Catecholaminergic polymorphic ventricular tachycardia

Summary

Catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990) is a disease (an umbrella term covering 7 Mondo subtypes) caused by variants in CASQ2, RYR2, TECRL, and 2 other genes, with 16 cohort genes and 13 clinical trials. The dominant Reactome pathway is Muscle contraction (8 cohort genes). Top therapeutic interventions include flecainide acetate.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal genes: CASQ2 (GenCC Definitive), RYR2 (GenCC Definitive), TECRL (GenCC Definitive), TRDN (GenCC Definitive) (+1 more)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 16
• ClinVar variants: 2,834
• Phenotypes (HPO): 10
• Clinical trials: 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Europe	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0004756	Ventricular tachycardia	Very frequent (80-99%)
HP:0001695	Cardiac arrest	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0004755	Supraventricular tachycardia	Frequent (30-79%)
HP:0005110	Atrial fibrillation	Frequent (30-79%)
HP:0031677	Polymorphic ventricular tachycardia	Frequent (30-79%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0001663	Ventricular fibrillation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	catecholaminergic polymorphic ventricular tachycardia
Mondo ID	MONDO:0017990
MeSH	C536334
OMIM	604772
Orphanet	3286
DOID	DOID:0060674
ICD-11	976309888
SNOMED CT	419671004
UMLS	C5574922
MedGen	1803763
GARD	0004421
Is cancer (heuristic)	no

Also known as: bidirectional tachycardia induced by catecholamine · catecholamine-induced polymorphic ventricular tachycardia · catecholaminergic polymorphic ventricular tachycardia · CPVT · double tachycardia induced by catecholamines · familial polymorphic ventricular tachycardia · malignant paroxysmal ventricular tachycardia · multifocal ventricular premature beats · polymorphic catecholergic ventricular tachycardia · stress-induced polymorphic ventricular tachycardia · syncopal paroxysmal tachycardia · ventricular tachycardia, catecholaminergic polymorphic

Data availability: 2,834 ClinVar variants · 21 GenCC gene-disease records · 35 cell lines.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › catecholaminergic polymorphic ventricular tachycardia

Related subtypes (9): short QT syndrome, atrioventricular block, sinoatrial node disorder, Wolff-Parkinson-White syndrome, postural orthostatic tachycardia syndrome, Brugada syndrome, progressive familial heart block, sinoatrial block, NKX2.5-related congenital, conduction and myopathic heart disease

Subtypes (7): catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 2, catecholaminergic polymorphic ventricular tachycardia 3, catecholaminergic polymorphic ventricular tachycardia 4, catecholaminergic polymorphic ventricular tachycardia 5, long QT syndrome 16, ventricular tachycardia, catecholaminergic polymorphic 6

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:

