic
334
VUS
159
Likely Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
39
0
23
0
62
Likely Pathogenic
13
1
6
0
20
VUS
5
314
14
1
334
Likely Benign
0
12
38
109
159
Benign
0
0
0
0
0
Conflicting
3
Total5732781110578

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DSP · protein map & ClinVar variants

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

Gene2Phenotype Curations

DSP-related arrhythmogenic right ventricular cardiomyopathy

definitive
ARLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Cardiac
G2P ↗
splice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletioninframe insertion

DSP-related arrhythmogenic right ventricular cardiomyopathy

definitive
ADLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Cardiac
G2P ↗
splice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletioninframe insertion

DSP-related hypertrophic cardiomyopathy

disputed
ADUndeterminedUncertain
Cardiac
G2P ↗

DSP-related dilated cardiomyopathy

definitive
ADUndeterminedAltered Gene Product Structure, Increased Gene Product Level
Cardiac
G2P ↗
frameshift variantmissense variantstop gained NMD triggeringsplice donor variant NMD triggeringsplice acceptor variant NMD triggering

DSP-related palmoplantar keratoderma, striate

definitive
ADLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

DSP-related developmental disorder

moderate
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

DSP-related skin fragility, woolly hair

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

DESMOPLAKIN; DSP
MIM #125647 · *

Arrhythmogenic right ventricular dysplasia 8

MIM #607450

Molecular basis of disorder known

Autosomal dominant

Cardiomyopathy, dilated, with woolly hair and keratoderma

MIM #605676

Molecular basis of disorder known

Autosomal recessive

Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis

MIM #615821

Molecular basis of disorder known

Autosomal dominant

Epidermolysis bullosa, lethal acantholytic

MIM #609638

Molecular basis of disorder known

Autosomal recessive

Keratosis palmoplantaris striata II

MIM #612908

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — DSP
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Top 10 resultsSearch PubMed ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

Recurrent Endometrial CarcinomaRecurrent Endometrial Clear Cell AdenocarcinomaRecurrent Endometrial Endometrioid Adenocarcinoma

Testing Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer

RECRUITING
NCT05950464Phase PHASE1National Cancer Institute (NCI)Started 2023-12-18
BET Bromodomain Inhibitor ZEN-3694Biopsy ProcedureBiospecimen Collection
Hepatocellular Carcinoma (HCC)

Radiation Therapy Followed by Durvalumab (MEDI4736) and Tremelimumab And Surgery Versus Radiation Therapy Followed by Surgery for Resectable Hepatocellular Carcinoma.

NOT YET RECRUITING
NCT07027436Phase PHASE3Hamilton Health Sciences CorporationStarted 2025-07-07
Chemotherapy/Radiation
Other Skin Changes Due to Chronic Exposure to Nonionizing Radiation

SUV PDL1/PD1 in Sun Damaged & Sun Protected Human Skin of Participants

RECRUITING
NCT06177106Phase NAUniversity of ArizonaStarted 2023-12-26
Solar Simulated Light
CardiomyopathiesGenetic PredispositionCardiomyopathy, Primary

Biomarkers in SCOTland CardiomyopatHy Registry (Bio-SCOTCH)

RECRUITING
NCT06446271NHS Greater Glasgow and ClydeStarted 2024-06-26
Plasma biomarker levels
Head and Neck Squamous Cell Carcinoma

PBI-MST-01 (NCT04541108) Substudy AZN-05: Intratumoral Microdosing of Rilvegostomig, Volrustomig, Sabestomig, and AZD9592 in HNSCC

RECRUITING
NCT06366451Phase EARLY_PHASE1Presage BiosciencesStarted 2024-05-22
RilvegostomigVolrustomigSabestomig
Arrhythmogenic Cardiomyopathies

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

RECRUITING
NCT05450783Nantes University HospitalStarted 2022-09-01
Biocollection
Metastatic Colorectal Cancer (mCRC)

DHF-20-1839-2: Clinical Performance Study Protocol for Therascreen® KRAS RGQ PCR Kit

RECRUITING
NCT06645236Phase NAQIAGEN Gaithersburg, IncStarted 2023-12-22
therascreen® KRAS RGQ PCR Kit