Familial isolated arrhythmogenic right ventricular dysplasia

Summary

Familial isolated arrhythmogenic right ventricular dysplasia (MONDO:0016342) is a disease (an umbrella term covering 16 Mondo subtypes) with 11 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (5 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Umbrella term: 16 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 655

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial isolated arrhythmogenic right ventricular dysplasia
Mondo ID	MONDO:0016342
OMIM	107970
Orphanet	217656
ICD-11	460188584
SNOMED CT	715865008
UMLS	C4274968
MedGen	901869
GARD	0017129
Is cancer (heuristic)	no

Also known as: familial isolated arrhythmogenic right ventricular cardiomyopathy · familial isolated arrhythmogenic right ventricular dysplasia · familial isolated arrhythmogenic ventricular cardiomyopathy · familial isolated arrhythmogenic ventricular dysplasia · familial isolated ARVC · familial isolated ARVD

Data availability: 655 ClinVar variants · 18 cell lines.

Disease family

An umbrella term covering 16 Mondo subtypes.

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

Related subtypes (8): Naxos disease, fatal infantile encephalocardiomyopathy, familial dilated cardiomyopathy, familial restrictive cardiomyopathy, left ventricular noncompaction, familial hypertrophic cardiomyopathy, NKX2.5-related congenital, conduction and myopathic heart disease, PRKAG2-related cardiomyopathy

Subtypes (16): 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 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:

293 uncertain significance, 131 conflicting classifications of pathogenicity, 104 likely benign, 26 pathogenic, 20 benign/likely benign, 19 pathogenic/likely pathogenic, 4 benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3233508	NM_003805.5(CRADD):c.393G>A (p.Trp131Ter)	CRADD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3773770	NM_024422.6(DSC2):c.647_654del (p.Thr216fs)	DSC2	Pathogenic	criteria provided, single submitter
3907391	NM_001943.5(DSG2):c.1377T>A (p.Tyr459Ter)	DSG2	Pathogenic	criteria provided, single submitter
1072470	NM_004415.4(DSP):c.4687_4688del (p.Leu1563fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180326	NM_004415.4(DSP):c.2821C>T (p.Arg941Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199881	NM_004415.4(DSP):c.3805C>T (p.Arg1269Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264512	NM_004415.4(DSP):c.3195C>G (p.Tyr1065Ter)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
3505484	NM_004415.4(DSP):c.6475dup (p.Tyr2159fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
405223	NM_004415.4(DSP):c.5745dup (p.Lys1916Ter)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
405232	NM_004415.4(DSP):c.5680_5683del (p.Ser1894fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44856	NM_004415.4(DSP):c.1273C>T (p.Arg425Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
44928	NM_004415.4(DSP):c.5428C>T (p.Gln1810Ter)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
451211	NM_004415.4(DSP):c.250C>T (p.Arg84Ter)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
4687148	NM_004415.4(DSP):c.6470_6474del (p.Asp2157fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
545955	NM_004415.4(DSP):c.5327_5330del (p.Glu1776fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620416	NM_004415.4(DSP):c.7066A>T (p.Lys2356Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321424	NM_001005242.3(PKP2):c.2044C>T (p.Gln682Ter)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
177995	NM_001005242.3(PKP2):c.2377del (p.Ser793fs)	PKP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188654	NM_001005242.3(PKP2):c.337-2A>T	PKP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
201965	NM_001005242.3(PKP2):c.2254T>C (p.Cys752Arg)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
202015	NM_001005242.3(PKP2):c.837_838del (p.Val280fs)	PKP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202018	NM_001005242.3(PKP2):c.1447del (p.Thr482_Leu483insTer)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
202022	NM_001005242.3(PKP2):c.1881del (p.Lys628fs)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
202027	NM_001005242.3(PKP2):c.397C>T (p.Gln133Ter)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
202035	NM_001005242.3(PKP2):c.1511del (p.Gly504fs)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
2573528	NM_001005242.3(PKP2):c.172G>T (p.Glu58Ter)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
36680	NM_001005242.3(PKP2):c.1481G>A (p.Trp494Ter)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
36682	NM_001005242.3(PKP2):c.1896G>A (p.Trp632Ter)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
406553	NM_001005242.3(PKP2):c.2437_2445+41del	PKP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
420209	NM_001005242.3(PKP2):c.2180_2181del (p.Leu727fs)	PKP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 39 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
CRADD	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
TMEM43	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TMEM43	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TMEM43	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TMEM43	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
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
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
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome
PKP2	Orphanet:130	Brugada syndrome
PKP2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
PKP2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
PKP2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
PKP2	Orphanet:54260	Left ventricular noncompaction
BAG3	Orphanet:154	Familial isolated dilated cardiomyopathy
BAG3	Orphanet:199340	BAG3-related myofibrillar myopathy

