Cardiac rhythm disease

Summary

Cardiac rhythm disease (MONDO:0007263) is a disease (an umbrella term covering 17 Mondo subtypes) with 48 cohort genes and 265 clinical trials. The dominant Reactome pathway is Cardiac conduction (16 cohort genes). Top therapeutic interventions include amiodarone, flecainide, and imipramine.

At a glance

• Umbrella term: 17 Mondo subtypes
• Cohort genes: 48
• ClinVar variants: 4,041
• Clinical trials: 265

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiac rhythm disease
Mondo ID	MONDO:0007263
NCIT	C2881
SNOMED CT	698247007
UMLS	C0003811
MedGen	2039
Is cancer (heuristic)	no

Also known as: arrhythmia

Data availability: 4,041 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 17 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease

Related subtypes (33): endocardium disorder, pericardium disorder, cardiac tuberculosis, heart conduction disease, hypertensive heart disease, heart valve disorder, cardiomyopathy, coronary artery disorder, heart failure, congenital heart disease, heart aneurysm, rheumatic heart disease, white forelock with malformations, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, microcephaly-cardiac defect-lung malsegmentation syndrome, PHACE syndrome, microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type, cardiac anomalies-heterotaxy syndrome, polyvalvular heart disease syndrome, Thomas syndrome, 22q11.2 deletion syndrome, myocardial rupture, heart neoplasm, aortopulmonary window, cor biloculare, inflammation of heart layer, myocardial disorder, carcinoid heart disease, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, coronary microvascular disorder, cardiac ventricle disorder, cardiogenetic disease, cardiogenic shock

Subtypes (17): ventricular fibrillation, cardiac arrest, atrial fibrillation, ventricular tachycardia, atrial tachycardia, torsade-de-pointes syndrome with short coupling interval, sinoatrial node dysfunction and deafness, sino-auricular heart block, multifocal atrial tachycardia, His bundle tachycardia, incessant infant ventricular tachycardia, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, sudden arrhythmia death syndrome, cardiac conduction defect, sudden cardiac arrest, cardiac conduction disease with or without cardiomyoopathy, cardiogenetic rhythm disorder

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:

240 uncertain significance, 235 likely benign, 67 conflicting classifications of pathogenicity, 31 benign/likely benign, 11 pathogenic, 9 pathogenic/likely pathogenic, 5 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
17621	NM_000070.3(CAPN3):c.550del (p.Thr184fs)	CAPN3	Pathogenic	reviewed by expert panel
1074305	NM_000238.4(KCNH2):c.2775del (p.Pro926fs)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076382	NM_000238.4(KCNH2):c.817C>T (p.Arg273Ter)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1397577	NM_000238.4(KCNH2):c.1629dup (p.Glu544fs)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
1414553	NM_000238.4(KCNH2):c.3105_3109dup (p.Asp1037fs)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
14420	NM_000238.4(KCNH2):c.1682C>T (p.Ala561Val)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14428	NM_000238.4(KCNH2):c.1744C>T (p.Arg582Cys)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14430	NM_000238.4(KCNH2):c.1468G>A (p.Ala490Thr)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14432	NM_000238.4(KCNH2):c.2453C>T (p.Ser818Leu)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
14435	NM_000238.4(KCNH2):c.2255G>A (p.Arg752Gln)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1171410	NM_000218.3(KCNQ1):c.1792_1793del (p.Lys598fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185948	NM_000218.3(KCNQ1):c.1097G>T (p.Arg366Leu)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395670	NM_000218.3(KCNQ1):c.1239del (p.Lys414fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1414164	NM_000218.3(KCNQ1):c.700C>T (p.Gln234Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
1426804	NM_000218.3(KCNQ1):c.1354del (p.Arg452fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
1455898	NM_000218.3(KCNQ1):c.745_746dup (p.Leu250fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
1771701	NM_000218.3(KCNQ1):c.1033-1_1117dup	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
1332487	NM_000335.5(SCN5A):c.2849_2850del (p.Pro950fs)	LOC110121269	Pathogenic	criteria provided, single submitter
1072847	NM_000335.5(SCN5A):c.934+1G>A	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
1185878	NM_000335.5(SCN5A):c.3762del (p.Leu1255fs)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
1435108	NM_054012.4(ASS1):c.892G>A (p.Glu298Lys)	ASS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098796	NM_000238.4(KCNH2):c.2959dup (p.Leu987fs)	KCNH2	Likely pathogenic	criteria provided, single submitter
1171507	NM_000238.4(KCNH2):c.77-1G>T	KCNH2	Likely pathogenic	criteria provided, single submitter
1331817	NM_000218.3(KCNQ1):c.1590+2T>A	KCNQ1	Likely pathogenic	criteria provided, single submitter
1171509	NM_000335.5(SCN5A):c.703+1G>T	SCN5A	Likely pathogenic	criteria provided, single submitter
178019	NM_024422.6(DSC2):c.802A>G (p.Thr268Ala)	DSC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1039516	NM_000238.4(KCNH2):c.76+3G>A	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172359	NM_000238.4(KCNH2):c.1509G>A (p.Val503=)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14433	NM_000238.4(KCNH2):c.2350C>T (p.Arg784Trp)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14441	NM_000238.4(KCNH2):c.2842C>T (p.Arg948Cys)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 118 · 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
MRC2	Limited	Autosomal dominant	cardiac rhythm disease

