Arrhythmogenic right ventricular cardiomyopathy

Summary

Arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587) is a disease caused by DES (GenCC Strong), with 50 cohort genes and 37 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (10 cohort genes). Top therapeutic interventions include flecainide, spironolactone, and ic14.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Causal gene: DES (GenCC Strong)
• Cohort genes: 50
• ClinVar variants: 1,696
• Clinical trials: 37

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	20	Worldwide	Validated
Point prevalence	1-5 / 10 000	43.5	Italy	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	arrhythmogenic right ventricular cardiomyopathy
Mondo ID	MONDO:0016587
MeSH	D019571
Orphanet	247
DOID	DOID:0050431
ICD-11	1931494126
NCIT	C84571
SNOMED CT	281170005
UMLS	C0349788
MedGen	87618
GARD	0005847
MedDRA	10058093
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy · arrhythmogenic right ventricular dysplasia · arrhythmogenic RVD · ARVD · right ventricular dysplasia

Data availability: 1,696 ClinVar variants · 11 GenCC gene-disease records · 15 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › arrhythmogenic right ventricular cardiomyopathy

Related subtypes (5): myocarditis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction

Subtypes (2): Naxos disease, familial isolated arrhythmogenic right ventricular dysplasia

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, 150 conflicting classifications of pathogenicity, 85 likely benign, 30 pathogenic/likely pathogenic, 26 pathogenic, 17 benign/likely benign, 11 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100657	NM_013266.4(CTNNA3):c.2293TTG[1] (p.Leu766del)	CTNNA3	Pathogenic	no assertion criteria provided
16826	NM_001927.4(DES):c.1216C>T (p.Arg406Trp)	DES	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162504	NM_024422.6(DSC2):c.663T>A (p.Tyr221Ter)	DSC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693178	NM_024422.6(DSC2):c.1577C>A (p.Ser526Ter)	DSC2	Pathogenic	criteria provided, single submitter
1693187	NM_024422.6(DSC2):c.501_502dup (p.Thr168fs)	DSC2	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
1693197	NM_001943.5(DSG2):c.1919_1932del (p.Gly640fs)	DSG2	Pathogenic	criteria provided, single submitter
162505	NM_004415.4(DSP):c.4180C>T (p.Gln1394Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163265	NM_004415.4(DSP):c.3630T>A (p.Tyr1210Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693206	NM_004415.4(DSP):c.7180_7181del (p.Arg2394fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
1693213	NM_004415.4(DSP):c.5380-1G>A	DSP	Pathogenic	criteria provided, single submitter
1693214	NM_004415.4(DSP):c.793_794del (p.Arg265fs)	DSP	Pathogenic	criteria provided, single submitter
1693215	NM_004415.4(DSP):c.5999del (p.Lys1999_Ser2000insTer)	DSP	Pathogenic	criteria provided, single submitter
178282	NM_004415.4(DSP):c.939+1G>A	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179720	NM_004415.4(DSP):c.1751del (p.Glu584fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179994	NM_004415.4(DSP):c.3526del (p.Val1176fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199905	NM_004415.4(DSP):c.6850C>T (p.Arg2284Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199915	NM_004415.4(DSP):c.273del (p.Glu92fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199916	NM_004415.4(DSP):c.928dup (p.Glu310fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199923	NM_004415.4(DSP):c.3735_3741dup (p.Asp1248fs)	DSP	Pathogenic	criteria provided, multiple submitters, no conflicts
199925	NM_004415.4(DSP):c.6273del (p.Ala2092fs)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222582	NM_004415.4(DSP):c.5851C>T (p.Arg1951Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228253	NM_004415.4(DSP):c.1873C>T (p.Gln625Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412593	NM_004415.4(DSP):c.3203_3204del (p.Glu1068fs)	DSP	Pathogenic	criteria provided, single submitter
267288	NM_001458.5(FLNC):c.2971C>T (p.Arg991Ter)	FLNC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14120	NM_000257.4(MYH7):c.2609G>A (p.Arg870His)	LOC126861898	Pathogenic	reviewed by expert panel
1443926	NM_001005242.3(PKP2):c.1264_1265del (p.Leu422fs)	PKP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693179	NM_001005242.3(PKP2):c.1904del (p.His635fs)	PKP2	Pathogenic	criteria provided, single submitter
1693180	NM_001005242.3(PKP2):c.861del (p.Arg287fs)	PKP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 119 · Orphanet: 171 · 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
DES	Definitive	Autosomal dominant	dilated cardiomyopathy 1I	15
LMNA	Definitive	Autosomal dominant	dilated cardiomyopathy 1A	40
PLN	Definitive	Autosomal dominant	dilated cardiomyopathy 1P	9
RYR2	Definitive	Autosomal dominant	arrhythmogenic right ventricular dysplasia 2	8
TNNC1	Definitive	Autosomal dominant	hypertrophic cardiomyopathy	10
TNNI3	Definitive	Autosomal recessive	dilated cardiomyopathy 2A	11
TNNT2	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 2	12
TPM1	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 3	6
CDH2	Strong	Autosomal dominant	arrhythmogenic right ventricular dysplasia, familial, 14	7
TJP1	Limited	Autosomal dominant	arrhythmogenic right ventricular cardiomyopathy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CDH2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DES	Orphanet:154	Familial isolated dilated cardiomyopathy
DES	Orphanet:85146	Neurogenic scapuloperoneal syndrome, Kaeser type
DES	Orphanet:98909	Desminopathy
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1
TNNC1	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TPM1	Orphanet:154	Familial isolated dilated cardiomyopathy
TPM1	Orphanet:54260	Left ventricular noncompaction
PLN	Orphanet:154	Familial isolated dilated cardiomyopathy
PLN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia

