Arrhythmogenic right ventricular dysplasia 1

Summary

Arrhythmogenic right ventricular dysplasia 1 (MONDO:0007152) is a disease with 10 cohort genes and 3 clinical trials. The dominant Reactome pathway is Formation of the cornified envelope (5 cohort genes). Top therapeutic interventions include ic14.

At a glance

• Cohort genes: 10
• ClinVar variants: 57
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular dysplasia 1
Mondo ID	MONDO:0007152
OMIM	107970
DOID	DOID:0110070
UMLS	C1862511
MedGen	349530
GARD	0024526
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 1 · arrhythmogenic right ventricular cardiomyopathy caused by mutation in TGFB3 · arrhythmogenic right ventricular dysplasia type 1 · arrhythmogenic right ventricular dysplasia, familial, 1 · arrhythmogenic right ventricular dysplasia, familial, type 1 · ARVC1 · ARVD1 · familial arrhythmogenic right ventricular dysplasia 1 · TGFB3 arrhythmogenic right ventricular cardiomyopathy

Data availability: 57 ClinVar variants · 1 GenCC gene-disease record.

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 1

Related subtypes (15): arrhythmogenic right ventricular dysplasia 13, 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

57 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 13 conflicting classifications of pathogenicity, 5 likely benign, 3 benign/likely benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031323	NM_003239.5(TGFB3):c.411del (p.Ser138fs)	TGFB3	Pathogenic	criteria provided, single submitter
410269	NM_003239.5(TGFB3):c.1034C>G (p.Ser345Ter)	TGFB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520206	NM_003239.5(TGFB3):c.1102_1105del (p.Leu368fs)	TGFB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
978281	NM_001005242.3(PKP2):c.2358-2A>G	PKP2	Likely pathogenic	criteria provided, single submitter
487471	NM_003239.5(TGFB3):c.927-1G>C	TGFB3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
862608	NM_003239.5(TGFB3):c.517-2A>G	TGFB3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
161222	NM_024422.6(DSC2):c.1018A>G (p.Thr340Ala)	DSC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978277	NM_024422.6(DSC2):c.1913_1916del (p.Gln638fs)	DSC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188467	NM_004415.4(DSP):c.5063C>T (p.Ala1688Val)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196764	NM_201384.3(PLEC):c.5471C>T (p.Ala1824Val)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196822	NM_201384.3(PLEC):c.8051G>A (p.Arg2684Gln)	PLEC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191779	NM_003239.5(TGFB3):c.487C>T (p.Arg163Trp)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410270	NM_003239.5(TGFB3):c.97G>A (p.Gly33Ser)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410273	NM_003239.5(TGFB3):c.488G>A (p.Arg163Gln)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410276	NM_003239.5(TGFB3):c.965T>C (p.Ile322Thr)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
543955	NM_003239.5(TGFB3):c.463C>T (p.Arg155Trp)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
579921	NM_003239.5(TGFB3):c.101A>G (p.His34Arg)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807144	NM_003239.5(TGFB3):c.756C>T (p.Gly252=)	TGFB3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
202444	NM_133378.4(TTN):c.37385_37387delAAG	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196720	NM_201384.3(PLEC):c.5390G>A (p.Arg1797His)	PLEC	Uncertain significance	criteria provided, multiple submitters, no conflicts
634815	NM_201384.3(PLEC):c.2354C>G (p.Ala785Gly)	PLEC	Uncertain significance	criteria provided, single submitter
201252	NM_001035.3(RYR2):c.4912T>A (p.Ser1638Thr)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
226037	NM_001035.3(RYR2):c.4196C>A (p.Thr1399Lys)	RYR2	Uncertain significance	criteria provided, single submitter
12474	NM_003239.5(TGFB3):c.-30G>A	TGFB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
12475	NM_003239.5(TGFB3):c.*495C>T	TGFB3	Uncertain significance	criteria provided, single submitter
1302541	NM_003239.5(TGFB3):c.260G>T (p.Arg87Met)	TGFB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1394740	NM_003239.5(TGFB3):c.230G>A (p.Arg77Gln)	TGFB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
191778	NM_003239.5(TGFB3):c.559G>A (p.Gly187Ser)	TGFB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2149468	NM_003239.5(TGFB3):c.50T>G (p.Phe17Cys)	TGFB3	Uncertain significance	criteria provided, multiple submitters, no conflicts
239523	NM_003239.5(TGFB3):c.82A>C (p.Thr28Pro)	TGFB3	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 53 · 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
TGFB3	Limited	Autosomal dominant	arrhythmogenic right ventricular dysplasia 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGFB3	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TGFB3	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TGFB3	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TGFB3	Orphanet:60030	Loeys-Dietz syndrome
TGFB3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
RYR2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
RYR2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
RYR2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
RYR2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
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
MYBPC3	Orphanet:154	Familial isolated dilated cardiomyopathy
MYBPC3	Orphanet:54260	Left ventricular noncompaction
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
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGFB3	HGNC:11769	ENSG00000119699	P10600	Transforming growth factor beta-3 proprotein	gencc,clinvar
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	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
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGFB3	Transforming growth factor beta-3 proprotein	Transforming growth factor beta-3 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains, which constitute the regulatory and active subunit of TGF-beta-3, respectively.
RYR2	Ryanodine receptor 2	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
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.
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.3