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
SCN1B	Orphanet:130	Brugada syndrome
SCN1B	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN1B	Orphanet:33069	Dravet syndrome
SCN1B	Orphanet:334	Hereditary atrial fibrillation
SCN1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1B	Orphanet:871	Hereditary progressive cardiac conduction defect
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
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
SDHB	Orphanet:139411	Carney triad
SDHB	Orphanet:201	Cowden syndrome
SDHB	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
SDHB	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHB	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHB	Orphanet:44890	Gastrointestinal stromal tumor
SDHB	Orphanet:97286	Carney-Stratakis syndrome
SLC25A15	Orphanet:415	Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
SLC4A3	Orphanet:51083	Congenital short QT syndrome
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
PRDM16	Orphanet:154	Familial isolated dilated cardiomyopathy
PRDM16	Orphanet:1606	1p36 deletion syndrome
PRDM16	Orphanet:54260	Left ventricular noncompaction
CACNB2	Orphanet:130	Brugada syndrome
CAPN3	Orphanet:267	Calpain-3-related limb-girdle muscular dystrophy R1
CAPN3	Orphanet:565909	Calpain-3-related limb-girdle muscular dystrophy D4
CASQ2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
NOS1AP	Orphanet:101016	Romano-Ward syndrome
HCN4	Orphanet:130	Brugada syndrome
HCN4	Orphanet:166282	Hereditary sick sinus syndrome
RANGRF	Orphanet:130	Brugada syndrome