Cohort genes → proteins

50 cohort genes, 47 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	50

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	gencc,clinvar
CDH2	HGNC:1759	ENSG00000170558	P19022	Cadherin-2	gencc,clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	gencc,clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	gencc,clinvar
TJP1	HGNC:11827	ENSG00000104067	Q07157	Tight junction protein 1	gencc
TNNC1	HGNC:11943	ENSG00000114854	P63316	Troponin C, slow skeletal and cardiac muscles	gencc
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	gencc
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	gencc
TPM1	HGNC:12010	ENSG00000140416	P09493	Tropomyosin alpha-1 chain	gencc
PLN	HGNC:9080	ENSG00000198523	P26678	Phospholamban	gencc
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SGCA	HGNC:10805	ENSG00000108823	Q16586	Alpha-sarcoglycan	clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
TGFB3	HGNC:11769	ENSG00000119699	P10600	Transforming growth factor beta-3 proprotein	clinvar
TMPO	HGNC:11875	ENSG00000120802	P42166	Lamina-associated polypeptide 2, isoform alpha	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
CACNB2	HGNC:1402	ENSG00000165995	Q08289	Voltage-dependent L-type calcium channel subunit beta-2	clinvar
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	clinvar
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	clinvar
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	clinvar
CALR3	HGNC:20407	ENSG00000269058	Q96L12	Calreticulin-3	clinvar
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
CTNNA3	HGNC:2511	ENSG00000183230	Q9UI47	Catenin alpha-3	clinvar
RBM20	HGNC:27424	ENSG00000203867	Q5T481	RNA-binding protein 20	clinvar
TMEM43	HGNC:28472	ENSG00000170876	Q9BTV4	Transmembrane protein 43	clinvar
C2orf49	HGNC:28772	ENSG00000135974	Q9BVC5	tRNA-splicing ligase complex subunit ASW	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	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
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	clinvar
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
DSG2-AS1	HGNC:51311	ENSG00000264859		DSG2 antisense RNA 1	clinvar
KCNJ8-AS1	HGNC:58193	ENSG00000256615		KCNJ8 antisense RNA 1	clinvar
ABCC9	HGNC:60	ENSG00000069431	O60706	ATP-binding cassette sub-family C member 9	clinvar
JUP	HGNC:6207	ENSG00000173801	P14923	Junction plakoglobin	clinvar
KCNE1	HGNC:6240	ENSG00000180509	P15382	Potassium voltage-gated channel subfamily E member 1	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar
LAMA4	HGNC:6484	ENSG00000112769	Q16363	Laminin subunit alpha-4	clinvar
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	clinvar
MYH6	HGNC:7576	ENSG00000197616	P13533	Myosin-6	clinvar
MYL2	HGNC:7583	ENSG00000111245	P10916	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	clinvar
MYOM1	HGNC:7613	ENSG00000101605	P52179	Myomesin-1	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CDH2	Cadherin-2	Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell.
DES	Desmin	Muscle-specific type III intermediate filament essential for proper muscular structure and function.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
TJP1	Tight junction protein 1	TJP1, TJP2, and TJP3 are closely related scaffolding proteins that link tight junction (TJ) transmembrane proteins such as claudins, junctional adhesion molecules, and occludin to the actin cytoskeleton.
TNNC1	Troponin C, slow skeletal and cardiac muscles	Troponin is the central regulatory protein of striated muscle contraction.
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TPM1	Tropomyosin alpha-1 chain	Binds to actin filaments in muscle and non-muscle cells.
PLN	Phospholamban	Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+).
RYR1	Ryanodine receptor 1	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 muscle contraction following depolarization of T-tubules.
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.
SGCA	Alpha-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
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.
TMPO	Lamina-associated polypeptide 2, isoform alpha	May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
CACNB2	Voltage-dependent L-type calcium channel subunit beta-2	Beta subunit of voltage-dependent calcium channels which contributes to the function of the calcium channel by increasing peak calcium current.
LDB3	LIM domain-binding protein 3	May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.
