The desmoplakin protein anchors intermediate filaments to desmosomal plaques and is essential for cell-cell adhesion in desmosomes. Mutations cause a spectrum of cardiomyopathies (including arrhythmogenic right ventricular dysplasia and dilated cardiomyopathy) often combined with skin abnormalities such as keratoderma, woolly hair, and in severe cases lethal acantholytic epidermolysis bullosa. The gene shows both autosomal dominant and autosomal recessive inheritance patterns and is highly constrained against loss-of-function variants.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAD/ARLOEUF 0.265 OMIM phenotypes
Clinical SummaryDSP
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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.
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Clinical Trials
7 active or recruiting trials — potential therapeutic options may be available
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GeneReview available — DSP
Authoritative clinical overview · Recommended first read
Open GeneReview ↗
Some data sources returned errors (1)

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

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
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
0.60Z-score
OE missense 0.96 (0.921.00)
1446 obs / 1511.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.18 (0.130.26)
00.351.4
Missense OE0.96 (0.921.00)
00.61.4
Synonymous OE1.05
01.21.6
LoF obs/exp: 24 / 129.9Missense obs/exp: 1446 / 1511.1Syn Z: -0.95
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveDSP-related arrhythmogenic right ventricular cardiomyopathyLOFAR
definitiveDSP-related arrhythmogenic right ventricular cardiomyopathyLOFAD
limitedDSP-related hypertrophic cardiomyopathyOTHERAD
definitiveDSP-related dilated cardiomyopathyOTHERAD
definitiveDSP-related palmoplantar keratoderma, striateLOFAD
moderateDSP-related developmental disorderOTHERAD
definitiveDSP-related skin fragility, woolly hairLOFAR
DN
0.5869th %ile
GOF
0.6248th %ile
LOF
0.53top 25%

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports loss-of-function (haploinsufficiency) as the primary mechanism.

LOF1 literature citation · LOEUF 0.26

Literature Evidence

LOFThe investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof.PMID:23137101

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants 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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

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
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
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
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
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
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
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
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