Cohort genes → proteins

48 cohort genes, 45 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	48

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MRC2	HGNC:16875	ENSG00000011028	Q9UBG0	C-type mannose receptor 2	gencc
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar
SDHB	HGNC:10681	ENSG00000117118	P21912	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	clinvar
SLC25A15	HGNC:10985	ENSG00000102743	Q9Y619	Mitochondrial ornithine transporter 1	clinvar
SLC4A3	HGNC:11029	ENSG00000114923	P48751	Anion exchange protein 3	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
PRDM16	HGNC:14000	ENSG00000142611	Q9HAZ2	Histone-lysine N-methyltransferase PRDM16	clinvar
CACNB2	HGNC:1402	ENSG00000165995	Q08289	Voltage-dependent L-type calcium channel subunit beta-2	clinvar
CAPN3	HGNC:1480	ENSG00000092529	P20807	Calpain-3	clinvar
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-2	clinvar
NAV3	HGNC:15998	ENSG00000067798	Q8IVL0	Neuron navigator 3	clinvar
NOS1AP	HGNC:16859	ENSG00000198929	O75052	Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein	clinvar
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	clinvar
RANGRF	HGNC:17679	ENSG00000108961	Q9HD47	Ran guanine nucleotide release factor	clinvar
SCN3B	HGNC:20665	ENSG00000166257	Q9NY72	Sodium channel regulatory subunit beta-3	clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	clinvar
CSNK1E	HGNC:2453	ENSG00000213923	P49674	Casein kinase I isoform epsilon	clinvar
TANGO2	HGNC:25439	ENSG00000183597	Q6ICL3	Transport and Golgi organization protein 2 homolog	clinvar
PPA2	HGNC:28883	ENSG00000138777	Q9H2U2	Inorganic pyrophosphatase 2, mitochondrial	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
DTNA	HGNC:3057	ENSG00000134769	Q9Y4J8	Dystrobrevin alpha	clinvar
SLC25A35	HGNC:31921	ENSG00000125434	Q3KQZ1	Solute carrier family 25 member 35	clinvar
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	clinvar
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	clinvar
KCNQ1-AS1	HGNC:42790	ENSG00000229414		KCNQ1 antisense RNA 1	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
ITFG2-AS1	HGNC:53128	ENSG00000258325		ITFG2 antisense RNA 1	clinvar
JUP	HGNC:6207	ENSG00000173801	P14923	Junction plakoglobin	clinvar
KCNA5	HGNC:6224	ENSG00000130037	P22460	Potassium voltage-gated channel subfamily A member 5	clinvar
KCNE1	HGNC:6240	ENSG00000180509	P15382	Potassium voltage-gated channel subfamily E member 1	clinvar
KCNE2	HGNC:6242	ENSG00000159197	Q9Y6J6	Potassium voltage-gated channel subfamily E member 2	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	clinvar
KCNJ8	HGNC:6269	ENSG00000121361	Q15842	ATP-sensitive inward rectifier potassium channel 8	clinvar
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	clinvar
KCNQ1OT1	HGNC:6295	ENSG00000269821		KCNQ1 opposite strand/antisense transcript 1	clinvar
LIG3	HGNC:6600	ENSG00000005156	P49916	DNA ligase 3	clinvar
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	clinvar
ASS1	HGNC:758	ENSG00000130707	P00966	Argininosuccinate synthase	clinvar
ATP1B1	HGNC:804	ENSG00000143153	P05026	Sodium/potassium-transporting ATPase subunit beta-1	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar
ACADVL	HGNC:92	ENSG00000072778	P49748	Very long-chain acyl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MRC2	C-type mannose receptor 2	May play a role as endocytotic lectin receptor displaying calcium-dependent lectin activity.
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.
SCN1B	Sodium channel regulatory subunit beta-1	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.
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SDHB	Succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial	Iron-sulfur protein (IP) subunit of the succinate dehydrogenase complex (mitochondrial respiratory chain complex II), responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
SLC25A15	Mitochondrial ornithine transporter 1	Mitochondrial ornithine-citrulline antiporter.
SLC4A3	Anion exchange protein 3	Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane.
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.
PRDM16	Histone-lysine N-methyltransferase PRDM16	Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context.
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.
CAPN3	Calpain-3	Calcium-regulated non-lysosomal thiol-protease.
CASQ2	Calsequestrin-2	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.
NAV3	Neuron navigator 3	Is involved in microtubule cytoskeleton organization and plays a role in cell migration.
NOS1AP	Carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein	Adapter protein involved in neuronal nitric-oxide (NO) synthesis regulation via its association with nNOS/NOS1.
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.
RANGRF	Ran guanine nucleotide release factor	May regulate the intracellular trafficking of RAN.
SCN3B	Sodium channel regulatory subunit beta-3	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
CSNK1E	Casein kinase I isoform epsilon	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
TANGO2	Transport and Golgi organization protein 2 homolog	May be involved in lipid homeostasis.
PPA2	Inorganic pyrophosphatase 2, mitochondrial	Hydrolyzes inorganic pyrophosphate.
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.
DTNA	Dystrobrevin alpha	May be involved in the formation and stability of synapses as well as being involved in the clustering of nicotinic acetylcholine receptors.
SLC25A35	Solute carrier family 25 member 35	Putative antiporter that exchanges dicarboxylates and sulfur oxoanions across the inner membrane of mitochondria.
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.
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.
JUP	Junction plakoglobin	Common junctional plaque protein.
KCNA5	Potassium voltage-gated channel subfamily A member 5	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.
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.
KCNE2	Potassium voltage-gated channel subfamily E member 2	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.
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.
KCNJ8	ATP-sensitive inward rectifier potassium channel 8	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
KCNQ1	Potassium voltage-gated channel subfamily KQT member 1	Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon.
LIG3	DNA ligase 3	Isoform 3 functions as a heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand-break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents.
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.
ASS1	Argininosuccinate synthase	One of the enzymes of the urea cycle, the metabolic pathway transforming neurotoxic amonia produced by protein catabolism into inocuous urea in the liver of ureotelic animals.
ATP1B1	Sodium/potassium-transporting ATPase subunit beta-1	This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
ACADVL	Very long-chain acyl-CoA dehydrogenase, mitochondrial	Very long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of e…

Protein-family classification

Druggable: 20 · Difficult: 7 · Unknown: 21 · Druggable fraction: 0.42

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	11	25.6×	3e-12
Phosphatase	1	1.8×	0.966
Scaffold/PPI	4	1.4×	0.966
Antibody/Immunoglobulin	2	1.2×	0.966
Enzyme (other)	4	1.0×	0.966
Other/Unknown	21	0.8×	0.966
Protease	1	0.8×	0.966
Kinase	1	0.6×	0.966
Transcription factor	3	0.5×	0.966

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MRC2	Other/Unknown	no		FN_type2_dom, Ricin_B_lectin, C-type_lectin-like
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
SDHB	Enzyme (other)	yes	1.3.5.1	2Fe-2S_ferredoxin-type, Succ_DH/fum_Rdtase_Fe-S, 2Fe2S_fd_BS
SLC25A15	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, Mitochondrial_Carrier
SLC4A3	Other/Unknown	no		Anion_exchange, Anion_exchange_3, HCO3_transpt_euk
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
PRDM16	Transcription factor	no	2.1.1.367	SET_dom, Znf_C2H2_type, Znf_C2H2_sf
CACNB2	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, VDCC_L_b2su
CAPN3	Protease	yes	3.4.22.54	Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom
CASQ2	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_sf
NAV3	Other/Unknown	no		CH_dom, AAA+_ATPase, ATPase_AAA_core
NOS1AP	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Adapter_Engulfment-Domain
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
RANGRF	Other/Unknown	no		Mog1, Mog1/PsbP_a/b/a-sand
SCN3B	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
CSNK1E	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TANGO2	Other/Unknown	no		TANGO2
PPA2	Phosphatase	yes	3.6.1.1	Pyrophosphatase, Pyrophosphatase_sf
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
DTNA	Transcription factor	no		Znf_ZZ, EF-hand-dom_pair, EF-hand_dom_typ1
SLC25A35	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, Mito_Carrier_Antiporter
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
AKAP9	Other/Unknown	no		ELK_dom, PACT_domain, AKAP9/Pericentrin
KCNQ1-AS1	Other/Unknown	no
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
ITFG2-AS1	Other/Unknown	no
JUP	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
KCNA5	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
KCNE1	Ion channel	yes		K_chnl_KCNE, KCNE1
KCNE2	Ion channel	yes		K_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE2
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
KCNJ8	Ion channel	yes		K_chnl_inward-rec_Kir6.1, K_chnl_inward-rec_Kir_cyto, Ig_E-set
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
KCNQ1OT1	Other/Unknown	no
LIG3	Transcription factor	no	6.5.1.1	DNA_ligase_ATP-dep, BRCT_dom, Znf_PARP
MYH7	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
ASS1	Enzyme (other)	yes	6.3.4.5	Arginosuc_synth, Rossmann-like_a/b/a_fold, Arginosuc_synth_CS
ATP1B1	Other/Unknown	no		Na/K_ATPase_sub_beta, Na/K_ATPase_sub_beta_sf
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
ACADVL	Enzyme (other)	yes	1.3.8.8	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

