Catecholaminergic polymorphic ventricular tachycardia 1

Summary

Catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484) is a disease caused by RYR2 (GenCC Strong), with 19 cohort genes and 3 clinical trials. The dominant Reactome pathway is Muscle contraction (9 cohort genes). Top therapeutic interventions include surlorian.

At a glance

• Causal gene: RYR2 (GenCC Strong)
• Cohort genes: 19
• ClinVar variants: 8,139
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	catecholaminergic polymorphic ventricular tachycardia 1
Mondo ID	MONDO:0011484
MeSH	C563409
OMIM	600996, 604772
DOID	DOID:0060675, DOID:0110071
NCIT	C123414
UMLS	C1631597
MedGen	351513
GARD	0024803
Is cancer (heuristic)	no

Also known as: arrhythmogenic right ventricular cardiomyopathy 2 · arrhythmogenic right ventricular dysplasia 2 · arrhythmogenic right ventricular dysplasia type 2 · arrhythmogenic right ventricular dysplasia, familial, 2 · arrhythmogenic right ventricular dysplasia, familial, type 2 · ARVC2 · ARVD2 · catecholaminergic polymorphic ventricular tachycardia 1 · catecholaminergic polymorphic ventricular tachycardia type 1 · CPVT1 · familial arrhythmogenic right ventricular dysplasia 2 · familial isolated arrhythmogenic right ventricular dysplasia caused by mutation in RYR2 · RYR2 familial isolated arrhythmogenic right ventricular dysplasia · ventricular tachycardia, catecholaminergic polymorphic, 1 · ventricular tachycardia, catecholaminergic polymorphic, 1, with or without atrial dysfunction and/or dilated cardiomyopathy

Data availability: 8,139 ClinVar variants · 2 GenCC gene-disease records · 29 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › familial isolated arrhythmogenic right ventricular dysplasia › catecholaminergic polymorphic ventricular tachycardia 1

Related subtypes (15): arrhythmogenic right ventricular dysplasia 13, arrhythmogenic right ventricular dysplasia 1, arrhythmogenic right ventricular dysplasia 3, arrhythmogenic right ventricular dysplasia 4, arrhythmogenic right ventricular dysplasia 5, arrhythmogenic right ventricular dysplasia 6, 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:

285 uncertain significance, 235 likely benign, 49 conflicting classifications of pathogenicity, 12 pathogenic, 8 benign/likely benign, 5 pathogenic/likely pathogenic, 4 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1009997	NM_001035.3(RYR2):c.12424G>A (p.Ala4142Thr)	LOC126806068	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1021015	NM_001035.3(RYR2):c.12334G>A (p.Asp4112Asn)	RYR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1051501	NM_001035.3(RYR2):c.6504C>A (p.His2168Gln)	RYR2	Pathogenic	criteria provided, single submitter
1066599	NM_001035.3(RYR2):c.14234A>G (p.Asp4745Gly)	RYR2	Pathogenic	criteria provided, single submitter
1067931	NM_001035.3(RYR2):c.14174A>G (p.Tyr4725Cys)	RYR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069130	NM_001035.3(RYR2):c.6933G>C (p.Glu2311Asp)	RYR2	Pathogenic	criteria provided, single submitter
1070571	NM_001035.3(RYR2):c.12269C>T (p.Pro4090Leu)	RYR2	Pathogenic	criteria provided, single submitter
1072597	NM_001035.3(RYR2):c.7421G>A (p.Arg2474Lys)	RYR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1072928	NM_001035.3(RYR2):c.514G>A (p.Gly172Arg)	RYR2	Pathogenic	criteria provided, single submitter
12954	NM_001035.3(RYR2):c.6737C>T (p.Ser2246Leu)	RYR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12955	NM_001035.3(RYR2):c.7422G>C (p.Arg2474Ser)	RYR2	Pathogenic	no assertion criteria provided
12956	NM_001035.3(RYR2):c.12312C>G (p.Asn4104Lys)	RYR2	Pathogenic	no assertion criteria provided
12957	NM_001035.3(RYR2):c.13489C>T (p.Arg4497Cys)	RYR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12958	NM_001035.3(RYR2):c.7157A>T (p.Asn2386Ile)	RYR2	Pathogenic	criteria provided, single submitter
1070395	NM_006073.4(TRDN):c.22+29A>G	TRDN	Pathogenic	criteria provided, multiple submitters, no conflicts
1074440	NM_006073.4(TRDN):c.423del (p.Glu142fs)	TRDN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075032	NM_006073.4(TRDN):c.531del (p.Glu178fs)	TRDN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1119951	NM_001035.3(RYR2):c.12587C>T (p.Thr4196Ile)	LOC126806068	Likely pathogenic	criteria provided, single submitter
1007679	NM_001035.3(RYR2):c.12343C>T (p.Leu4115Phe)	RYR2	Likely pathogenic	criteria provided, single submitter
1013805	NM_001035.3(RYR2):c.14651_14652insTCC (p.Met4884delinsIlePro)	RYR2	Likely pathogenic	criteria provided, single submitter
1067138	NM_001035.3(RYR2):c.537T>A (p.Asp179Glu)	RYR2	Likely pathogenic	criteria provided, single submitter
1035127	NM_001232.4(CASQ2):c.1097T>C (p.Leu366Pro)	CASQ2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1222044	NM_001232.4(CASQ2):c.737+6T>A	CASQ2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1284371	NM_001035.3(RYR2):c.4148G>A (p.Arg1383His)	LOC126806067	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003245	NM_001035.3(RYR2):c.12638A>G (p.Glu4213Gly)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014648	NM_001035.3(RYR2):c.12865A>G (p.Ser4289Gly)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003697	NM_001035.3(RYR2):c.8792G>T (p.Arg2931Leu)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006238	NM_001035.3(RYR2):c.39C>G (p.Phe13Leu)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007678	NM_001035.3(RYR2):c.7315G>A (p.Ala2439Thr)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1008646	NM_001035.3(RYR2):c.5645A>G (p.Glu1882Gly)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 74 · 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
RYR2	Definitive	Autosomal dominant	arrhythmogenic right ventricular dysplasia 2	8