287 uncertain significance, 163 likely benign, 121 conflicting classifications of pathogenicity, 22 benign/likely benign, 3 pathogenic/likely pathogenic, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067931	NM_001035.3(RYR2):c.14174A>G (p.Tyr4725Cys)	RYR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12959	NM_001035.3(RYR2):c.1298T>C (p.Leu433Pro)	RYR2	Pathogenic	criteria provided, multiple submitters, no conflicts
201214	NM_001035.3(RYR2):c.1258C>T (p.Arg420Trp)	RYR2	Pathogenic	criteria provided, multiple submitters, no conflicts
201276	NM_001035.3(RYR2):c.7159G>A (p.Ala2387Thr)	RYR2	Pathogenic/Likely 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
1035886	NM_001035.3(RYR2):c.11579C>T (p.Thr3860Ile)	RYR2	Likely pathogenic	criteria provided, single submitter
1066855	NC_000001.10:g.(?237205802)(237519305_?)dup	RYR2	Likely pathogenic	criteria provided, single submitter
190518	NM_005751.5(AKAP9):c.510G>C (p.Glu170Asp)	AKAP9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197538	NM_000719.7(CACNA1C):c.6116C>G (p.Ala2039Gly)	CACNA1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195838	NM_001267550.2(TTN):c.3988C>T (p.Arg1330Cys)	LOC101927055	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
138943	NM_001035.3(RYR2):c.3888C>T (p.Asn1296=)	LOC126806067	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201170	NM_001035.3(RYR2):c.4096A>G (p.Thr1366Ala)	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
1315962	NM_001035.3(RYR2):c.12752A>G (p.Asn4251Ser)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1332070	NM_001035.3(RYR2):c.13252A>G (p.Lys4418Glu)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1332236	NM_001035.3(RYR2):c.12664G>A (p.Glu4222Lys)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165127	NM_001035.3(RYR2):c.12859T>C (p.Tyr4287His)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1765515	NM_001035.3(RYR2):c.12717G>C (p.Leu4239=)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201183	NM_001035.3(RYR2):c.12492G>A (p.Gln4164=)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201185	NM_001035.3(RYR2):c.12858C>T (p.Ser4286=)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201332	NM_001035.3(RYR2):c.12427A>C (p.Lys4143Gln)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201401	NM_001035.3(RYR2):c.12526G>A (p.Val4176Met)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2099802	NM_001035.3(RYR2):c.12647C>T (p.Ala4216Val)	LOC126806068	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
1014565	NM_001035.3(RYR2):c.3431G>A (p.Arg1144Gln)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1026347	NM_001035.3(RYR2):c.5590C>A (p.Leu1864Met)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1039726	NM_001035.3(RYR2):c.5793T>G (p.Asp1931Glu)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043759	NM_001035.3(RYR2):c.8407C>T (p.Arg2803Trp)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 79 · Orphanet: 39 · 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
CASQ2	Definitive	Autosomal recessive	catecholaminergic polymorphic ventricular tachycardia	8
PKP2	Definitive	Autosomal dominant	arrhythmogenic right ventricular dysplasia 9	6
RYR2	Definitive	Autosomal dominant	arrhythmogenic right ventricular dysplasia 2	8
TECRL	Definitive	Autosomal recessive	catecholaminergic polymorphic ventricular tachycardia	7
TRDN	Definitive	Autosomal recessive	catecholaminergic polymorphic ventricular tachycardia	7
CALM1	Strong	Autosomal dominant	catecholaminergic polymorphic ventricular tachycardia 4	7
CALM2	Strong	Autosomal dominant	catecholaminergic polymorphic ventricular tachycardia	5
CALM3	Moderate	Autosomal dominant	catecholaminergic polymorphic ventricular tachycardia	5
ANK2	Limited	Autosomal dominant	catecholaminergic polymorphic ventricular tachycardia	11
KCNJ2	Limited	Autosomal dominant	catecholaminergic polymorphic ventricular tachycardia	15

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
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
TECRL	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CALM2	Orphanet:101016	Romano-Ward syndrome
CALM2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CALM3	Orphanet:101016	Romano-Ward syndrome
CALM3	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
ANK2	Orphanet:101016	Romano-Ward syndrome
KCNJ2	Orphanet:334	Hereditary atrial fibrillation
KCNJ2	Orphanet:37553	Andersen-Tawil syndrome
KCNJ2	Orphanet:51083	Congenital short QT syndrome
PKP2	Orphanet:130	Brugada syndrome
PKP2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
PKP2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
PKP2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
PKP2	Orphanet:54260	Left ventricular noncompaction
CACNA1C	Orphanet:101016	Romano-Ward syndrome
CACNA1C	Orphanet:130	Brugada syndrome
CACNA1C	Orphanet:528084	Non-specific syndromic intellectual disability
CACNA1C	Orphanet:595098	Timothy syndrome type 1
CACNA1C	Orphanet:595105	Timothy syndrome type 2
CACNA1C	Orphanet:595109	Atypical Timothy syndrome
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
AKAP9	Orphanet:101016	Romano-Ward syndrome
AKAP9	Orphanet:130	Brugada syndrome
GABRA1	Orphanet:307	Juvenile myoclonic epilepsy
GABRA1	Orphanet:33069	Dravet syndrome
GABRA1	Orphanet:64280	Childhood absence epilepsy
MYBPC3	Orphanet:154	Familial isolated dilated cardiomyopathy
MYBPC3	Orphanet:54260	Left ventricular noncompaction