Expression context

Cohort genes with no expression data: 0.

42 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)	48
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	10
heart right ventricle	4
left ventricle myocardium	4
cardiac atrium	4
cortical plate	4
cardiac ventricle	3
heart left ventricle	3
liver	3
right lobe of liver	3
right atrium auricular region	3
hindlimb stylopod muscle	3
left testis	3
stromal cell of endometrium	2
tendon of biceps brachii	2
tibia	2
myocardium	2
buccal mucosa cell	2
C1 segment of cervical spinal cord	2
middle temporal gyrus	2
right testis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRC2	293	ubiquitous	marker	tendon of biceps brachii, stromal cell of endometrium, tibia
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
SDHB	293	ubiquitous	marker	heart left ventricle, cardiac ventricle, apex of heart
SLC25A15	198	ubiquitous	marker	liver, right lobe of liver, duodenum
SLC4A3	203	ubiquitous	marker	apex of heart, right atrium auricular region, cardiac atrium
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
PRDM16	202	broad	marker	sural nerve, pigmented layer of retina, ascending aorta
CACNB2	237	broad	marker	adrenal tissue, mucosa of stomach, buccal mucosa cell
CAPN3	134	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue, C1 segment of cervical spinal cord
CASQ2	213	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
NAV3	232	ubiquitous	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23
NOS1AP	203	ubiquitous	marker	CA1 field of hippocampus, type B pancreatic cell, olfactory bulb
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
RANGRF	274	ubiquitous	marker	left testis, right testis, testis
SCN3B	193	broad	marker	middle temporal gyrus, orbitofrontal cortex, cortical plate
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
CSNK1E	275	ubiquitous	marker	cortical plate, ganglionic eminence, left ovary
TANGO2	217	ubiquitous	marker	apex of heart, granulocyte, blood
PPA2	286	ubiquitous	marker	calcaneal tendon, parotid gland, mucosa of sigmoid colon
DSC2	256	ubiquitous	marker	gingival epithelium, gingiva, oral cavity
DSC3	177	broad	marker	upper leg skin, gingival epithelium, gingiva
DSG2	238	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, jejunal mucosa
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
DTNA	266	ubiquitous	marker	medial globus pallidus, globus pallidus, C1 segment of cervical spinal cord
SLC25A35	186	ubiquitous	marker	kidney epithelium, left testis, right testis
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium
AKAP9	292	ubiquitous	marker	jejunal mucosa, bronchial epithelial cell, cortical plate

Protein interactions among cohort

Intra-cohort edges: 82.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
SDHA	6,141
SDHB	5,471
JUP	4,618
PPA2	3,655
AKAP9	3,537
KCNQ1	3,235
CACNA1C	3,145
ASS1	3,101
ACADVL	2,988