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
SCN4B	Orphanet:101016	Romano-Ward syndrome
SCN4B	Orphanet:334	Hereditary atrial fibrillation
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
TRDN	Orphanet:101016	Romano-Ward syndrome
TRDN	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CALM1	Orphanet:101016	Romano-Ward syndrome
CALM1	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CASQ2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
ACTN2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTN2	Orphanet:708129	Autosomal recessive ACTN2-related distal myopathy
ACTN2	Orphanet:708133	Autosomal dominant ACTN2-related distal myopathy
TRPM4	Orphanet:130	Brugada syndrome
TRPM4	Orphanet:316	Progressive symmetric erythrokeratodermia
TRPM4	Orphanet:871	Hereditary progressive cardiac conduction defect
DMPK	Orphanet:589821	Congenital-onset Steinert myotonic dystrophy
DMPK	Orphanet:589824	Childhood-onset Steinert myotonic dystrophy
DMPK	Orphanet:589827	Juvenile-onset Steinert myotonic dystrophy
DMPK	Orphanet:589830	Adult-onset Steinert myotonic dystrophy
DMPK	Orphanet:589833	Late-onset Steinert myotonic dystrophy
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
ANK2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:51083	Congenital short QT syndrome
LAMA4	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

19 cohort genes, 18 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	19

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	gencc,clinvar
SCN4B	HGNC:10592	ENSG00000177098	Q8IWT1	Sodium channel regulatory subunit beta-4	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
TRDN	HGNC:12261	ENSG00000186439	Q13061	Triadin	clinvar
CALM1	HGNC:1442	ENSG00000198668	P0DP23	Calmodulin-1	clinvar
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-2	clinvar
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	clinvar
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	clinvar
DMPK	HGNC:2933	ENSG00000104936	Q09013	Myotonin-protein kinase	clinvar
DSG2	HGNC:3049	ENSG00000046604	Q14126	Desmoglein-2	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
MT1HL1	HGNC:31864	ENSG00000244020	P0DM35	Metallothionein 1H-like protein 1	clinvar
TRDN-AS1	HGNC:40592	ENSG00000235535		TRDN antisense RNA 1	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar
LAMA4	HGNC:6484	ENSG00000112769	Q16363	Laminin subunit alpha-4	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	clinvar
ATP1A1	HGNC:799	ENSG00000163399	P05023	Sodium/potassium-transporting ATPase subunit alpha-1	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.
SCN4B	Sodium channel regulatory subunit beta-4	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
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.
TRDN	Triadin	Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction.
CALM1	Calmodulin-1	Calmodulin acts as part of a calcium signal transduction pathway by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding.
CASQ2	Calsequestrin-2	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.
DMPK	Myotonin-protein kinase	Non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function.
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.
MT1HL1	Metallothionein 1H-like protein 1	Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids.
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.
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.
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.
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
ATP1A1	Sodium/potassium-transporting ATPase subunit alpha-1	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.