HCN4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	Hyperpolarization-activated ion channel that are permeable to Na(+) and K(+) ions with very slow activation and inactivation.
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.
CALR3	Calreticulin-3	During spermatogenesis, may act as a lectin-independent chaperone for specific client proteins such as ADAM3.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
CTNNA3	Catenin alpha-3	May be involved in formation of stretch-resistant cell-cell adhesion complexes.
RBM20	RNA-binding protein 20	RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes encoding key structural proteins involved in cardiac development, such as TTN (Titin), CACNA1C, CAMK2D or PDLIM5/ENH.
TMEM43	Transmembrane protein 43	May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane.
C2orf49	tRNA-splicing ligase complex subunit ASW	Accessory subunit of the tRNA-splicing ligase complex that acts by directly joining spliced tRNA halves to mature-sized tRNAs by incorporating the precursor-derived splice junction phosphate into the mature tRNA as a canonical 3’,5’-phosph…
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
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.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
AKAP9	A-kinase anchor protein 9	Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus.
ANK2	Ankyrin-2	Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells.
ABCC9	ATP-binding cassette sub-family C member 9	Subunit of ATP-sensitive potassium channels (KATP).
JUP	Junction plakoglobin	Common junctional plaque protein.
KCNE1	Potassium voltage-gated channel subfamily E member 1	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
LAMA4	Laminin subunit alpha-4	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
MYH6	Myosin-6	Muscle contraction.
MYL2	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	Contractile protein that plays a role in heart development and function.
MYOM1	Myomesin-1	Major component of the vertebrate myofibrillar M band.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 15 · Difficult: 9 · Unknown: 26 · 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	8	17.9×	1e-07
Antibody/Immunoglobulin	4	2.3×	0.244
Scaffold/PPI	6	2.1×	0.244
Phosphatase	1	1.7×	0.763
Transporter	1	1.6×	0.763
Other/Unknown	26	0.9×	0.951
Kinase	1	0.6×	0.951
Transcription factor	3	0.5×	0.951

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
CDH2	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
DES	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
TJP1	Scaffold/PPI	no		ZU5_dom, SH3_domain, PDZ
TNNC1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TPM1	Other/Unknown	no		Tropomyosin
PLN	Other/Unknown	no		PLB
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SGCA	Other/Unknown	no		Cadg, Sarcoglycan_alpha/epsilon, Cadherin-like_sf
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
TGFB3	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
TMPO	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM-like_dom
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
CACNB2	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, VDCC_L_b2su
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM
CALR3	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, Calreticulin
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
CTNNA3	Other/Unknown	no		Alpha_catenin, Vinculin/catenin, Alpha-catenin/vinculin-like_sf
RBM20	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
TMEM43	Other/Unknown	no		TMEM43_fam
C2orf49	Other/Unknown	no		Ashwin
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
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
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
AKAP9	Other/Unknown	no		ELK_dom, PACT_domain, AKAP9/Pericentrin
TTN-AS1	Other/Unknown	no
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
DSG2-AS1	Other/Unknown	no
KCNJ8-AS1	Other/Unknown	no
ABCC9	Transporter	yes		ABCC8/9, ABCC9, ABC_transporter-like_ATP-bd
JUP	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
KCNE1	Ion channel	yes		K_chnl_KCNE, KCNE1
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
LAMA4	Other/Unknown	no		EGF, Laminin_G, LE_dom
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
MYH6	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
MYL2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
MYOM1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

