Arrhythmogenic right ventricular dysplasia 10

Summary

Arrhythmogenic right ventricular dysplasia 10 (MONDO:0012434) is a disease caused by DSG2 (GenCC Definitive), with 6 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (3 cohort genes).

At a glance

• Causal gene: DSG2 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 1,544

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular dysplasia 10
Mondo ID	MONDO:0012434
MeSH	C565707
OMIM	610193
DOID	DOID:0110081
UMLS	C1857777
MedGen	347543
GARD	0024865
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 10 · arrhythmogenic right ventricular cardiomyopathy caused by mutation in DSG2 · arrhythmogenic right ventricular dysplasia 10 · arrhythmogenic right ventricular dysplasia type 10 · arrhythmogenic right ventricular dysplasia, familial, 10 · arrhythmogenic right ventricular dysplasia, familial, type 10 · ARVC10 · ARVD10 · DSG2 arrhythmogenic right ventricular cardiomyopathy

Data availability: 1,544 ClinVar variants · 5 GenCC gene-disease records · 5 cell lines.

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 10

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 11, 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:

284 uncertain significance, 165 likely benign, 98 conflicting classifications of pathogenicity, 20 pathogenic, 13 likely pathogenic, 12 benign/likely benign, 6 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075406	NM_001943.5(DSG2):c.676_680del (p.Thr226fs)	DSG2	Pathogenic	criteria provided, single submitter
1075858	NM_001943.5(DSG2):c.2480_2712del (p.Asp827fs)	DSG2	Pathogenic	criteria provided, single submitter
1075931	NM_001943.5(DSG2):c.1672C>T (p.Gln558Ter)	DSG2	Pathogenic	criteria provided, single submitter
1325803	NM_001943.5(DSG2):c.523+1G>T	DSG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1353815	NM_001943.5(DSG2):c.1705C>T (p.Gln569Ter)	DSG2	Pathogenic	criteria provided, single submitter
1387457	NM_001943.5(DSG2):c.613_658dup (p.Ile220delinsThrCysLeuSerSerSerValLeuProLysTer)	DSG2	Pathogenic	criteria provided, single submitter
1427568	NM_001943.5(DSG2):c.527_533del (p.Thr176fs)	DSG2	Pathogenic	criteria provided, single submitter
1455568	NM_001943.5(DSG2):c.27C>A (p.Tyr9Ter)	DSG2	Pathogenic	criteria provided, single submitter
1456782	NM_001943.5(DSG2):c.423del (p.Lys141fs)	DSG2	Pathogenic	criteria provided, single submitter
1459522	NM_001943.5(DSG2):c.917G>A (p.Trp306Ter)	DSG2	Pathogenic	criteria provided, single submitter
1459763	NC_000018.9:g.(?29115223)(29118951_?)del	DSG2	Pathogenic	criteria provided, single submitter
1459814	NM_001943.5(DSG2):c.909del (p.Asp304fs)	DSG2	Pathogenic	criteria provided, single submitter
16810	NM_001943.5(DSG2):c.146G>A (p.Arg49His)	DSG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16812	NM_001943.5(DSG2):c.137G>A (p.Arg46Gln)	DSG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1752786	NM_001943.5(DSG2):c.630del (p.Phe211fs)	DSG2	Pathogenic	criteria provided, multiple submitters, no conflicts
1793874	NM_001943.5(DSG2):c.2617C>T (p.Gln873Ter)	DSG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199800	NM_001943.5(DSG2):c.769C>T (p.Gln257Ter)	DSG2	Pathogenic	criteria provided, multiple submitters, no conflicts
199831	NM_001943.5(DSG2):c.2372_2373del (p.Thr791fs)	DSG2	Pathogenic	criteria provided, multiple submitters, no conflicts
2024795	NM_001943.5(DSG2):c.1759dup (p.Thr587fs)	DSG2	Pathogenic	criteria provided, single submitter
2093339	NM_001943.5(DSG2):c.912_941delinsAATTGGCTGGCAAATTTTACATTTGAAATGAAGGAGGTTATTTCCTTCATTTGAATTGGCTGGCAAATTTTACATTTGAAATGA (p.Asp304_Ser314delinsGluIleGlyTrpGlnIleLeuHisLeuLysTer)	DSG2	Pathogenic	criteria provided, single submitter
2110919	NM_001943.5(DSG2):c.361G>T (p.Glu121Ter)	DSG2	Pathogenic	criteria provided, single submitter
2118301	NM_001943.5(DSG2):c.290del (p.Pro97fs)	DSG2	Pathogenic	criteria provided, single submitter
2424328	NC_000018.9:g.(?29115213)(29126706_?)del	DSG2	Pathogenic	criteria provided, single submitter
2572599	NM_001943.5(DSG2):c.382del (p.Thr128fs)	DSG2	Pathogenic	criteria provided, single submitter
2573007	NM_001943.5(DSG2):c.1211C>G (p.Ser404Ter)	DSG2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1701778	NM_001943.5(DSG2):c.2990del (p.Gly997fs)	DSG2-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066747	NM_001943.5(DSG2):c.1423+1G>T	DSG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068205	NM_001943.5(DSG2):c.379-1G>A	DSG2	Likely pathogenic	criteria provided, single submitter
1296982	NM_001943.5(DSG2):c.1015-2A>C	DSG2	Likely pathogenic	criteria provided, single submitter
1301518	NM_001943.5(DSG2):c.829-2A>T	DSG2	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 18 · 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
DSG2	Definitive	Autosomal dominant	arrhythmogenic right ventricular dysplasia 10	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DSG2	Orphanet:154	Familial isolated dilated cardiomyopathy
DSG2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSG2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSG2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DYNC2H1	Orphanet:474	Jeune syndrome
DYNC2H1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:93270	Short rib-polydactyly syndrome, Saldino-Noonan type
DYNC2H1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
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
PRKAR1A	Orphanet:1359	Carney complex
PRKAR1A	Orphanet:1501	Adrenocortical carcinoma
PRKAR1A	Orphanet:520	Acute promyelocytic leukemia
PRKAR1A	Orphanet:615	Familial atrial myxoma
PRKAR1A	Orphanet:647772	Isolated primary pigmented nodular adrenocortical disease
PRKAR1A	Orphanet:950	Acrodysostosis