Cohort genes → proteins

16 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	16

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	gencc,clinvar
TRDN	HGNC:12261	ENSG00000186439	Q13061	Triadin	gencc,clinvar
CALM1	HGNC:1442	ENSG00000198668	P0DP23	Calmodulin-1	gencc,clinvar
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-2	gencc,clinvar
TECRL	HGNC:27365	ENSG00000205678	Q5HYJ1	Trans-2,3-enoyl-CoA reductase-like	gencc,clinvar
CALM2	HGNC:1445	ENSG00000143933	P0DP24	Calmodulin-2	gencc
CALM3	HGNC:1449	ENSG00000160014	P0DP25	Calmodulin-3	gencc
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	gencc
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	gencc
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	gencc
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	clinvar
KLHL8	HGNC:18644	ENSG00000145332	Q9P2G9	Kelch-like protein 8	clinvar
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	clinvar
GABRA1	HGNC:4075	ENSG00000022355	P14867	Gamma-aminobutyric acid receptor subunit alpha-1	clinvar
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	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.
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.
CALM2	Calmodulin-2	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.
CALM3	Calmodulin-3	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.
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.
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
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.
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
KLHL8	Kelch-like protein 8	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex required for The BCR(KLHL8) ubiquitin ligase complex mediates ubiquitination and degradation of RAPSN.
AKAP9	A-kinase anchor protein 9	Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus.
GABRA1	Gamma-aminobutyric acid receptor subunit alpha-1	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 11 · Druggable fraction: 0.25

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	3	20.9×	0.001
Other/Unknown	11	1.2×	0.433
Antibody/Immunoglobulin	1	1.8×	0.570
Scaffold/PPI	1	1.1×	0.615

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
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
TECRL	Other/Unknown	no		3-oxo-5_a-steroid_4-DH_C, SRD5A/TECR, TECRL_Ubl
CALM2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
CALM3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
KLHL8	Other/Unknown	no		BTB/POZ_dom, Kelch_1, Gal_Oxase/kelch_b-propeller
AKAP9	Other/Unknown	no		ELK_dom, PACT_domain, AKAP9/Pericentrin
GABRA1	Other/Unknown	no		GABAAa_rcpt, GABBAa1_rcpt, GABAA/Glycine_rcpt
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

15 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)	16
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	4
left ventricle myocardium	4
myocardium	3
skeletal muscle tissue of rectus abdominis	3
lateral nuclear group of thalamus	3
apex of heart	3
middle temporal gyrus	2
biceps brachii	1
gastrocnemius	1
medial globus pallidus	1
parietal lobe	1
Brodmann (1909) area 23	1
orbitofrontal cortex	1
left testis	1
prefrontal cortex	1
right frontal lobe	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
dorsal motor nucleus of vagus nerve	1
inferior vagus X ganglion	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
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
TECRL	135	tissue_specific	yes	myocardium, heart right ventricle, left ventricle myocardium
CALM2	310	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex
CALM3	297	ubiquitous	marker	prefrontal cortex, right frontal lobe, left testis
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
KCNJ2	256	ubiquitous	marker	inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve
PKP2	237	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
KLHL8	256	ubiquitous	marker	corpus epididymis, kidney epithelium, secondary oocyte
AKAP9	292	ubiquitous	marker	jejunal mucosa, bronchial epithelial cell, cortical plate
GABRA1	130	tissue_specific	marker	lateral nuclear group of thalamus, endothelial cell, middle temporal gyrus
MYBPC3	149	tissue_specific	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
AKAP9	3,537
CACNA1C	3,145
ACTN2	2,781
RYR2	2,653
GABRA1	2,469
CASQ2	1,977
PKP2	1,861
MYBPC3	1,800
TRDN	1,799

Intra-cohort edges

A	B	Sources
ACTN2	CACNA1C	biogrid_interaction
CACNA1C	CALM1	intact
CACNA1C	CASQ2	string_interaction
CACNA1C	RYR2	biogrid_interaction, string_interaction
CALM1	RYR2	biogrid_interaction
CASQ2	RYR2	string_interaction
CASQ2	TECRL	string_interaction
CASQ2	TRDN	string_interaction
PKP2	RYR2	string_interaction
RYR2	TECRL	string_interaction
RYR2	TRDN	string_interaction
TECRL	TRDN	string_interaction