45 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)	50
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	12
heart right ventricle	8
hindlimb stylopod muscle	8
gastrocnemius	7
left ventricle myocardium	6
right atrium auricular region	6
cardiac atrium	5
myocardium	4
gluteal muscle	4
jejunal mucosa	3
ventricular zone	2
saphenous vein	2
mucosa of stomach	2
skin of abdomen	2
corpus callosum	2
lower esophagus mucosa	2
skeletal muscle tissue of biceps brachii	2
buccal mucosa cell	2
tibialis anterior	2
medial globus pallidus	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
CDH2	233	ubiquitous	marker	heart right ventricle, ventricular zone, stromal cell of endometrium
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
TJP1	137	ubiquitous	marker	corpus callosum, lower esophagus mucosa, sural nerve
TNNC1	207	broad	marker	triceps brachii, gluteal muscle, heart right ventricle
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
TPM1	305	ubiquitous	marker	left ventricle myocardium, heart right ventricle, myocardium
PLN	243	broad	marker	heart right ventricle, myocardium, left ventricle myocardium
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SGCA	190	broad	marker	hindlimb stylopod muscle, gastrocnemius, apex of heart
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
TGFB3	244	broad	marker	saphenous vein, endocervix, gall bladder
TMPO	287	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
CACNB2	237	broad	marker	adrenal tissue, mucosa of stomach, buccal mucosa cell
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart
CALR3	57	broad	yes	right testis, left testis, testis
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
CTNNA3	211	broad	marker	corpus callosum, heart right ventricle, medial globus pallidus
RBM20	191	broad	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
TMEM43	287	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
C2orf49	277	ubiquitous	marker	calcaneal tendon, tibia, tendon
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
DSC2	256	ubiquitous	marker	gingival epithelium, gingiva, oral cavity

Protein interactions among cohort

Intra-cohort edges: 124.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
ANK2	6,423
PTPN11	6,009
TJP1	5,826
CDH2	5,623
JUP	4,618
TTN	4,237
SOS1	3,625
AKAP9	3,537
TPM1	3,514

Intra-cohort edges

A	B	Sources
ABCC9	DSG2	string_interaction
ABCC9	LDB3	string_interaction
ABCC9	MYBPC3	string_interaction
ABCC9	RBM20	string_interaction
ABCC9	SCN5A	string_interaction
AKAP9	KCNE1	string_interaction
AKAP9	KCNH2	string_interaction
ANK2	DMD	intact
ANK2	TTN	string_interaction
CACNA1C	CACNB2	intact, string_interaction
CACNA1C	HCN4	string_interaction
CACNA1C	KCNE1	string_interaction
CACNA1C	KCNH2	string_interaction
CACNA1C	RYR2	biogrid_interaction, string_interaction
CACNB2	HCN4	string_interaction
CACNB2	KCNH2	string_interaction
CACNB2	SCN5A	string_interaction
CALR3	MYPN	string_interaction
CALR3	RYR2	string_interaction
CDH2	CTNNA3	biogrid_interaction, intact, string_interaction
CDH2	JUP	biogrid_interaction, intact
CDH2	PKP2	string_interaction
CDH2	TJP1	string_interaction
CTNNA3	DSC2	string_interaction
CTNNA3	DSG2	string_interaction
CTNNA3	JUP	string_interaction
CTNNA3	PKP2	string_interaction
CTNNA3	TMEM43	string_interaction
DES	DMD	string_interaction
DES	DSP	string_interaction
DMD	FLNC	string_interaction
DMD	SGCA	string_interaction
DSC2	DSG2	intact, string_interaction
DSC2	DSP	string_interaction
DSC2	JUP	biogrid_interaction, string_interaction
DSC2	LMNA	string_interaction
DSC2	PKP2	string_interaction
DSC2	RYR2	string_interaction
DSC2	TGFB3	string_interaction
DSC2	TMEM43	string_interaction
DSC3	DSG2	intact, string_interaction
DSC3	DSP	string_interaction
DSC3	JUP	biogrid_interaction, string_interaction
DSC3	PKP2	string_interaction
DSC3	RYR2	string_interaction
DSC3	TGFB3	string_interaction
DSC3	TMEM43	string_interaction
DSG2	DSP	string_interaction
DSG2	JUP	intact, string_interaction
DSG2	MYBPC3	string_interaction