Protein-family classification

Druggable: 7 · Difficult: 3 · Unknown: 9 · Druggable fraction: 0.37

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	4	23.5×	1e-04
Antibody/Immunoglobulin	2	3.1×	0.410
Scaffold/PPI	2	1.8×	0.603
Kinase	1	1.5×	0.754
Other/Unknown	9	0.8×	0.914
Transcription factor	1	0.4×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SCN4B	Antibody/Immunoglobulin	yes		Myelin_P0-rel, Ig_sub, Ig-like_dom
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
TRDN	Other/Unknown	no		Asp-B-hydro/Triadin_dom, Triadin
CALM1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CASQ2	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_sf
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM
DMPK	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
DSG2	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
MT1HL1	Other/Unknown	no		Metalthion_vert, TNFR/NGFR_Cys_rich_reg, Metalthion_dom_sf
TRDN-AS1	Other/Unknown	no
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
LAMA4	Other/Unknown	no		EGF, Laminin_G, LE_dom
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ATP1A1	Transcription factor	no	7.2.2.3	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC

Expression context

Cohort genes with no expression data: 0.

18 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)	19
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	7
heart left ventricle	3
heart right ventricle	2
left ventricle myocardium	2
myocardium	2
cardiac ventricle	2
skeletal muscle tissue of rectus abdominis	2
lateral nuclear group of thalamus	2
mucosa of stomach	2
cardiac atrium	2
right atrium auricular region	2
dorsal root ganglion	1
lateral globus pallidus	1
putamen	1
biceps brachii	1
gastrocnemius	1
medial globus pallidus	1
parietal lobe	1
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1

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
SCN4B	223	broad	marker	lateral globus pallidus, dorsal root ganglion, putamen
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
TRDN	182	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, gastrocnemius
CALM1	295	ubiquitous	marker	lateral nuclear group of thalamus, medial globus pallidus, parietal lobe
CASQ2	213	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart
DMPK	246	broad	marker	apex of heart, right coronary artery, mucosa of stomach
DSG2	238	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, jejunal mucosa
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
MT1HL1	84	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, heart left ventricle, apex of heart
TRDN-AS1	137	tissue_specific	marker	apex of heart, heart left ventricle, cardiac ventricle
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
KCNH2	211	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
LAMA4	268	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, nerve
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
MYBPC3	149	tissue_specific	marker	apex of heart, right atrium auricular region, cardiac atrium
ATP1A1	305	ubiquitous	marker	renal medulla, right lobe of thyroid gland, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
ANK2	6,423
ATP1A1	3,520
DSP	2,897
ACTN2	2,781
LAMA4	2,688
RYR2	2,653
DMPK	2,467
SCN5A	2,090
DSG2	2,033