Structural data

PDB: 12 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALM1	P0DP23	337
GABRA1	P14867	86
CACNA1C	Q13936	33
RYR2	Q92736	26
CALM3	P0DP25	26
CALM2	P0DP24	21
MYBPC3	Q14896	17
ACTN2	P35609	16
ANK2	Q01484	11
CASQ2	O14958	4
KCNJ2	P63252	3
PKP2	Q99959	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL8	Q9P2G9	90.73
TECRL	Q5HYJ1	84.32
TRDN	Q13061	47.65
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 198. Enrichment computed across 16 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Muscle contraction	8	41.1×	8e-10	RYR2, CALM1, CASQ2, CACNA1C, ACTN2, AKAP9, KCNJ2, MYBPC3
Cardiac conduction	6	43.5×	2e-07	RYR2, CALM1, CASQ2, CACNA1C, AKAP9, KCNJ2
CASP4 inflammasome assembly	3	253.8×	1e-05	CALM1, CALM2, CALM3
Enterobacterial factors antagonize host defense	3	163.1×	3e-05	CALM1, CALM2, CALM3
Ion homeostasis	4	54.4×	3e-05	RYR2, TRDN, CALM1, CASQ2
Stimuli-sensing channels	4	36.2×	1e-04	RYR2, TRDN, CALM1, CASQ2
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	2	117.1×	0.004	CALM1, ACTN2
Phase 2 - plateau phase	2	101.5×	0.004	CACNA1C, AKAP9
Ras activation upon Ca2+ influx through NMDA receptor	2	76.1×	0.006	CALM1, ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	2	72.5×	0.006	CALM1, ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	2	72.5×	0.006	CALM1, ACTN2
Long-term potentiation	2	63.4×	0.006	CALM1, ACTN2
Neurotransmitter receptors and postsynaptic signal transmission	3	20.0×	0.006	CALM1, ACTN2, KCNJ2
Ion channel transport	3	19.2×	0.006	RYR2, CALM1, CASQ2
Phase 0 - rapid depolarisation	2	46.1×	0.011	CALM1, CACNA1C
Transmission across Chemical Synapses	3	15.2×	0.011	CALM1, ACTN2, KCNJ2
GABA receptor activation	2	42.3×	0.011	GABRA1, KCNJ2
Striated Muscle Contraction	2	41.1×	0.011	ACTN2, MYBPC3
Oncogenic MAPK signaling	2	33.1×	0.017	CALM1, AKAP9
Ionotropic activity of kainate receptors	1	380.7×	0.023	CALM1
Activation of kainate receptors upon glutamate binding	1	380.7×	0.023	CALM1
Sensory perception of sour taste	1	380.7×	0.023	KCNJ2
Post NMDA receptor activation events	2	27.2×	0.023	CALM1, ACTN2
Activation of NMDA receptors and postsynaptic events	2	24.6×	0.024	CALM1, ACTN2
Signaling by BRAF and RAF1 fusions	2	22.7×	0.027	CALM1, AKAP9
Response to elevated platelet cytosolic Ca2+	2	21.8×	0.028	CALM1, ACTN2
Neuronal System	3	8.8×	0.031	CALM1, ACTN2, KCNJ2
Cam-PDE 1 activation	1	190.3×	0.035	CALM1
Classical Kir channels	1	190.3×	0.035	KCNJ2
Loss of phosphorylation of MECP2 at T308	1	190.3×	0.035	CALM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 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 cardiac muscle contraction by regulation of the release of sequestered calcium ion	8	337.0×	2e-17	RYR2, TRDN, CALM1, CASQ2, CACNA1C, CALM2, CALM3, ANK2
regulation of heart rate	6	175.5×	4e-11	RYR2, CALM1, CASQ2, CALM2, CALM3, ANK2
detection of calcium ion	5	351.1×	7e-11	RYR2, CALM1, CASQ2, CALM2, CALM3
regulation of cardiac muscle contraction	5	277.2×	2e-10	RYR2, CALM1, CALM2, CALM3, ANK2
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	5	210.7×	7e-10	TRDN, CALM1, CASQ2, CALM2, CALM3
regulation of heart rate by cardiac conduction	5	117.0×	1e-08	CACNA1C, AKAP9, ANK2, KCNJ2, PKP2
negative regulation of calcium ion export across plasma membrane	3	789.9×	7e-08	CALM1, CALM2, CALM3
presynaptic endocytosis	3	632.0×	2e-07	CALM1, CALM2, CALM3
regulation of cell communication by electrical coupling involved in cardiac conduction	3	351.1×	1e-06	CALM1, CALM2, CALM3
calcineurin-mediated signaling	3	287.2×	2e-06	CALM1, CALM2, CALM3
cell communication by electrical coupling involved in cardiac conduction	3	263.3×	2e-06	RYR2, CACNA1C, PKP2
regulation of ventricular cardiac muscle cell action potential	3	263.3×	2e-06	RYR2, CACNA1C, PKP2
regulation of membrane repolarization	3	243.1×	3e-06	CASQ2, AKAP9, KCNJ2
regulation of calcium-mediated signaling	3	210.7×	4e-06	CALM1, CALM2, CALM3
regulation of cardiac muscle cell contraction	3	210.7×	4e-06	ANK2, KCNJ2, MYBPC3
ventricular cardiac muscle cell action potential	3	185.9×	5e-06	RYR2, ANK2, PKP2
negative regulation of ryanodine-sensitive calcium-release channel activity	2	1053.2×	8e-06	CALM1, CALM2
Purkinje myocyte to ventricular cardiac muscle cell signaling	2	1053.2×	8e-06	RYR2, CASQ2
negative regulation of high voltage-gated calcium channel activity	2	1053.2×	8e-06	CALM1, CALM3
cardiac muscle cell action potential involved in contraction	3	131.7×	1e-05	CACNA1C, KCNJ2, PKP2
regulation of atrial cardiac muscle cell action potential	2	702.2×	2e-05	RYR2, ANK2
intracellular calcium ion homeostasis	4	36.3×	3e-05	RYR2, TRDN, CASQ2, ANK2
regulation of cytokinesis	3	79.0×	5e-05	CALM1, CALM2, CALM3
cardiac muscle contraction	3	75.2×	6e-05	RYR2, CASQ2, MYBPC3
sarcoplasmic reticulum calcium ion transport	2	421.3×	6e-05	RYR2, ANK2
substantia nigra development	3	68.7×	7e-05	CALM1, CALM2, CALM3
regulation of cardiac muscle cell action potential	2	351.1×	8e-05	CALM1, CALM3
regulation of SA node cell action potential	2	351.1×	8e-05	RYR2, ANK2
response to calcium ion	3	59.6×	1e-04	CALM1, CALM2, CALM3
G2/M transition of mitotic cell cycle	3	58.5×	1e-04	CALM1, CALM2, CALM3