Cohort genes → proteins

11 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
CRADD	HGNC:2340	ENSG00000169372	P78560	Death domain-containing protein CRADD	clinvar
TMEM43	HGNC:28472	ENSG00000170876	Q9BTV4	Transmembrane protein 43	clinvar
DSC2	HGNC:3036	ENSG00000134755	Q02487	Desmocollin-2	clinvar
DSC3	HGNC:3037	ENSG00000134762	Q14574	Desmocollin-3	clinvar
DSG2	HGNC:3049	ENSG00000046604	Q14126	Desmoglein-2	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
DSCAS	HGNC:51116	ENSG00000265888		DSC1/DSC2 antisense RNA	clinvar
MHRT	HGNC:51291			myosin heavy chain associated RNA transcript	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar
BAG3	HGNC:939	ENSG00000151929	O95817	BAG family molecular chaperone regulator 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
CRADD	Death domain-containing protein CRADD	Adapter protein that associates with PIDD1 and the caspase CASP2 to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis.
TMEM43	Transmembrane protein 43	May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane.
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.
DSG2	Desmoglein-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
BAG3	BAG family molecular chaperone regulator 3	Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 8 · Druggable fraction: 0.09

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
Ion channel	1	10.1×	0.195
Scaffold/PPI	2	3.1×	0.195
Other/Unknown	8	1.3×	0.206

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
CRADD	Other/Unknown	no		Death_dom, CARD, DEATH-like_dom_sf
TMEM43	Other/Unknown	no		TMEM43_fam
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	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
DSCAS	Other/Unknown	no
MHRT	Other/Unknown	no
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
BAG3	Scaffold/PPI	no		WW_dom, BAG_domain, WW_dom_sf

Expression context

Cohort genes with no expression data: 1.

8 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)	10
unknown	1

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
cardiac ventricle	2
heart left ventricle	2
male germ line stem cell (sensu Vertebrata) in testis	2
gingiva	2
gingival epithelium	2
upper leg skin	2
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
oral cavity	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
hair follicle	1
skin of hip	1
primordial germ cell in gonad	1
skin of leg	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
CRADD	260	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, heart left ventricle, cardiac ventricle
TMEM43	287	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
DSC2	256	ubiquitous	marker	gingival epithelium, gingiva, oral cavity
DSC3	177	broad	marker	upper leg skin, gingival epithelium, gingiva
DSG2	238	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, jejunal mucosa
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
DSCAS	119	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, skin of leg
MHRT
PKP2	237	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
BAG3	286	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, body of tongue

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BAG3	4,957
DSP	2,897
SCN5A	2,090
DSG2	2,033
TMEM43	1,864
PKP2	1,861
DSC2	1,659
DSC3	1,474
CRADD	639
DSCAS	0