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DSG2	HGNC:3049	ENSG00000046604	Q14126	Desmoglein-2	gencc,clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
DSC2	HGNC:3036	ENSG00000134755	Q02487	Desmocollin-2	clinvar
DSC3	HGNC:3037	ENSG00000134762	Q14574	Desmocollin-3	clinvar
DSG2-AS1	HGNC:51311	ENSG00000264859		DSG2 antisense RNA 1	clinvar
PRKAR1A	HGNC:9388	ENSG00000108946	P10644	cAMP-dependent protein kinase type I-alpha regulatory subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DSG2	Desmoglein-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.
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.
PRKAR1A	cAMP-dependent protein kinase type I-alpha regulatory subunit	Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 6 · 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	6	1.8×	0.030

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DSG2	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
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
DSG2-AS1	Other/Unknown	no
PRKAR1A	Other/Unknown	no		cNMP-bd_dom, cAMP_dep_PK_reg_su_I/II_a/b, cAMP_dep_PK_reg_su

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	2
gingival epithelium	2
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
bronchial epithelial cell	1
right uterine tube	1
secondary oocyte	1
oral cavity	1
upper leg skin	1
buccal mucosa cell	1
oocyte	1
sperm	1
germinal epithelium of ovary	1
lateral nuclear group of thalamus	1
mucosa of paranasal sinus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DSG2	238	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, jejunal mucosa
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
DSC2	256	ubiquitous	marker	gingival epithelium, gingiva, oral cavity
DSC3	177	broad	marker	upper leg skin, gingival epithelium, gingiva
DSG2-AS1	124		marker	oocyte, buccal mucosa cell, sperm
PRKAR1A	295	ubiquitous	marker	mucosa of paranasal sinus, germinal epithelium of ovary, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAR1A	3,586
DSG2	2,033
DYNC2H1	1,885
DSC2	1,659
DSC3	1,474
DSG2-AS1	0

Intra-cohort edges

A	B	Sources
DSC2	DSG2	intact, string_interaction
DSC3	DSG2	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DSG2	Q14126	12
DYNC2H1	Q8NCM8	4
DSC2	Q02487	3
PRKAR1A	P10644	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DSC3	Q14574	75.53

