DSP

Chr 6ADAR

desmoplakin

Also known as: DCWHKTA, DP

NCBI Gene: 1832 ENSG00000096696 UniProt: P15924 OMIM: 125647

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.265 OMIM phenotypes

Clinical Summary— DSP

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Gene-Disease Validity (ClinGen)

hypertrophic cardiomyopathy · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

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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

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 1.000

Z-score 8.61

OE 0.18 (0.13–0.26)

Highly constrained

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

Missense Constraint?

0.60Z-score

OE missense 0.96 (0.92–1.00)

1446 obs / 1511.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.13–0.26)

0≤0.351.4

Missense OE?0.96 (0.92–1.00)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

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

This gene — mechanism propensity

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 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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

References

1.PMID 23137101 ↗

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

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

CardiomyopathiesGenetic PredispositionCardiomyopathy, Primary

Biomarkers in SCOTland CardiomyopatHy Registry (Bio-SCOTCH)

RECRUITING

NCT06446271NHS Greater Glasgow and ClydeStarted 2024-06-26

Plasma biomarker levels

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

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

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

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

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