Intra-cohort edges

A	B	Sources
ACADVL	PPA2	biogrid_interaction
AKAP9	KCNE1	string_interaction
AKAP9	KCNE2	string_interaction
AKAP9	KCNH2	string_interaction
AKAP9	KCNQ1	biogrid_interaction, intact, string_interaction
ASS1	PPA2	intact
ASS1	SLC25A15	string_interaction
ATP1B1	SDHA	biogrid_interaction
CACNA1C	CACNB2	intact, string_interaction
CACNA1C	CASQ2	string_interaction
CACNA1C	HCN4	string_interaction
CACNA1C	KCNE1	string_interaction
CACNA1C	KCNE2	biogrid_interaction, string_interaction
CACNA1C	KCNH2	string_interaction
CACNA1C	KCNJ8	string_interaction
CACNA1C	RYR2	biogrid_interaction, string_interaction
CACNA1C	SCN3B	string_interaction
CACNB2	HCN4	string_interaction
CACNB2	KCNH2	string_interaction
CACNB2	KCNJ8	string_interaction
CACNB2	SCN1B	string_interaction
CACNB2	SCN3B	string_interaction
CACNB2	SCN5A	string_interaction
CASQ2	KCNH2	string_interaction
CASQ2	RYR2	string_interaction
CASQ2	SCN5A	string_interaction
DSC2	DSG2	intact, string_interaction
DSC2	DSP	string_interaction
DSC2	JUP	biogrid_interaction, string_interaction
DSC2	PKP2	string_interaction
DSC2	RYR2	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
DSG2	DSP	string_interaction
DSG2	JUP	intact, string_interaction
DSG2	PKP2	string_interaction
DSG2	RYR2	string_interaction
DSG2	SCN5A	string_interaction
DSP	JUP	intact, string_interaction
DSP	PKP2	string_interaction
HCN4	KCNE2	biogrid_interaction, string_interaction
HCN4	RANGRF	string_interaction
HCN4	SCN1B	string_interaction
HCN4	SCN3B	string_interaction
HCN4	SCN5A	string_interaction
JUP	PKP2	string_interaction
JUP	RYR2	string_interaction