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	11.2×	0.276
Scaffold/PPI	2	3.5×	0.276
Antibody/Immunoglobulin	1	2.9×	0.384
Kinase	1	2.8×	0.384
Other/Unknown	5	0.9×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGFB3	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
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
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS

Expression context

Cohort genes with no expression data: 0.

10 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	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	2
left ventricle myocardium	2
gingiva	2
gingival epithelium	2
upper leg skin	2
apex of heart	2
endocervix	1
gall bladder	1
saphenous vein	1
myocardium	1
biceps brachii	1
gluteal muscle	1
skeletal muscle tissue of biceps brachii	1
oral cavity	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
hair follicle	1
skin of hip	1
cardiac atrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGFB3	244	broad	marker	saphenous vein, endocervix, gall bladder
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
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
MYBPC3	149	tissue_specific	marker	apex of heart, right atrium auricular region, cardiac atrium
PKP2	237	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
PLEC	3,529
TGFB3	2,972
DSP	2,897
RYR2	2,653
DSG2	2,033
PKP2	1,861
MYBPC3	1,800
DSC2	1,659
DSC3	1,474

Intra-cohort edges

A	B	Sources
DSC2	DSG2	intact, string_interaction
DSC2	DSP	string_interaction
DSC2	PKP2	string_interaction
DSC2	RYR2	string_interaction
DSC2	TGFB3	string_interaction
DSC3	DSG2	intact, string_interaction
DSC3	DSP	string_interaction
DSC3	PKP2	string_interaction
DSC3	RYR2	string_interaction
DSC3	TGFB3	string_interaction
DSG2	DSP	string_interaction
DSG2	MYBPC3	string_interaction
DSG2	PKP2	string_interaction
DSG2	RYR2	string_interaction
DSG2	TGFB3	string_interaction
DSP	PKP2	string_interaction
MYBPC3	TTN	string_interaction
PKP2	RYR2	string_interaction
PKP2	TGFB3	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
RYR2	Q92736	26
MYBPC3	Q14896	17
PLEC	Q15149	14
DSG2	Q14126	12
TGFB3	P10600	11
DSP	P15924	4
DSC2	Q02487	3
PKP2	Q99959	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: 31. Enrichment computed across 10 evidence-associated genes (10 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 10 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	43.9×	1e-06	DSC2, DSC3, DSG2, DSP, PKP2
Keratinization	5	27.9×	6e-06	DSC2, DSC3, DSG2, DSP, PKP2
Apoptotic cleavage of cell adhesion proteins	2	207.6×	4e-04	DSG2, DSP
Striated Muscle Contraction	2	61.7×	0.004	TTN, MYBPC3
Platelet degranulation	2	17.6×	0.034	TGFB3, TTN
Muscle contraction	2	15.4×	0.036	RYR2, MYBPC3
Type I hemidesmosome assembly	1	103.8×	0.041	PLEC
Caspase-mediated cleavage of cytoskeletal proteins	1	95.2×	0.041	PLEC
Elastic fibre formation	1	33.6×	0.090	TGFB3
TGF-beta receptor signaling activates SMADs	1	32.6×	0.090	TGFB3
Molecules associated with elastic fibres	1	30.9×	0.090	TGFB3
RND1 GTPase cycle	1	26.6×	0.090	DSP
RND3 GTPase cycle	1	25.9×	0.090	DSP
Ion homeostasis	1	20.4×	0.095	RYR2
Signaling by TGF-beta Receptor Complex	1	20.0×	0.095	TGFB3
Assembly of collagen fibrils and other multimeric structures	1	20.0×	0.095	PLEC
Response to elevated platelet cytosolic Ca2+	1	16.3×	0.107	TGFB3
ECM proteoglycans	1	15.0×	0.107	TGFB3
RHOG GTPase cycle	1	14.8×	0.107	DSG2
Stimuli-sensing channels	1	13.6×	0.110	RYR2
RAC2 GTPase cycle	1	12.7×	0.112	DSG2
RAC3 GTPase cycle	1	11.9×	0.112	DSG2
Signaling by TGFB family members	1	11.5×	0.112	TGFB3
Cardiac conduction	1	10.9×	0.112	RYR2