Intra-cohort edges

A	B	Sources
CALM1	RYR2	biogrid_interaction
CALM1	SCN5A	intact
CASQ2	KCNH2	string_interaction
CASQ2	RYR2	string_interaction
CASQ2	SCN5A	string_interaction
CASQ2	TRDN	string_interaction
DSG2	DSP	string_interaction
DSG2	MYBPC3	string_interaction
DSG2	RYR2	string_interaction
DSG2	SCN5A	string_interaction
KCNH2	SCN4B	string_interaction
KCNH2	SCN5A	string_interaction
RYR2	TRDN	string_interaction
SCN4B	SCN5A	string_interaction
SCN5A	TRPM4	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALM1	P0DP23	337
TRPM4	Q8TD43	29
LMNA	P02545	28
RYR2	Q92736	26
KCNH2	Q12809	24
MYBPC3	Q14896	17
SCN5A	Q14524	16
ACTN2	P35609	16
ATP1A1	P05023	13
DSG2	Q14126	12
ANK2	Q01484	11
SCN4B	Q8IWT1	5
CASQ2	O14958	4
DSP	P15924	4
DMPK	Q09013	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MT1HL1	P0DM35	74.02
LAMA4	Q16363	73.75
TRDN	Q13061	47.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 195. Enrichment computed across 19 evidence-associated genes (17 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 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Muscle contraction	9	40.9×	4e-11	RYR2, SCN4B, SCN5A, CALM1, CASQ2, ACTN2, KCNH2, MYBPC3 (+1 more)
Cardiac conduction	7	44.8×	8e-09	RYR2, SCN4B, SCN5A, CALM1, CASQ2, KCNH2, ATP1A1
Ion homeostasis	6	72.0×	8e-09	RYR2, TRDN, CALM1, CASQ2, DMPK, ATP1A1
Stimuli-sensing channels	4	32.0×	3e-04	RYR2, TRDN, CALM1, CASQ2
Interaction between L1 and Ankyrins	3	65.0×	5e-04	SCN4B, SCN5A, ANK2
Phase 0 - rapid depolarisation	3	61.1×	5e-04	SCN4B, SCN5A, CALM1
Ion channel transport	4	22.6×	7e-04	RYR2, CALM1, CASQ2, ATP1A1
Apoptotic cleavage of cell adhesion proteins	2	122.1×	0.003	DSG2, DSP
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	2	103.3×	0.003	CALM1, ACTN2
Ras activation upon Ca2+ influx through NMDA receptor	2	67.2×	0.006	CALM1, ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	2	64.0×	0.006	CALM1, ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	2	64.0×	0.006	CALM1, ACTN2
L1CAM interactions	3	21.2×	0.006	SCN4B, SCN5A, ANK2
Long-term potentiation	2	56.0×	0.008	CALM1, ACTN2
Striated Muscle Contraction	2	36.3×	0.018	ACTN2, MYBPC3
Sensory perception of sweet, bitter, and umami (glutamate) taste	2	32.8×	0.020	SCN4B, TRPM4
Oncogenic MAPK signaling	2	29.2×	0.024	CALM1, LMNA
Ionotropic activity of kainate receptors	1	335.9×	0.028	CALM1
Activation of kainate receptors upon glutamate binding	1	335.9×	0.028	CALM1
Ion transport by P-type ATPases	2	24.4×	0.028	CALM1, ATP1A1
Post NMDA receptor activation events	2	24.0×	0.028	CALM1, ACTN2
Activation of NMDA receptors and postsynaptic events	2	21.7×	0.033	CALM1, ACTN2
Transport of small molecules	4	5.9×	0.033	RYR2, CALM1, CASQ2, ATP1A1
Breakdown of the nuclear lamina	1	223.9×	0.035	LMNA
Signaling by BRAF and RAF1 fusions	2	20.1×	0.035	CALM1, LMNA
Response to elevated platelet cytosolic Ca2+	2	19.2×	0.036	CALM1, ACTN2
Cam-PDE 1 activation	1	167.9×	0.040	CALM1
Loss of phosphorylation of MECP2 at T308	1	167.9×	0.040	CALM1
Axon guidance	3	8.0×	0.040	SCN4B, SCN5A, ANK2
Neuronal System	3	7.8×	0.040	CALM1, ACTN2, KCNH2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 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	7	145.6×	5e-12	SCN4B, SCN5A, TRPM4, DSG2, DSP, ANK2, KCNH2
cardiac muscle contraction	6	133.8×	4e-10	RYR2, SCN4B, SCN5A, CASQ2, KCNH2, MYBPC3
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	5	187.2×	4e-09	RYR2, TRDN, CALM1, CASQ2, ANK2
regulation of heart rate	5	130.0×	2e-08	RYR2, SCN5A, CALM1, CASQ2, ANK2
regulation of ventricular cardiac muscle cell action potential	4	312.1×	2e-08	RYR2, TRPM4, DSG2, DSP
ventricular cardiac muscle cell action potential	4	220.3×	1e-07	RYR2, SCN5A, ANK2, KCNH2
regulation of ventricular cardiac muscle cell membrane repolarization	4	187.2×	2e-07	SCN4B, SCN5A, ANK2, KCNH2
intracellular calcium ion homeostasis	5	40.4×	4e-06	RYR2, TRDN, CASQ2, DMPK, ANK2
detection of calcium ion	3	187.2×	1e-05	RYR2, CALM1, CASQ2
regulation of cardiac muscle cell contraction	3	187.2×	1e-05	SCN5A, ANK2, MYBPC3
regulation of cardiac muscle contraction	3	147.8×	2e-05	RYR2, CALM1, ANK2
Purkinje myocyte to ventricular cardiac muscle cell signaling	2	936.2×	2e-05	RYR2, CASQ2
cardiac muscle cell action potential involved in contraction	3	117.0×	4e-05	SCN4B, SCN5A, ATP1A1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	3	112.3×	4e-05	TRDN, CALM1, CASQ2
membrane depolarization during Purkinje myocyte cell action potential	2	624.1×	5e-05	SCN5A, TRPM4
membrane depolarization during bundle of His cell action potential	2	624.1×	5e-05	SCN5A, TRPM4
regulation of atrial cardiac muscle cell action potential	2	624.1×	5e-05	RYR2, ANK2
AV node cell action potential	2	468.1×	1e-04	SCN4B, SCN5A
sarcoplasmic reticulum calcium ion transport	2	374.5×	1e-04	RYR2, ANK2
membrane depolarization during AV node cell action potential	2	374.5×	1e-04	SCN5A, TRPM4
membrane depolarization during SA node cell action potential	2	374.5×	1e-04	SCN5A, ANK2
SA node cell action potential	2	312.1×	2e-04	SCN5A, ANK2
regulation of SA node cell action potential	2	312.1×	2e-04	RYR2, ANK2
regulation of cell communication by electrical coupling	2	267.5×	2e-04	TRDN, CASQ2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	2	267.5×	2e-04	DSG2, DSP
desmosome organization	2	234.1×	3e-04	DSG2, DSP
negative regulation of potassium ion transport	2	208.1×	4e-04	CASQ2, ACTN2
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	2	187.2×	4e-04	RYR2, TRDN
membrane depolarization during action potential	2	187.2×	4e-04	SCN5A, KCNH2
membrane repolarization during cardiac muscle cell action potential	2	187.2×	4e-04	KCNH2, ATP1A1