Structural data

PDB: 36 · AlphaFold-only: 9 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYH7	P12883	43
SCN1B	Q07699	39
CACNA1C	Q13936	33
KCNQ1	P51787	28
RYR2	Q92736	26
KCNH2	Q12809	24
AGXT	P21549	17
SCN5A	Q14524	16
LIG3	P49916	13
DSG2	Q14126	12
ANK2	Q01484	11
ATP1B1	P05026	11
HCN4	Q9Y3Q4	8
SDHB	P21912	6
MRC2	Q9UBG0	5
SDHA	P31040	5
CAPN3	P20807	5
KCNE1	P15382	5
SLC4A3	P48751	4
CASQ2	O14958	4
DSP	P15924	4
CACNB2	Q08289	3
SCN3B	Q9NY72	3
TANGO2	Q6ICL3	3
DSC2	Q02487	3
KCNJ2	P63252	3
ACADVL	P49748	3
PRDM16	Q9HAZ2	2
CSNK1E	P49674	2
RANGRF	Q9HD47	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A35	Q3KQZ1	87.99
SLC25A15	Q9Y619	87.43
PPA2	Q9H2U2	87.39
KCNJ8	Q15842	84.00
DSC3	Q14574	75.53
KCNA5	P22460	72.64
NOS1AP	O75052	65.59
NAV3	Q8IVL0	48.21
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 176. Enrichment computed across 48 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
Cardiac conduction	16	43.5×	7e-21	RYR2, SCN1B, SCN5A, CACNA1C, CACNB2, CASQ2, RANGRF, SCN3B (+8 more)
Muscle contraction	16	30.9×	1e-18	RYR2, SCN1B, SCN5A, CACNA1C, CACNB2, CASQ2, RANGRF, SCN3B (+8 more)
Phase 3 - rapid repolarisation	6	171.3×	2e-11	AKAP9, KCNA5, KCNE1, KCNE2, KCNH2, KCNQ1
Phase 2 - plateau phase	6	114.2×	3e-10	CACNA1C, CACNB2, AKAP9, KCNE1, KCNE2, KCNQ1
Phase 0 - rapid depolarisation	6	51.9×	5e-08	SCN1B, SCN5A, CACNA1C, CACNB2, RANGRF, SCN3B
Interaction between L1 and Ankyrins	4	36.8×	1e-04	SCN1B, SCN5A, SCN3B, ANK2
Formation of the cornified envelope	6	13.2×	1e-04	DSC2, DSC3, DSG2, DSP, JUP, PKP2
Potassium Channels	5	16.8×	2e-04	KCNA5, KCNH2, KCNJ2, KCNJ8, KCNQ1
Keratinization	6	8.4×	0.001	DSC2, DSC3, DSG2, DSP, JUP, PKP2
Axon guidance	6	6.8×	0.004	SCN1B, SCN5A, CACNA1C, CACNB2, SCN3B, ANK2
Neuronal System	6	6.6×	0.004	CACNB2, KCNA5, KCNH2, KCNJ2, KCNJ8, KCNQ1
Nervous system development	6	6.4×	0.004	SCN1B, SCN5A, CACNA1C, CACNB2, SCN3B, ANK2
L1CAM interactions	4	12.0×	0.004	SCN1B, SCN5A, SCN3B, ANK2
NCAM1 interactions	3	18.6×	0.007	CACNA1C, CACNB2, COL5A1
Voltage gated Potassium channels	3	18.2×	0.007	KCNA5, KCNH2, KCNQ1
Apoptotic cleavage of cell adhesion proteins	2	51.9×	0.007	DSG2, DSP
Urea cycle	2	43.9×	0.009	SLC25A15, ASS1
Ion homeostasis	3	15.3×	0.009	RYR2, CASQ2, ATP1B1
Inwardly rectifying K+ channels	2	35.7×	0.013	KCNJ2, KCNJ8
Maturation of TCA enzymes and regulation of TCA cycle	2	28.6×	0.019	SDHA, SDHB
Citric acid cycle (TCA cycle)	2	21.1×	0.033	SDHA, SDHB
Adrenaline,noradrenaline inhibits insulin secretion	2	19.7×	0.037	CACNA1C, CACNB2
Sensory perception of sour taste	1	142.8×	0.047	KCNJ2
SLC25A15 variants cause hyperornithinemia-hyperammonemia-homocitrullinemia syndrome	1	142.8×	0.047	SLC25A15
ASS1 variants cause citrullinemia	1	142.8×	0.047	ASS1
Sensory perception of taste	2	16.8×	0.047	SCN1B, KCNJ2
Ion channel transport	3	7.2×	0.053	RYR2, CASQ2, ATP1B1
Sensory Perception	3	7.1×	0.053	SCN1B, CACNB2, KCNJ2
NCAM signaling for neurite out-growth	2	13.6×	0.057	CACNA1C, CACNB2
Pyrophosphate hydrolysis	1	95.2×	0.059	PPA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 44 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	19	161.7×	1e-36	SCN1B, SCN5A, CACNA1C, CACNB2, HCN4, SCN3B, DSC2, DSG2 (+11 more)
ventricular cardiac muscle cell action potential	9	202.8×	1e-17	RYR2, SCN5A, SCN3B, ANK2, KCNE1, KCNE2, KCNH2, KCNQ1 (+1 more)
regulation of ventricular cardiac muscle cell membrane repolarization	9	172.3×	6e-17	SCN1B, SCN5A, NOS1AP, AKAP9, ANK2, KCNE1, KCNE2, KCNH2 (+1 more)
regulation of ventricular cardiac muscle cell action potential	7	223.4×	5e-14	RYR2, CACNA1C, DSC2, DSG2, DSP, JUP, PKP2
cardiac muscle cell action potential involved in contraction	8	127.7×	7e-14	SCN1B, SCN5A, CACNA1C, SCN3B, KCNE1, KCNE2, KCNJ2, PKP2
cardiac muscle contraction	9	82.1×	8e-14	RYR2, SCN1B, SCN5A, CASQ2, SCN3B, KCNH2, KCNQ1, MYH7 (+1 more)
regulation of heart rate	8	85.1×	2e-12	RYR2, SCN5A, CASQ2, HCN4, RANGRF, ANK2, KCNJ8, MYH7
membrane depolarization during cardiac muscle cell action potential	6	191.5×	1e-11	SCN1B, SCN5A, CACNA1C, HCN4, SCN3B, KCNJ2
regulation of membrane repolarization	6	176.8×	2e-11	CASQ2, AKAP9, KCNE2, KCNH2, KCNJ2, KCNQ1
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	5	273.6×	1e-10	DSC2, DSG2, DSP, JUP, PKP2
membrane repolarization during action potential	5	191.5×	8e-10	KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1
membrane repolarization during cardiac muscle cell action potential	5	191.5×	8e-10	KCNE1, KCNH2, KCNJ2, KCNQ1, ATP1B1
atrial cardiac muscle cell action potential	5	191.5×	8e-10	SCN5A, SCN3B, ANK2, KCNA5, KCNQ1
membrane repolarization during ventricular cardiac muscle cell action potential	5	191.5×	8e-10	KCNE1, KCNE2, KCNH2, KCNJ8, KCNQ1
potassium ion import across plasma membrane	7	58.3×	8e-10	HCN4, KCNE2, KCNH2, KCNJ2, KCNJ8, KCNQ1, ATP1B1
potassium ion export across plasma membrane	5	119.7×	1e-08	KCNA5, KCNE1, KCNE2, KCNH2, KCNQ1
SA node cell action potential	4	255.3×	2e-08	SCN5A, HCN4, SCN3B, ANK2
positive regulation of potassium ion transmembrane transport	5	112.7×	2e-08	NOS1AP, KCNE1, KCNH2, KCNJ2, KCNQ1
potassium ion transmembrane transport	8	24.7×	2e-08	HCN4, KCNA5, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ8, KCNQ1
membrane depolarization during action potential	4	153.2×	2e-07	SCN1B, SCN5A, SCN3B, KCNH2
membrane depolarization during atrial cardiac muscle cell action potential	3	383.0×	4e-07	SCN5A, CACNA1C, CACNB2
cell communication by electrical coupling involved in cardiac conduction	4	127.7×	4e-07	RYR2, CACNA1C, ATP1B1, PKP2
membrane repolarization	4	117.8×	6e-07	KCNE1, KCNE2, KCNH2, ATP1B1
membrane depolarization during AV node cell action potential	3	229.8×	3e-06	SCN5A, CACNA1C, CACNB2
membrane depolarization during SA node cell action potential	3	229.8×	3e-06	SCN5A, HCN4, ANK2
striated muscle contraction	4	76.6×	3e-06	RYR2, CASQ2, DTNA, MYH7
positive regulation of sodium ion transport	4	76.6×	3e-06	SCN1B, SCN5A, SCN3B, PKP2
regulation of SA node cell action potential	3	191.5×	5e-06	RYR2, HCN4, ANK2
negative regulation of delayed rectifier potassium channel activity	3	191.5×	5e-06	KCNE1, KCNE2, KCNQ1
cellular response to cAMP	5	33.0×	6e-06	HCN4, AKAP9, KCNE1, KCNQ1, ASS1

