Arrhythmogenic right ventricular dysplasia 11

Summary

Arrhythmogenic right ventricular dysplasia 11 (MONDO:0012506) is a disease caused by DSC2 (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (3 cohort genes).

At a glance

• Causal gene: DSC2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,348

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular dysplasia 11
Mondo ID	MONDO:0012506
MeSH	C566471
OMIM	610476
DOID	DOID:0110082
UMLS	C1864850
MedGen	351237
GARD	0024870
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 11 · arrhythmogenic right ventricular dysplasia 11 · arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair · arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and wooly hair · arrhythmogenic right ventricular dysplasia type 11 · arrhythmogenic right ventricular dysplasia, familial, 11 · arrhythmogenic right ventricular dysplasia, familial, 11, and mild palmoplantar keratoderma with or without woolly hair · arrhythmogenic right ventricular dysplasia, familial, 11, with mild palmoplantar keratoderma and woolly hair · arrhythmogenic right ventricular dysplasia, familial, type 11 · ARVC11 · ARVD11 · DSC2 familial isolated arrhythmogenic right ventricular dysplasia · familial isolated arrhythmogenic right ventricular dysplasia caused by mutation in DSC2

Data availability: 1,348 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › familial isolated arrhythmogenic right ventricular dysplasia › arrhythmogenic right ventricular dysplasia 11

Related subtypes (15): arrhythmogenic right ventricular dysplasia 13, arrhythmogenic right ventricular dysplasia 1, arrhythmogenic right ventricular dysplasia 3, arrhythmogenic right ventricular dysplasia 4, arrhythmogenic right ventricular dysplasia 5, arrhythmogenic right ventricular dysplasia 6, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 8, arrhythmogenic right ventricular dysplasia 9, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular dysplasia 12, familial isolated arrhythmogenic ventricular dysplasia, left dominant form, familial isolated arrhythmogenic ventricular dysplasia, biventricular form, familial isolated arrhythmogenic ventricular dysplasia, right dominant form, arrhythmogenic right ventricular dysplasia, familial, 14

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

281 uncertain significance, 193 likely benign, 70 conflicting classifications of pathogenicity, 25 pathogenic, 17 benign/likely benign, 7 likely pathogenic, 4 benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068704	NM_024422.6(DSC2):c.729del (p.Phe243fs)	DSC2	Pathogenic	criteria provided, single submitter
1074769	NM_024422.6(DSC2):c.110_114del (p.Leu37fs)	DSC2	Pathogenic	criteria provided, single submitter
1075964	NM_024422.6(DSC2):c.1571del (p.Thr524fs)	DSC2	Pathogenic	criteria provided, single submitter
1319918	NM_024422.6(DSC2):c.685del (p.Pro228_Leu229insTer)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1322771	NM_024422.6(DSC2):c.1858C>T (p.Gln620Ter)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1338897	NM_024422.6(DSC2):c.30G>A (p.Trp10Ter)	DSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359544	NM_024422.6(DSC2):c.1720_1733del (p.Asn573_Ser574insTer)	DSC2	Pathogenic	criteria provided, single submitter
1381031	NM_024422.6(DSC2):c.2136dup (p.Thr713fs)	DSC2	Pathogenic	criteria provided, single submitter
1405349	NM_024422.6(DSC2):c.1053_1059del (p.His351fs)	DSC2	Pathogenic	criteria provided, single submitter
1429683	NM_024422.6(DSC2):c.1023dup (p.Ile342fs)	DSC2	Pathogenic	criteria provided, single submitter
1451178	NM_024422.6(DSC2):c.2084G>A (p.Trp695Ter)	DSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455627	NM_024422.6(DSC2):c.1840_1841dup (p.Ser614fs)	DSC2	Pathogenic	criteria provided, single submitter
162504	NM_024422.6(DSC2):c.663T>A (p.Tyr221Ter)	DSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16848	NM_024422.6(DSC2):c.1430del (p.Thr477fs)	DSC2	Pathogenic	no assertion criteria provided
1750194	NM_024422.6(DSC2):c.587_597del (p.Tyr196fs)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1779905	NM_024422.6(DSC2):c.1777G>T (p.Glu593Ter)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1967841	NM_024422.6(DSC2):c.929delinsTT (p.Gln310fs)	DSC2	Pathogenic	criteria provided, single submitter
2024891	NM_024422.6(DSC2):c.991C>T (p.Gln331Ter)	DSC2	Pathogenic	criteria provided, single submitter
2132520	NM_024422.6(DSC2):c.1260del (p.Lys421fs)	DSC2	Pathogenic	criteria provided, single submitter
235909	NM_024422.6(DSC2):c.1660C>T (p.Gln554Ter)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2413319	NM_024422.6(DSC2):c.1187T>G (p.Leu396Ter)	DSC2	Pathogenic	criteria provided, single submitter
2426820	NC_000018.9:g.(?28681846)(28681934_?)del	DSC2	Pathogenic	criteria provided, single submitter
2426821	NC_000018.9:g.(?28673522)(28673606_?)del	DSC2	Pathogenic	criteria provided, single submitter
2705962	NM_024422.6(DSC2):c.1187dup (p.Leu396fs)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
2824457	NM_024422.6(DSC2):c.2203C>T (p.Gln735Ter)	DSC2	Pathogenic	criteria provided, single submitter
2835126	NM_024422.6(DSC2):c.2136del (p.Phe712fs)	DSC2	Pathogenic	criteria provided, single submitter
2866650	NM_024422.6(DSC2):c.2307T>A (p.Cys769Ter)	DSC2	Pathogenic	criteria provided, single submitter
2880847	NM_024422.6(DSC2):c.686del (p.Leu229fs)	DSC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1067443	NM_024422.6(DSC2):c.474+1G>T	DSC2	Likely pathogenic	criteria provided, single submitter
1482220	NM_024422.6(DSC2):c.2250+1G>C	DSC2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DSC2	Definitive	Semidominant	arrhythmogenic right ventricular dysplasia 11	7
DSC3	Definitive	Semidominant	arrhythmogenic right ventricular dysplasia 11	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSC2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSC2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSC2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSC3	Orphanet:217407	Hereditary hypotrichosis with recurrent skin vesicles