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 12

Druggability breadth: 10 of 19 evidence-associated genes (53%) 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
CALM1	CLOZAPINE
DMPK	FEDRATINIB
KCNH2	CETIRIZINE
LMNA	BEPRIDIL
ATP1A1	DIGOXIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
KCNH2	706	4
SCN5A	108	4
DMPK	20	4
CALM1	6	4
ATP1A1	5	4
RYR2	1	2
SCN4B	0	0
TRDN	0	0
CASQ2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNH2, LMNA, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	LMNA, SCN5A
DIBUCAINE	4	KCNH2, LMNA, SCN5A
IMIPRAMINE	4	KCNH2, LMNA, SCN5A
DROPERIDOL	4	KCNH2, LMNA, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	KCNH2, SCN5A
PALONOSETRON	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	LMNA, SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	DMPK, KCNH2, SCN5A
QUINIDINE	4	KCNH2, SCN5A
DARUNAVIR	4	KCNH2, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	KCNH2, LMNA, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	KCNH2, LMNA, SCN5A
NIMODIPINE	4	LMNA, SCN5A
FELODIPINE	4	LMNA, SCN5A
NICARDIPINE	4	KCNH2, LMNA, SCN5A
AMLODIPINE	4	KCNH2, SCN5A
PHENYTOIN	4	KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, 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
DMPK	210	Binding:210
ATP1A1	50	Binding:50
CALM1	23	Binding:23
RYR2	15	Binding:15
TRPM4	14	Binding:13, Functional:1
LMNA	12	Binding:9, Functional:3
DSP	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DMPK	2.7.11.1	non-specific serine/threonine protein kinase
ATP1A1	7.2.2.3	P-type Na+ transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594
DMPK	210
KCNH2	4,851

Pharmacogenomics

Cohort genes with a PharmGKB record: 18; 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	KCNH2, LMNA, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	LMNA, SCN5A
DIBUCAINE	4	KCNH2, LMNA, SCN5A
IMIPRAMINE	4	KCNH2, LMNA, SCN5A
DROPERIDOL	4	KCNH2, LMNA, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	KCNH2, SCN5A
PALONOSETRON	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	LMNA, SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	DMPK, KCNH2, SCN5A
QUINIDINE	4	KCNH2, SCN5A
DARUNAVIR	4	KCNH2, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	KCNH2, LMNA, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	KCNH2, LMNA, SCN5A
NIMODIPINE	4	LMNA, SCN5A
FELODIPINE	4	LMNA, SCN5A
NICARDIPINE	4	KCNH2, LMNA, SCN5A
AMLODIPINE	4	KCNH2, SCN5A
PHENYTOIN	4	KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	SCN5A, CALM1, DMPK, KCNH2, LMNA, ATP1A1
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	3	SCN4B, TRPM4, MYBPC3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	TRDN, CASQ2, ACTN2, DSG2, DSP, MT1HL1, TRDN-AS1, ANK2, LAMA4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SCN4B	0	SCN5A
TRDN	0	RYR2
CASQ2	0	RYR2
ACTN2	0	—
TRPM4	14	—
DSG2	0	—
DSP	2	—
MT1HL1	0	—
TRDN-AS1	0	—
ANK2	0	—
LAMA4	0	—
MYBPC3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	2
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05122975	PHASE2	TERMINATED	Treatment of an Inherited Ventricular Arrhythmia
NCT06005428	PHASE2	TERMINATED	Effectiveness of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT06661278	Not specified	RECRUITING	Evaluation of Exercise Testing and Physical Activity in Children and Adolescents Living With Inherited Arrhythmias

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SURLORIAN	2	1