Therapeutics

Drug target analysis

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

Druggability breadth: 6 of 16 evidence-associated genes (38%) 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
CALM1	CLOZAPINE
CACNA1C	REMIFENTANIL
GABRA1	DIAZEPAM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1C	85	4
GABRA1	60	4
CALM1	6	4
RYR2	1	2
TRDN	0	0
CASQ2	0	0
TECRL	0	0
CALM2	0	0
CALM3	0	0
ANK2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOZAPINE	4	CACNA1C, CALM1, GABRA1
TRIFLUOPERAZINE	4	CALM1
PROMETHAZINE	4	CALM1
CHLORPROMAZINE	4	CACNA1C, CALM1
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NIMODIPINE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GABRA1	842	Binding:701, Functional:124, ADMET:13, Toxicity:4
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
KCNJ2	31	Binding:23, ADMET:8
CALM1	23	Binding:23
RYR2	15	Binding:15
CALM2	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1C	575
GABRA1	842

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; 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)
CLOZAPINE	4	CACNA1C, CALM1, GABRA1
TRIFLUOPERAZINE	4	CALM1
PROMETHAZINE	4	CALM1
CHLORPROMAZINE	4	CACNA1C, CALM1
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NIMODIPINE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CALM1, CACNA1C, GABRA1
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	2	KCNJ2, MYBPC3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	10	TRDN, CASQ2, TECRL, CALM2, CALM3, ANK2, PKP2, ACTN2, KLHL8, AKAP9

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)
TRDN	0	RYR2
CASQ2	0	RYR2, CACNA1C
TECRL	0	—
CALM2	1	—
CALM3	0	—
ANK2	0	—
KCNJ2	31	—
PKP2	0	—
ACTN2	0	—
KLHL8	0	—
AKAP9	0	—
MYBPC3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 13.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06658899	PHASE2	RECRUITING	A Phase 2 Study of CRD-4730 in CPVT
NCT07263139	PHASE2	RECRUITING	Safety, Tolerability, and Exploratory Efficacy of AGP100 in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT07148089	PHASE1	RECRUITING	A Study of SGT-501 Gene Therapy in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT04189822	Not specified	ENROLLING_BY_INVITATION	Hearts in Rhythm Organization (HiRO)National Registry and Bio Bank
NCT05521451	Not specified	RECRUITING	Clinical Cohort Study - TRUST
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
NCT01117454	Not specified	COMPLETED	Flecainide for Catecholaminergic Polymorphic Ventricular Tachycardia
NCT02927223	Not specified	COMPLETED	Atropine in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT04124237	Not specified	COMPLETED	Long Term Monitoring for Risk of Sudden Death
NCT04650009	Not specified	COMPLETED	Physical Activity in Children With Inherited Cardiac Diseases
NCT04712136	Not specified	COMPLETED	Healthy-related Quality of Life and Physical Activity of Children With Cardiac Malformations
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLECAINIDE ACETATE	4	1
CHEMBL4557433	0	1