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. Enrichment computed across 6 evidence-associated genes (5 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 5 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	52.7×	8e-04	DSG2, DSC2, DSC3
Keratinization	3	33.4×	0.002	DSG2, DSC2, DSC3
Hedgehog ‘off’ state	2	71.4×	0.006	DYNC2H1, PRKAR1A
Apoptotic cleavage of cell adhesion proteins	1	207.6×	0.041	DSG2
ALK mutants bind TKIs	1	190.3×	0.041	PRKAR1A
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	175.7×	0.041	PRKAR1A
PKA activation in glucagon signalling	1	134.3×	0.041	PRKAR1A
PKA activation	1	126.9×	0.041	PRKAR1A
PKA-mediated phosphorylation of CREB	1	114.2×	0.041	PRKAR1A
DARPP-32 events	1	95.2×	0.041	PRKAR1A
Anti-inflammatory response favouring Leishmania parasite infection	1	78.8×	0.041	PRKAR1A
Leishmania parasite growth and survival	1	78.8×	0.041	PRKAR1A
Calmodulin induced events	1	76.1×	0.041	PRKAR1A
CaM pathway	1	76.1×	0.041	PRKAR1A
Ca-dependent events	1	73.7×	0.041	PRKAR1A
Aquaporin-mediated transport	1	73.7×	0.041	PRKAR1A
Glucagon signaling in metabolic regulation	1	69.2×	0.041	PRKAR1A
G-protein mediated events	1	65.3×	0.041	PRKAR1A
DAG and IP3 signaling	1	63.4×	0.041	PRKAR1A
Response of endothelial cells to shear stress	1	60.1×	0.041	PRKAR1A
FCGR3A-mediated IL10 synthesis	1	58.6×	0.041	PRKAR1A
Signaling by ALK in cancer	1	54.4×	0.041	PRKAR1A
Opioid Signalling	1	53.1×	0.041	PRKAR1A
PLC beta mediated events	1	53.1×	0.041	PRKAR1A
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	53.1×	0.041	PRKAR1A
Vasopressin regulates renal water homeostasis via Aquaporins	1	53.1×	0.041	PRKAR1A
Cellular responses to mechanical stimuli	1	51.9×	0.041	PRKAR1A
ADORA2B mediated anti-inflammatory cytokines production	1	50.8×	0.041	PRKAR1A
GPER1 signaling	1	49.6×	0.041	PRKAR1A
Regulation of insulin secretion	1	43.9×	0.044	PRKAR1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	2	963.0×	8e-05	DSG2, DSC2
regulation of ventricular cardiac muscle cell action potential	2	561.7×	9e-05	DSG2, DSC2
homophilic cell-cell adhesion	3	84.3×	9e-05	DSG2, DSC2, DSC3
cell-cell adhesion	3	60.9×	1e-04	DSG2, DSC2, DSC3
regulation of heart rate by cardiac conduction	2	149.8×	8e-04	DSG2, DSC2
cell adhesion	3	22.5×	0.002	DSG2, DSC2, DSC3
Purkinje myocyte development	1	1685.2×	0.004	DSG2
cardiac muscle cell-cardiac muscle cell adhesion	1	1685.2×	0.004	DSC2
positive regulation of protein localization to cell-cell junction	1	1123.5×	0.005	DSG2
negative regulation of endothelial cell differentiation	1	674.1×	0.008	DSG2
desmosome organization	1	421.3×	0.012	DSG2
negative regulation of inflammatory response to wounding	1	337.0×	0.014	DSG2
mesenchymal to epithelial transition	1	306.4×	0.014	DSG2
intraciliary retrograde transport	1	224.7×	0.017	DYNC2H1
negative regulation of activated T cell proliferation	1	210.7×	0.017	PRKAR1A
spinal cord motor neuron differentiation	1	187.2×	0.017	DYNC2H1
maternal process involved in female pregnancy	1	187.2×	0.017	DSG2
cellular response to glucagon stimulus	1	168.5×	0.018	PRKAR1A
vascular endothelial cell response to laminar fluid shear stress	1	146.5×	0.018	PRKAR1A
cilium movement involved in cell motility	1	134.8×	0.018	DYNC2H1
positive regulation of sprouting angiogenesis	1	134.8×	0.018	DSG2
coronary vasculature development	1	124.8×	0.018	DYNC2H1
positive regulation of p38MAPK cascade	1	124.8×	0.018	DSC2
negative regulation of inflammatory response to antigenic stimulus	1	120.4×	0.018	PRKAR1A
negative regulation of cAMP/PKA signal transduction	1	120.4×	0.018	PRKAR1A
cardiac muscle cell proliferation	1	116.2×	0.018	PRKAR1A
renal water homeostasis	1	102.1×	0.019	PRKAR1A
mesoderm formation	1	99.1×	0.019	PRKAR1A
response to progesterone	1	99.1×	0.019	DSG2
dorsal/ventral pattern formation	1	84.3×	0.020	DYNC2H1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DSG2	0	0
DYNC2H1	0	0
DSC2	0	0
DSC3	0	0
DSG2-AS1	0	0
PRKAR1A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PRKAR1A	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	DSG2, DYNC2H1, DSC2, DSC3, DSG2-AS1, PRKAR1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DSG2	0	—
DYNC2H1	0	—
DSC2	0	—
DSC3	0	—
DSG2-AS1	0	—
PRKAR1A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.