Therapeutics

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 11 · Phased (≥1): 16 · Undrugged: 32

Druggability breadth: 25 of 48 evidence-associated genes (52%) 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
SDHA	LINEZOLID
CACNA1C	REMIFENTANIL
CACNB2	NIMODIPINE
HCN4	IVABRADINE
CSNK1E	AFATINIB
KCNA5	DRONEDARONE HYDROCHLORIDE
KCNE1	AMBRISENTAN
KCNH2	CETIRIZINE
KCNQ1	AMBRISENTAN
ATP1B1	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
SCN5A	108	4
CACNA1C	85	4
CSNK1E	37	4
KCNQ1	15	4
KCNE1	14	4
KCNA5	8	4
ATP1B1	5	4
SCN1B	2	2
CACNB2	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1C, KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	CACNA1C, KCNH2, SCN5A
IMIPRAMINE	4	CACNA1C, KCNH2, SCN5A
DROPERIDOL	4	CACNA1C, KCNH2, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNE1, KCNH2, KCNQ1, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	CACNA1C, KCNA5, KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	CACNA1C, KCNA5, KCNH2, SCN5A
DARUNAVIR	4	KCNE1, KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNE1, KCNH2, KCNQ1, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	CACNA1C, KCNH2, SCN5A
NIMODIPINE	4	CACNA1C, CACNB2, SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	CACNA1C, KCNH2, SCN5A
AMLODIPINE	4	CACNA1C, KCNH2, SCN5A
PHENYTOIN	4	CACNA1C, KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
CSNK1E	420	Binding:416, ADMET:2, Functional:2
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
KCNA5	152	Binding:130, Functional:14, ADMET:5, Toxicity:3
KCNE1	117	Functional:63, Binding:47, ADMET:6, Toxicity:1
ATP1B1	50	Binding:50
KCNJ8	43	Functional:38, Binding:5
KCNJ2	31	Binding:23, ADMET:8
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
CACNB2	22	Binding:20, ADMET:1, Toxicity:1
RYR2	15	Binding:15
SCN1B	15	Binding:7, ADMET:6, Toxicity:2
LIG3	9	Binding:9
AGXT	8	Binding:8
SDHB	4	Binding:4
SDHA	3	Binding:3
PRDM16	2	Binding:2
DSP	2	Binding:2
ACADVL	2	Binding:2
JUP	1	Binding:1
ASS1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SDHB	1.3.5.1	succinate dehydrogenase
PRDM16	2.1.1.367, 2.1.1.370	[histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine4 N-dimethyltransferase
CAPN3	3.4.22.54, 3.4.22.56	calpain-3, caspase-3
CSNK1E	2.7.11.1	non-specific serine/threonine protein kinase
PPA2	3.6.1.1	inorganic diphosphatase
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase
LIG3	6.5.1.1	DNA ligase (ATP)
ASS1	6.3.4.5	argininosuccinate synthase
ACADVL	1.3.8.8, 1.3.8.9	long-chain acyl-CoA dehydrogenase, very-long-chain acyl-CoA dehydrogenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594
CACNA1C	575
CSNK1E	420
KCNA5	152
KCNE1	117
KCNH2	4,851
KCNQ1	179