Intra-cohort edges

A	B	Sources
DSC2	DSG2	intact, string_interaction
DSC2	DSP	string_interaction
DSC2	PKP2	string_interaction
DSC2	TMEM43	string_interaction
DSC3	DSG2	intact, string_interaction
DSC3	DSP	string_interaction
DSC3	PKP2	string_interaction
DSC3	TMEM43	string_interaction
DSG2	DSP	string_interaction
DSG2	PKP2	string_interaction
DSG2	SCN5A	string_interaction
DSG2	TMEM43	string_interaction
DSP	PKP2	string_interaction
DSP	TMEM43	string_interaction
PKP2	SCN5A	string_interaction
PKP2	TMEM43	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 3 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN5A	Q14524	16
DSG2	Q14126	12
DSP	P15924	4
CRADD	P78560	3
DSC2	Q02487	3
PKP2	Q99959	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM43	Q9BTV4	89.92
DSC3	Q14574	75.53
BAG3	O95817	57.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 11 evidence-associated genes (8 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 8 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	5	54.9×	2e-07	DSC2, DSC3, DSG2, DSP, PKP2
Keratinization	5	34.8×	1e-06	DSC2, DSC3, DSG2, DSP, PKP2
Apoptotic cleavage of cell adhesion proteins	2	259.6×	2e-04	DSG2, DSP
TP53 Regulates Transcription of Caspase Activators and Caspases	1	119.0×	0.046	CRADD
Cellular response to heat stress	1	49.2×	0.072	BAG3
Interaction between L1 and Ankyrins	1	46.0×	0.072	SCN5A
Phase 0 - rapid depolarisation	1	43.3×	0.072	SCN5A
RND1 GTPase cycle	1	33.2×	0.074	DSP
RND3 GTPase cycle	1	32.4×	0.074	DSP
RHOG GTPase cycle	1	18.5×	0.103	DSG2
Regulation of HSF1-mediated heat shock response	1	17.4×	0.103	BAG3
RAC2 GTPase cycle	1	15.9×	0.103	DSG2
L1CAM interactions	1	15.0×	0.103	SCN5A
RAC3 GTPase cycle	1	14.9×	0.103	DSG2
Cardiac conduction	1	13.6×	0.105	SCN5A
Muscle contraction	1	9.7×	0.136	SCN5A
Axon guidance	1	5.6×	0.210	SCN5A
Nervous system development	1	5.4×	0.210	SCN5A
Cellular responses to stress	1	4.6×	0.229	BAG3
Cellular responses to stimuli	1	3.9×	0.251	BAG3
Neutrophil degranulation	1	2.9×	0.313	DSP
Developmental Biology	1	1.8×	0.437	SCN5A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 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	4	1070.0×	1e-10	DSC2, DSG2, DSP, PKP2
regulation of ventricular cardiac muscle cell action potential	4	624.1×	7e-10	DSC2, DSG2, DSP, PKP2
regulation of heart rate by cardiac conduction	5	208.1×	7e-10	SCN5A, DSC2, DSG2, DSP, PKP2
desmosome organization	3	702.2×	2e-07	DSG2, DSP, PKP2
cell-cell adhesion	5	56.4×	2e-07	DSC2, DSC3, DSG2, DSP, PKP2
homophilic cell-cell adhesion	3	46.8×	5e-04	DSC2, DSC3, DSG2
ventricular cardiac muscle cell action potential	2	220.3×	6e-04	SCN5A, PKP2
positive regulation of sodium ion transport	2	187.2×	7e-04	SCN5A, PKP2
cardiac muscle cell action potential involved in contraction	2	156.0×	9e-04	SCN5A, PKP2
extrinsic apoptotic signaling pathway via death domain receptors	2	89.2×	0.002	CRADD, BAG3
striated muscle cell apoptotic process	1	1872.4×	0.005	BAG3
maintenance of protein localization at cell tip	1	1872.4×	0.005	PKP2
sodium ion transport	2	60.4×	0.005	SCN5A, TMEM43
cellular response to mechanical stimulus	2	48.0×	0.006	CRADD, BAG3
Purkinje myocyte development	1	936.2×	0.006	DSG2
positive regulation of cell communication by electrical coupling	1	936.2×	0.006	TMEM43
cardiac muscle cell-cardiac muscle cell adhesion	1	936.2×	0.006	DSC2
bundle of His cell action potential	1	936.2×	0.006	SCN5A
AV node cell to bundle of His cell communication	1	936.2×	0.006	SCN5A
negative regulation of striated muscle cell apoptotic process	1	624.1×	0.007	BAG3
regulation of cell-substrate adhesion	1	624.1×	0.007	PKP2
membrane depolarization during Purkinje myocyte cell action potential	1	624.1×	0.007	SCN5A
membrane depolarization during bundle of His cell action potential	1	624.1×	0.007	SCN5A
protein transport along microtubule	1	624.1×	0.007	BAG3
membrane depolarization during atrial cardiac muscle cell action potential	1	624.1×	0.007	SCN5A
positive regulation of protein localization to cell-cell junction	1	624.1×	0.007	DSG2
cell adhesion	3	12.5×	0.007	DSC2, DSC3, DSG2
AV node cell action potential	1	468.1×	0.009	SCN5A
negative regulation of endothelial cell differentiation	1	374.5×	0.009	DSG2
maintenance of animal organ identity	1	374.5×	0.009	PKP2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 10

Druggability breadth: 4 of 11 evidence-associated genes (36%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN5A	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
CRADD	0	0
TMEM43	0	0
DSC2	0	0
DSC3	0	0
DSG2	0	0
DSP	0	0
DSCAS	0	0
MHRT	0	0
PKP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
BAG3	8	Binding:8
DSP	2	Binding:2
TMEM43	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN5A	594

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN5A
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	10	CRADD, TMEM43, DSC2, DSC3, DSG2, DSP, DSCAS, MHRT, PKP2, BAG3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PKP2	0	SCN5A
CRADD	0	—
TMEM43	1	—
DSC2	0	—
DSC3	0	—
DSG2	0	—
DSP	2	—
DSCAS	0	—
MHRT	0	—
BAG3	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.