Structural data

PDB: 33 · AlphaFold-only: 14 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
SOS1	Q07889	91
TTN	Q8WZ42	64
TNNC1	P63316	61
TNNI3	P19429	39
CACNA1C	Q13936	33
TRPM4	Q8TD43	29
LMNA	P02545	28
RYR2	Q92736	26
TNNT2	P45379	25
KCNH2	Q12809	24
TJP1	Q07157	19
MYBPC3	Q14896	17
SCN5A	Q14524	16
TPM1	P09493	14
TMPO	P42166	14
FLNC	Q14315	14
DSG2	Q14126	12
TGFB3	P10600	11
ANK2	Q01484	11
MYOM1	P52179	9
HCN4	Q9Y3Q4	8
PLN	P26678	7
DMD	P11532	6
KCNE1	P15382	5
DSP	P15924	4
CACNB2	Q08289	3
DSC2	Q02487	3
MYL2	P10916	3
RYR1	P21817	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM43	Q9BTV4	89.92
ABCC9	O60706	81.72
CTNNA3	Q9UI47	81.65
SGCA	Q16586	80.15
CDH2	P19022	79.68
DES	P17661	77.73
CALR3	Q96L12	77.43
DSC3	Q14574	75.53
MYH6	P13533	74.91
LAMA4	Q16363	73.75
C2orf49	Q9BVC5	66.31
MYPN	Q86TC9	52.71
RBM20	Q5T481	48.52
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 309. Enrichment computed across 50 evidence-associated genes (40 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 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	10	77.2×	8e-15	DES, TNNC1, TNNI3, TNNT2, TPM1, TTN, DMD, MYBPC3 (+2 more)
Muscle contraction	12	23.1×	9e-12	RYR2, RYR1, SCN5A, CACNA1C, CACNB2, AKAP9, ABCC9, KCNE1 (+4 more)
Cardiac conduction	9	24.5×	7e-09	RYR2, RYR1, SCN5A, CACNA1C, CACNB2, AKAP9, ABCC9, KCNE1 (+1 more)
Phase 2 - plateau phase	4	76.1×	1e-05	CACNA1C, CACNB2, AKAP9, KCNE1
Ion homeostasis	5	25.5×	8e-05	RYR2, RYR1, TNNI3, ABCC9, PLN
Phase 3 - rapid repolarisation	3	85.7×	2e-04	AKAP9, KCNE1, KCNH2
Formation of the cornified envelope	6	13.2×	2e-04	DSC2, DSC3, DSG2, DSP, JUP, PKP2
Apoptotic cleavage of cell adhesion proteins	3	77.9×	2e-04	TJP1, DSG2, DSP
Keratinization	6	8.4×	0.002	DSC2, DSC3, DSG2, DSP, JUP, PKP2
Phase 0 - rapid depolarisation	3	25.9×	0.006	SCN5A, CACNA1C, CACNB2
Formation of the dystrophin-glycoprotein complex (DGC)	3	23.1×	0.008	SGCA, DMD, LAMA4
NCAM signaling for neurite out-growth	3	20.4×	0.011	SOS1, CACNA1C, CACNB2
Activated NTRK2 signals through FRS2 and FRS3	2	47.6×	0.018	SOS1, PTPN11
Depolymerization of the Nuclear Lamina	2	38.1×	0.025	LMNA, TMPO
Signaling by FLT3 ITD and TKD mutants	2	38.1×	0.025	SOS1, PTPN11
Tie2 Signaling	2	30.1×	0.034	SOS1, PTPN11
Initiation of Nuclear Envelope (NE) Reformation	2	30.1×	0.034	LMNA, TMPO
Axon guidance	5	5.6×	0.034	SCN5A, SOS1, CACNA1C, CACNB2, ANK2
Non-integrin membrane-ECM interactions	3	11.6×	0.034	SGCA, DMD, LAMA4
Nervous system development	5	5.4×	0.034	SCN5A, SOS1, CACNA1C, CACNB2, ANK2
FRS-mediated FGFR3 signaling	2	27.2×	0.035	SOS1, PTPN11
FRS-mediated FGFR4 signaling	2	24.8×	0.041	SOS1, PTPN11
Nuclear Envelope Breakdown	2	22.8×	0.044	LMNA, TMPO
FRS-mediated FGFR1 signaling	2	22.8×	0.044	SOS1, PTPN11
FRS-mediated FGFR2 signaling	2	22.0×	0.046	SOS1, PTPN11
Adrenaline,noradrenaline inhibits insulin secretion	2	19.7×	0.054	CACNA1C, CACNB2
Downstream signal transduction	2	19.0×	0.056	SOS1, PTPN11
Interaction between L1 and Ankyrins	2	18.4×	0.058	SCN5A, ANK2