Pharmacogenomics

Cohort genes with a PharmGKB record: 46; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	CACNA1C, KCNH2, SCN5A
DROPERIDOL	4	CACNA1C, KCNH2, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNE1, KCNH2, KCNQ1, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	CACNA1C, KCNA5, KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
DARUNAVIR	4	KCNE1, KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNE1, KCNH2, KCNQ1, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	CACNA1C, KCNE1, KCNH2, KCNQ1, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	CACNA1C, KCNH2, SCN5A
NIMODIPINE	4	CACNA1C, CACNB2, SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	CACNA1C, KCNH2, SCN5A
AMLODIPINE	4	CACNA1C, KCNH2, SCN5A
PHENYTOIN	4	CACNA1C, 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)	11	SCN5A, SDHA, CACNA1C, CACNB2, HCN4, CSNK1E, KCNA5, KCNE1, KCNH2, KCNQ1 (+1 more)
B	Phased (≥1) drug, not yet approved	5	RYR2, SCN1B, KCNJ8, LIG3, ACADVL
C	Druggable family + PDB, no drug	7	SDHB, CAPN3, SCN3B, AGXT, KCNE2, KCNJ2, ASS1
D	Druggable family + AlphaFold only, no drug	1	PPA2
E	Difficult family or no structure, no drug	24	MRC2, SLC25A15, SLC4A3, PRDM16, CASQ2, NAV3, NOS1AP, RANGRF, COL5A1, TANGO2 (+14 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SDHB	4	SDHA
CASQ2	0	RYR2, CACNA1C
RANGRF	0	SCN5A
SCN3B	0	SCN5A
AKAP9	0	KCNQ1, KCNE1
KCNE2	0	KCNQ1, KCNH2, SCN5A
PKP2	0	SCN5A
MRC2	0	—
SLC25A15	0	—
SLC4A3	0	—
PRDM16	2	—
CAPN3	0	—
NAV3	0	—
NOS1AP	0	—
COL5A1	0	—
TANGO2	0	—
PPA2	0	—
DSC2	0	—
DSC3	0	—
DSG2	0	—
DSP	2	—
DTNA	0	—
SLC25A35	0	—
AGXT	8	—
KCNQ1-AS1	0	—
ANK2	0	—
ITFG2-AS1	0	—
JUP	1	—
KCNJ2	31	—
KCNQ1OT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 265.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	199
PHASE4	25
PHASE3	24
PHASE2	10
PHASE1	3
PHASE2/PHASE3	2
PHASE1/PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants
NCT01834872	PHASE4	UNKNOWN	Safety and Feasibility of Arrhythmia Ablation Using the Amigo Remote Robotic System as Compared With Manual Ablation
NCT01841242	PHASE4	COMPLETED	Comparison of Alcoholic Chlorhexidine 2% Versus Alcoholic Povidone Iodine for Infections Prevention With Cardiac Resynchronization Therapy Device Implantation
NCT01991223	PHASE4	UNKNOWN	Dexmedetomidine for Catheter-related Bladder Discomfort
NCT02045173	PHASE4	COMPLETED	Automate Detection of Sleep Apnea by ApneascanTM
NCT02203630	PHASE4	TERMINATED	Phenylephrine Versus Norepinephrine for Septic Shock in Critically Ill Patients
NCT02565069	PHASE4	COMPLETED	Identification for the Treatment of Complex Arrhythmias
NCT03273634	PHASE4	COMPLETED	The Effect of Proton Pump Inhibition on Palpitations
NCT03289429	PHASE4	UNKNOWN	Antiarrhythmic and Cardioprotective Effects of Atorvastatin Versus Magnesium Sulfate in Cardiac Valve Replacement Surgery
NCT03895411	PHASE4	UNKNOWN	Efficacy and Safety of Sotalol in Children With Arrhythmia
NCT05486377	PHASE4	COMPLETED	Remimazolam vs Desflurane for General Anesthesia for Ablation of Arrhythmia
NCT06574555	PHASE4	COMPLETED	Norepinephrine ED90 Bolus After Spinal Anesthesia in Cesarean Section
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000476	PHASE3	COMPLETED	Digitalis Investigation Group (DIG)
NCT00000480	PHASE3	COMPLETED	Multicenter Unsustained Tachycardia Trial (MUSTT)
NCT00000492	PHASE3	COMPLETED	Beta-Blocker Heart Attack Trial (BHAT)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000517	PHASE3	COMPLETED	Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF)
NCT00000518	PHASE3	COMPLETED	Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM)
NCT00000531	PHASE3	COMPLETED	Antiarrhythmics Versus Implantable Defibrillators (AVID)
NCT00000540	PHASE3	COMPLETED	Coronary Artery Bypass Graft (CABG) Patch Trial
NCT00000556	PHASE3	COMPLETED	Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
NCT00000561	PHASE3	COMPLETED	Mode Selection Trial in Sinus Node Dysfunction (MOST)
NCT00000609	PHASE3	COMPLETED	Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
NCT00004559	PHASE3	COMPLETED	Fatty Acid Antiarrhythmia Trial (FAAT)
NCT00004560	PHASE3	COMPLETED	Public Access Defibrillation (PAD) Community Trial
NCT00035490	PHASE3	COMPLETED	Efficacy and Safety Evaluation of Azimilide Dihydrochloride in Patients With Implantable Cardioverter Defibrillators

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMIODARONE	4	12
FLECAINIDE	4	6
IMIPRAMINE	4	6
SOTALOL	4	5
ATORVASTATIN	4	4
PROCAINAMIDE	4	4
PROPAFENONE	4	4
QUINIDINE	4	4
DILTIAZEM	4	3
DISOPYRAMIDE	4	3
PROPRANOLOL	4	3
ATROPINE	4	2
MEXILETINE	4	2
MORICIZINE	4	2
NOREPINEPHRINE	4	2
PHENYLEPHRINE	4	2
CEFAZOLIN	4	1
CHLORHEXIDINE	4	1
COLCHICINE	4	1
DEXMEDETOMIDINE	4	1
DIGOXIN	4	1
ENCAINIDE	4	1
LANSOPRAZOLE	4	1
MAGNESIUM SULFATE	4	1
METOPROLOL TARTRATE	4	1
OLIVE OIL	4	1
OLMESARTAN MEDOXOMIL	4	1
REMIMAZOLAM BESYLATE	4	1
VERAPAMIL	4	1
WARFARIN	4	1