Platelet activation, signaling and aggregation	1	10.6×	0.112	TGFB3
Ion channel transport	1	9.6×	0.119	RYR2
Extracellular matrix organization	1	6.3×	0.170	TGFB3
Hemostasis	1	3.6×	0.272	TGFB3
Transport of small molecules	1	2.5×	0.357	RYR2
Neutrophil degranulation	1	2.3×	0.370	DSP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of ventricular cardiac muscle cell action potential	5	702.2×	3e-12	RYR2, DSC2, DSG2, DSP, PKP2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	4	963.0×	2e-10	DSC2, DSG2, DSP, PKP2
desmosome organization	3	632.0×	4e-07	DSG2, DSP, PKP2
regulation of heart rate by cardiac conduction	4	149.8×	4e-07	DSC2, DSG2, DSP, PKP2
cell-cell adhesion	5	50.8×	7e-07	DSC2, DSC3, DSG2, DSP, PKP2
cardiac muscle contraction	3	120.4×	4e-05	RYR2, TTN, MYBPC3
sarcomere organization	3	114.9×	4e-05	TTN, MYBPC3, PLEC
cardiac muscle hypertrophy	2	337.0×	3e-04	RYR2, TTN
cell communication by electrical coupling involved in cardiac conduction	2	280.9×	4e-04	RYR2, PKP2
ventricular cardiac muscle cell action potential	2	198.3×	6e-04	RYR2, PKP2
homophilic cell-cell adhesion	3	42.1×	6e-04	DSC2, DSC3, DSG2
intermediate filament cytoskeleton organization	2	187.2×	6e-04	DSP, PLEC
striated muscle contraction	2	168.5×	7e-04	RYR2, TTN
ventricular cardiac muscle tissue morphogenesis	2	140.4×	1e-03	MYBPC3, PKP2
cell adhesion	4	15.0×	1e-03	DSC2, DSC3, DSG2, MYBPC3
cardiac muscle cell development	2	124.8×	0.001	TTN, PLEC
adherens junction organization	2	102.1×	0.002	DSP, PLEC
response to progesterone	2	99.1×	0.002	TGFB3, DSG2
positive regulation of protein secretion	2	68.8×	0.003	TGFB3, TTN
protein-containing complex organization	1	1685.2×	0.004	PLEC
establishment of protein localization to endoplasmic reticulum	1	1685.2×	0.004	RYR2
maintenance of protein localization at cell tip	1	1685.2×	0.004	PKP2
actomyosin contractile ring assembly actin filament organization	1	1685.2×	0.004	PLEC
intermediate filament organization	2	48.1×	0.005	DSP, PLEC
wound healing	2	45.5×	0.005	DSP, PLEC
Purkinje myocyte development	1	842.6×	0.006	DSG2
skeletal myofibril assembly	1	842.6×	0.006	PLEC
regulation of muscle filament sliding	1	842.6×	0.006	MYBPC3
uterine wall breakdown	1	842.6×	0.006	TGFB3
detection of hypoxia	1	842.6×	0.006	TGFB3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 5 of 10 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR2	1	2
TGFB3	0	0
TTN	0	0
DSC2	0	0
DSC3	0	0
DSG2	0	0
DSP	0	0
MYBPC3	0	0
PKP2	0	0
PLEC	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ALADORIAN	2	RYR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RYR2	15	Binding:15
PLEC	12	Binding:12
DSP	2	Binding:2
TGFB3	1	Binding:1
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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)
ALADORIAN	2	RYR2

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	RYR2
C	Druggable family + PDB, no drug	2	TTN, MYBPC3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	TGFB3, DSC2, DSC3, DSG2, DSP, PKP2, PLEC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TGFB3	1	—
TTN	1	—
DSC2	0	—
DSC3	0	—
DSG2	0	—
DSP	2	—
MYBPC3	0	—
PKP2	0	—
PLEC	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06275893	PHASE1/PHASE2	COMPLETED	IC14 (Atibuclimab) in Arrhythmogenic Cardiomyopathy
NCT05524077	Not specified	ACTIVE_NOT_RECRUITING	Catheter Ablation Versus Anti-arrhythmic Drugs for Ventricular Tachycardia
NCT06409585	Not specified	RECRUITING	Cardiomyopathies and Heart Muscle Diseases: Cardiac Imaging in the Evaluation of Myocardial Fibrosis Transition

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
IC14	2	1