FLT3 Signaling	2	17.3×	0.061	SOS1, PTPN11
Signaling by CSF1 (M-CSF) in myeloid cells	2	17.3×	0.061	SOS1, PTPN11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 46 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 heart rate by cardiac conduction	15	122.1×	5e-26	SCN5A, CACNA1C, CACNB2, HCN4, TRPM4, CTNNA3, DSC2, DSG2 (+7 more)
cardiac muscle contraction	12	104.7×	1e-19	RYR2, SCN5A, TNNC1, TNNI3, TNNT2, TPM1, TTN, DMD (+4 more)
regulation of ventricular cardiac muscle cell action potential	9	274.8×	1e-19	RYR2, CACNA1C, TRPM4, CTNNA3, DSC2, DSG2, DSP, JUP (+1 more)
ventricular cardiac muscle tissue morphogenesis	8	122.1×	2e-13	TNNC1, TNNI3, TNNT2, TPM1, MYBPC3, MYH6, MYL2, PKP2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	6	314.0×	2e-13	CTNNA3, DSC2, DSG2, DSP, JUP, PKP2
sarcomere organization	9	74.9×	2e-13	TNNT2, TPM1, TTN, LDB3, MYPN, FLNC, MYBPC3, MYH6 (+1 more)
muscle filament sliding	6	137.4×	2e-10	TNNC1, TNNI3, TNNT2, TPM1, TTN, MYH6
ventricular cardiac muscle cell action potential	6	129.3×	2e-10	RYR2, SCN5A, ANK2, KCNE1, KCNH2, PKP2
membrane depolarization during AV node cell action potential	4	293.1×	1e-08	SCN5A, CACNA1C, CACNB2, TRPM4
regulation of heart rate	6	61.1×	3e-08	RYR2, SCN5A, HCN4, DMD, ANK2, MYH6
cell-cell adhesion	9	19.9×	3e-08	CDH2, TJP1, CTNNA3, DSC2, DSC3, DSG2, DSP, JUP (+1 more)
regulation of ventricular cardiac muscle cell membrane repolarization	5	91.6×	8e-08	SCN5A, AKAP9, ANK2, KCNE1, KCNH2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	5	73.3×	2e-07	RYR2, CACNA1C, DMD, ANK2, PLN
membrane depolarization during atrial cardiac muscle cell action potential	3	366.4×	7e-07	SCN5A, CACNA1C, CACNB2
regulation of heart contraction	5	53.9×	1e-06	DES, TNNT2, TPM1, MYH6, PLN
regulation of cardiac muscle cell contraction	4	97.7×	2e-06	SCN5A, ANK2, MYBPC3, PLN
muscle contraction	6	27.1×	3e-06	DES, RYR1, SGCA, TTN, HCN4, MYH6
membrane depolarization during SA node cell action potential	3	219.8×	6e-06	SCN5A, HCN4, ANK2
striated muscle contraction	4	73.3×	6e-06	RYR2, RYR1, TTN, MYH6
SA node cell action potential	3	183.2×	9e-06	SCN5A, HCN4, ANK2
regulation of SA node cell action potential	3	183.2×	9e-06	RYR2, HCN4, ANK2
cardiac muscle cell action potential involved in contraction	4	61.1×	1e-05	SCN5A, CACNA1C, KCNE1, PKP2
desmosome organization	3	137.4×	2e-05	DSG2, DSP, PKP2
heart development	7	12.0×	4e-05	TGFB3, TNNI3, CACNA1C, LDB3, MYL2, PKP2, PTPN11
regulation of muscle contraction	3	109.9×	5e-05	TNNC1, TNNT2, TPM1
cardiac muscle cell contraction	3	109.9×	5e-05	TNNC1, ABCC9, KCNE1
membrane depolarization during cardiac muscle cell action potential	3	91.6×	8e-05	SCN5A, CACNA1C, HCN4
cell communication by electrical coupling involved in cardiac conduction	3	91.6×	8e-05	RYR2, CACNA1C, PKP2
regulation of cardiac muscle contraction by calcium ion signaling	3	84.5×	1e-04	RYR2, TNNI3, ANK2
regulation of the force of heart contraction	3	64.7×	2e-04	MYH6, MYL2, PLN

