DES

Chr 2ADAR

desmin

Also known as: CDCD3, CSM1, CSM2, LGMD1D, LGMD1E, LGMD2R

NCBI Gene: 1674 ENSG00000175084 UniProt: P17661

This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Cardiomyopathy, dilated, 1IMIM #604765

Myopathy, myofibrillar, 1MIM #601419

ADAR

Scapuloperoneal syndrome, neurogenic, Kaeser typeMIM #181400

UniProtNeurogenic scapuloperoneal syndrome Kaeser type

Active trials

Pathogenic / LP

494

ClinVar variants

Pubs (1 yr)

1.8

Missense Z

0.60

LOEUF

Clinical Summary— DES

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Gene-Disease Validity (ClinGen)

arrhythmogenic right ventricular cardiomyopathy · ADModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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ClinVar Variants

50 Pathogenic / Likely Pathogenic· 279 VUS of 494 total submissions

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Clinical Trials

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

📖

GeneReview available — DES

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.60LOEUF

pLI 0.009

Z-score 3.05

OE 0.33 (0.19–0.60)

Moderately constrained

More LoF-intolerant than ~75% 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.

1.77Z-score

OE missense 0.71 (0.63–0.79)

206 obs / 291.1 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.0.33 (0.19–0.60)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.63–0.79)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.87

0≤1.21.6

LoF obs/exp: 8 / 24.2Missense obs/exp: 206 / 291.1Syn Z: 1.11

0.96top 5%

GOF

0.87top 5%

LOF

0.1598th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNWe conclude that the L345P desmin missense mutation causes myopathy by interfering in a dominant-negative manner with the dimerization-polymerization process of intermediate filament assembly.PMID:10545598

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

494 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic23

VUS279

Likely Benign158

Benign1

Conflicting6

Pathogenic

Likely Pathogenic

279

VUS

158

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	2	13	0	27
Likely Pathogenic	14	6	3	0	23
VUS	8	240	27	4	279
Likely Benign	1	2	60	95	158
Benign	0	0	1	0	1
Conflicting	—				6
Total	35	250	104	99	494

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

View in ClinVar →

Protein Context — Lollipop Plot

DES · protein map & ClinVar variants

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

Gene2Phenotype Curations

DES-related myofibrillar myopathy

definitive

ARUndeterminedAbsent Gene Product, Altered Gene Product Structure

Cardiac

G2P ↗

missense variantinframe deletionstop gained NMD triggeringstop gained NMD escapingframeshift variant NMD triggeringsplice acceptor variant NMD escapingsplice donor variant NMD escapingframeshift variant NMD escaping

DES-related myofibrillar myopathy

definitive

ADUndeterminedAbsent Gene Product, Altered Gene Product Structure

Cardiac

G2P ↗

DES-related dilated cardiomyopathy

definitive

ADUndeterminedAltered Gene Product Structure

Cardiac

G2P ↗

missense variantsplice acceptor variant NMD escaping

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

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

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GeneReview available — DES

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Hemophilia A

Study to Test the Safety and How Well Patients With Severe Hemophilia A Respond to Treatment With BAY 2599023 (DTX 201), a Drug Therapy That Delivers a Healthy Version of the Defective Factor VIII Gene Into the Nucleus of Liver Cells Using an Altered, Non-infectious Virus (AAV) as a "Shuttle"

ACTIVE NOT RECRUITING

NCT03588299Phase PHASE1, PHASE2BayerStarted 2018-11-07

BAY2599023 (DTX201)

Breast AdenocarcinomaEstrogen Receptor NegativeHER2/Neu Negative

Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer

ACTIVE NOT RECRUITING

NCT02488967Phase PHASE3NRG OncologyStarted 2015-07-26

CarboplatinCyclophosphamideDoxorubicin Hydrochloride

Endometriosis

" Development of Primary Cultures of Diaphragmatic Myoblasts for Basic Research Purposes "

NOT YET RECRUITING

NCT07380308Assistance Publique - Hôpitaux de ParisStarted 2026-02-01

During the surgery planned as part of the routine care of the patient, a part of the tissue sample will be saved in order to carry out the analysis planned for the research.

StrokeAtrial Fibrillation

Biological Bank for Atrial Fibrillation and Stroke

RECRUITING

NCT03611816Hospices Civils de LyonStarted 2018-04-23

Blood takenBlood takenBlood taken

Recurrent Non-Small Cell Lung CarcinomaStage IV Non-Small Cell Lung Cancer

Maintenance Chemotherapy With or Without Local Consolidative Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer

ACTIVE NOT RECRUITING

NCT03137771Phase PHASE2NRG OncologyStarted 2017-04-07

3-Dimensional Conformal Radiation Therapy (3D-CRT)DocetaxelGemcitabine

Spinal Muscular Atrophy Type ISpinal Muscular Atrophy Type IISpinal Muscular Atrophy Type III

Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi

ACTIVE NOT RECRUITING

NCT04042025Phase PHASE3Novartis Gene TherapiesStarted 2020-02-10

Onasemnogene Abeparvovec-xioi

Recurrent MelanomaStage IIIA Cutaneous Melanoma AJCC v7Stage IIIB Cutaneous Melanoma AJCC v7

Ipilimumab With or Without High-Dose Recombinant Interferon Alfa-2b in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

ACTIVE NOT RECRUITING

NCT01708941Phase PHASE2National Cancer Institute (NCI)Started 2013-01-18

IpilimumabLaboratory Biomarker AnalysisRecombinant Interferon Alfa-2b

AnophthalmiaMicrophthalmiaAniridia

National Cohort on Congenital Defects of the Eye

RECRUITING

NCT05954403Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2017-07-11

Stage III Colon Cancer

Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease

RECRUITING

NCT05174169Phase PHASE2, PHASE3NRG OncologyStarted 2022-03-10

Signatera testmFOLFOX6 3-6 monthCAPOX 3 month

Clinical Stage III Cutaneous Melanoma AJCC v8Clinical Stage IV Cutaneous Melanoma AJCC v8Metastatic Cutaneous Melanoma

Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

ACTIVE NOT RECRUITING

NCT02506153Phase PHASE3National Cancer Institute (NCI)Started 2015-11-10

Biospecimen CollectionComputed TomographyIpilimumab

Previously Treated Non-Small Cell Lung Cancer

Lung-MAP: A Master Screening Protocol for Previously-Treated Non-Small Cell Lung Cancer

RECRUITING

NCT03851445Phase PHASE2, PHASE3SWOG Cancer Research NetworkStarted 2019-02-06

Screening Platform

Asthma; EosinophilicSevere Asthma

Predictive Signature of Benralizumab Response

RECRUITING

NCT04565483Phase PHASE4Nantes University HospitalStarted 2021-10-11