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSC2	HGNC:3036	ENSG00000134755	Q02487	Desmocollin-2	gencc,clinvar
DSC3	HGNC:3037	ENSG00000134762	Q14574	Desmocollin-3	gencc,clinvar
DSC1	HGNC:3035	ENSG00000134765	Q08554	Desmocollin-1	clinvar
DSCAS	HGNC:51116	ENSG00000265888		DSC1/DSC2 antisense RNA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSC2	Desmocollin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
DSC3	Desmocollin-3	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
DSC1	Desmocollin-1	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSC2	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin
DSC3	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin
DSC1	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin_pro_dom
DSCAS	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
upper leg skin	2
oral cavity	1
skin of hip	1
upper arm skin	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSC2	256	ubiquitous	marker	gingival epithelium, gingiva, oral cavity
DSC3	177	broad	marker	upper leg skin, gingival epithelium, gingiva
DSC1	102	tissue_specific	marker	upper leg skin, skin of hip, upper arm skin
DSCAS	119	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSC2	1,659
DSC3	1,474
DSC1	831
DSCAS	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DSC2	Q02487	3
DSC1	Q08554	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DSC3	Q14574	75.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the cornified envelope	3	87.8×	4e-06	DSC2, DSC3, DSC1
Keratinization	3	55.7×	9e-06	DSC2, DSC3, DSC1
Neutrophil degranulation	1	7.7×	0.124	DSC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
homophilic cell-cell adhesion	3	140.4×	5e-06	DSC2, DSC3, DSC1
cell-cell adhesion	3	101.5×	7e-06	DSC2, DSC3, DSC1
desmosome maintenance	1	2808.7×	0.001	DSC1
cardiac muscle cell-cardiac muscle cell adhesion	1	2808.7×	0.001	DSC2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	1	802.5×	0.004	DSC2
regulation of ventricular cardiac muscle cell action potential	1	468.1×	0.005	DSC2
cell adhesion	2	25.0×	0.005	DSC2, DSC3
positive regulation of p38MAPK cascade	1	208.1×	0.009	DSC2
hair follicle morphogenesis	1	165.2×	0.010	DSC1
establishment of skin barrier	1	151.8×	0.010	DSC1
regulation of heart rate by cardiac conduction	1	124.8×	0.011	DSC2
negative regulation of epithelial cell proliferation	1	96.8×	0.013	DSC1
cellular response to starvation	1	64.6×	0.018	DSC2
in utero embryonic development	1	24.0×	0.044	DSC3
protein stabilization	1	22.3×	0.044	DSC3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSC1	1	2
DSC2	0	0
DSC3	0	0
DSCAS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DSC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DSC1	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	DSC1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	DSC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	DSC2, DSC3, DSCAS

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DSC2	0	—
DSC3	0	—
DSCAS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.