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

2 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Flecainide	Phase 2
Spironolactone	Phase 2

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 11 · Phased (≥1): 12 · Undrugged: 38

Druggability breadth: 29 of 50 evidence-associated genes (58%) 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
LMNA	BEPRIDIL
TNNC1	FINGOLIMOD
SCN5A	BEPRIDIL
SOS1	IDARUBICIN
CACNA1C	REMIFENTANIL
CACNB2	NIMODIPINE
HCN4	IVABRADINE
ABCC9	PINACIDIL ANHYDROUS
KCNE1	AMBRISENTAN
KCNH2	CETIRIZINE
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
KCNH2	706	4
SCN5A	108	4
CACNA1C	85	4
KCNE1	14	4
PTPN11	8	4
SOS1	5	4
ABCC9	5	4
TNNC1	2	4
CACNB2	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1C, KCNH2, LMNA, SCN5A
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	CACNA1C, KCNH2, LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA, SCN5A
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	CACNA1C, KCNH2, LMNA, SCN5A
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	CACNA1C, KCNH2, LMNA, SCN5A
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	CACNA1C, KCNH2, LMNA, SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KCNH2	4,851	Binding:3558, Toxicity:1071, Functional:169, ADMET:53
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
SOS1	421	Binding:409, Functional:12
KCNE1	117	Functional:63, Binding:47, ADMET:6, Toxicity:1
ABCC9	61	Functional:46, Binding:15
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
CACNB2	22	Binding:20, ADMET:1, Toxicity:1
RYR1	16	Binding:13, Functional:3
RYR2	15	Binding:15
TRPM4	14	Binding:13, Functional:1
LMNA	12	Binding:9, Functional:3
TNNC1	8	Binding:8
TMPO	7	Binding:7
CDH2	4	Binding:3, Functional:1
TPM1	3	Binding:3
TNNI3	2	Binding:2
TNNT2	2	Binding:2
DSP	2	Binding:2
TJP1	1	Binding:1
TGFB3	1	Binding:1
TTN	1	Binding:1
TMEM43	1	Binding:1
JUP	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594
SOS1	421
CACNA1C	575
KCNE1	117
KCNH2	4,851
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 47; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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	CACNA1C, KCNH2, LMNA, SCN5A
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	CACNA1C, KCNH2, LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA, SCN5A
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	CACNA1C, KCNH2, LMNA, SCN5A
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	CACNA1C, KCNH2, LMNA, SCN5A
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	CACNA1C, KCNH2, LMNA, SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	LMNA, TNNC1, SCN5A, SOS1, CACNA1C, CACNB2, HCN4, ABCC9, KCNE1, KCNH2 (+1 more)
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	6	RYR1, TTN, TRPM4, FLNC, MYBPC3, MYOM1
D	Druggable family + AlphaFold only, no drug	1	MYPN
E	Difficult family or no structure, no drug	31	CDH2, DES, TJP1, TNNI3, TNNT2, TPM1, PLN, SGCA, TGFB3, TMPO (+21 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RBM20	0	ABCC9
AKAP9	0	KCNE1
PKP2	0	SCN5A
CDH2	4	—
DES	0	—
TJP1	1	—
TNNI3	2	—
TNNT2	2	—
TPM1	3	—
PLN	0	—
RYR1	16	—
SGCA	0	—
TGFB3	1	—
TMPO	7	—
TTN	1	—
LDB3	0	—
TRPM4	14	—
CALR3	0	—
MYPN	0	—
CTNNA3	0	—
TMEM43	1	—
C2orf49	0	—
DMD	0	—
DSC2	0	—
DSC3	0	—
DSG2	0	—
DSP	2	—
FLNC	0	—
TTN-AS1	0	—
ANK2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 37.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	32
PHASE2	3
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03593317	PHASE2	RECRUITING	Blockade of the Renin-angiotensin-aldosterone System in Patients With ARVD
NCT06174220	PHASE2	RECRUITING	Targeted Therapy With Glycogen Synthase Kinase-3 Inhibition for Arrhythmogenic Cardiomyopathy
NCT03685149	PHASE2	COMPLETED	Pilot Randomized Trial With Flecainide in ARVC Patients
NCT06275893	PHASE1/PHASE2	COMPLETED	IC14 (Atibuclimab) in Arrhythmogenic Cardiomyopathy
NCT06228924	PHASE1	RECRUITING	Open-label, Dose Escalation Study of Safety and Preliminary Efficacy of TN-401 in Adults With PKP2 Mutation-associated ARVC
NCT02432092	Not specified	RECRUITING	Pediatric Cardiomyopathy Mutation Analysis
NCT03049254	Not specified	RECRUITING	Mayo AVC Registry and Biobank
NCT03527342	Not specified	ENROLLING_BY_INVITATION	Sahlgrenska Cardiomyopathy Project
NCT04189822	Not specified	ENROLLING_BY_INVITATION	Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
NCT04257994	Not specified	RECRUITING	Distribution of Cell-cell Junction Proteins in Arrhythmic Disorders
NCT04265040	Not specified	RECRUITING	DZHK TORCH-Plus is a Registry for Patients With Cardiomyopathies and Serves as Source for Cardiovascular Research Studies
NCT05209776	Not specified	RECRUITING	Local Inflammation in Arrhythmogenic Right Ventricular Cardiomyopathy
NCT05521451	Not specified	RECRUITING	Clinical Cohort Study - TRUST
NCT06040242	Not specified	RECRUITING	Arrhythmogenic Activity During Exercise in ARVC Patients
NCT06311708	Not specified	RECRUITING	Non-interventional Study of Seroprevalence of Pre-existing Antibodies Against Adenovirus-associated Virus Vector (AAV9) and the Progression of Disease in Patients With Plakophilin 2 (PKP2)-Associated Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
NCT06546137	Not specified	RECRUITING	National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry
NCT06748261	Not specified	NOT_YET_RECRUITING	AI-enabled Screening and Diagnosis of Cardiomyopathies Using Coronary CTA
NCT07563660	Not specified	RECRUITING	FAPI PET/CT Imaging in Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (FAPI-ARVC))
NCT00024505	Not specified	COMPLETED	Multidisciplinary Study of Right Ventricular Dysplasia
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00999947	Not specified	COMPLETED	Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
NCT01271816	Not specified	TERMINATED	Prolonged Monitoring to Detect Ventricular Arrhythmias in Presymptomatic Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Patients
NCT01804699	Not specified	COMPLETED	National ARVC Data Registry and Bio Bank
NCT02187263	Not specified	UNKNOWN	German Centre for Cardiovascular Research Cardiomyopathy Register
NCT02291393	Not specified	COMPLETED	The Role of High Density Surface ECG in the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
NCT02302274	Not specified	COMPLETED	Diagnostic Value and Safety of Flecainide Infusion Test in Brugada Syndrome
NCT02989480	Not specified	UNKNOWN	PET-detected Myocardial Inflammation is a Characteristic of Cardiac Sarcoid But Not of ARVC
NCT03061994	Not specified	UNKNOWN	Metabolomic Study of All-age Cardiomyopathy
NCT03076580	Not specified	UNKNOWN	An Integrative-Omics Study of Cardiomyopathy Patients for Diagnosis and Prognosis in China
NCT03177018	Not specified	COMPLETED	DNA Analysis From Isolated Cardiomyocytes in the Molecular Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
NCT03572569	Not specified	UNKNOWN	Risk Stratification in Children and Adolescents With Primary Cardiomyopathy
NCT04124237	Not specified	COMPLETED	Long Term Monitoring for Risk of Sudden Death
NCT04712136	Not specified	COMPLETED	Healthy-related Quality of Life and Physical Activity of Children With Cardiac Malformations
NCT04895540	Not specified	UNKNOWN	South Asian Arrhythmogenic Cardiomyopathy Registry
NCT05024708	Not specified	UNKNOWN	Athlete’s Heart or Arrhythmogenic Right Ventricular Cardiomyopathy: Contribution of Exercise Cardiovascular Magnetic Resonance (CMR)
NCT05799833	Not specified	UNKNOWN	Low QRS Voltages in Young Healthy Individuals and Athletes

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLECAINIDE	4	3
SPIRONOLACTONE	4	1
IC14	2	1
TIDEGLUSIB	2	1
CHEMBL454299	0	1