Cardiac arrest

Summary

Cardiac arrest (MONDO:0000745) is a disease with 21 cohort genes and 646 clinical trials. The dominant Reactome pathway is Muscle contraction (5 cohort genes). Top therapeutic interventions include amiodarone, vasopressin, and thiamine ion.

At a glance

• Cohort genes: 21
• ClinVar variants: 39
• Clinical trials: 646

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiac arrest
Mondo ID	MONDO:0000745
MeSH	D006323
DOID	DOID:0060319
ICD-10-CM	I46
ICD-11	395422191
SNOMED CT	410429000
UMLS	C0018790
MedGen	5456
Is cancer (heuristic)	no

Also known as: circulatory arrest

Data availability: 39 ClinVar variants.

Disease family

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

Related subtypes (16): ventricular fibrillation, 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

39 retrieved; paginated sample, class counts are floors:

17 uncertain significance, 15 conflicting classifications of pathogenicity, 3 benign/likely benign, 2 pathogenic/likely pathogenic, 1 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
180326	NM_004415.4(DSP):c.2821C>T (p.Arg941Ter)	DSP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13637	NM_002667.5(PLN):c.116T>G (p.Leu39Ter)	PLN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179829	NM_000335.5(SCN5A):c.1936del (p.Gln646fs)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
222498	NM_001148.6(ANK2):c.5509G>A (p.Ala1837Thr)	ANK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222502	NM_001148.6(ANK2):c.7458C>G (p.His2486Gln)	ANK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518526	NM_000722.4(CACNA2D1):c.1648G>T (p.Asp550Tyr)	CACNA2D1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180291	NM_201596.3(CACNB2):c.1206+3A>T	CACNB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191629	NM_001943.5(DSG2):c.1063G>A (p.Ala355Thr)	DSG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44317	NM_001943.5(DSG2):c.437G>T (p.Arg146Leu)	DSG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180323	NM_004415.4(DSP):c.2260G>A (p.Glu754Lys)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222574	NM_004415.4(DSP):c.2047G>A (p.Glu683Lys)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222585	NM_004415.4(DSP):c.7249G>T (p.Asp2417Tyr)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222648	NM_005477.3(HCN4):c.2197G>A (p.Val733Ile)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180270	NM_001148.6(ANK2):c.6206G>A (p.Arg2069His)	LOC126807136	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
42711	NM_000256.3(MYBPC3):c.3392T>C (p.Ile1131Thr)	MYBPC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43995	NM_001134363.3(RBM20):c.2662G>A (p.Asp888Asn)	RBM20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222801	NM_000335.5(SCN5A):c.559A>G (p.Thr187Ala)	SCN5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
46820	NM_001267550.2(TTN):c.29230C>T (p.Arg9744Cys)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180266	NM_005751.5(AKAP9):c.11378C>G (p.Ser3793Cys)	AKAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
222487	NM_005751.5(AKAP9):c.1067A>T (p.Asp356Val)	AKAP9	Uncertain significance	criteria provided, multiple submitters, no conflicts
222492	NM_005751.5(AKAP9):c.11276C>T (p.Pro3759Leu)	AKAP9	Uncertain significance	criteria provided, single submitter
222503	NM_001148.6(ANK2):c.7577C>T (p.Ser2526Leu)	ANK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
180290	NM_201596.3(CACNB2):c.1642G>A (p.Gly548Ser)	CACNB2	Uncertain significance	criteria provided, multiple submitters, no conflicts
222520	NM_201596.3(CACNB2):c.1594T>G (p.Ser532Ala)	CACNB2	Uncertain significance	criteria provided, single submitter
222554	NM_130797.4(DPP6):c.1039G>A (p.Ala347Thr)	DPP6	Uncertain significance	criteria provided, single submitter
222564	NM_001943.5(DSG2):c.2188A>G (p.Thr730Ala)	DSG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
222678	NM_004982.4(KCNJ8):c.83G>C (p.Arg28Pro)	KCNJ8	Uncertain significance	criteria provided, multiple submitters, no conflicts
180427	NM_002471.4(MYH6):c.4713G>T (p.Lys1571Asn)	LOC126861896	Uncertain significance	criteria provided, multiple submitters, no conflicts
222745	NM_003803.4(MYOM1):c.3708C>A (p.Ser1236Arg)	MYOM1	Uncertain significance	criteria provided, single submitter
569179	NM_006393.3(NEBL):c.535C>T (p.Arg179Ter)	NEBL	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 66 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
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
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
CACNA2D1	Orphanet:130	Brugada syndrome
CACNA2D1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA2D1	Orphanet:51083	Congenital short QT syndrome
CACNB2	Orphanet:130	Brugada syndrome
SLMAP	Orphanet:130	Brugada syndrome
HCN4	Orphanet:130	Brugada syndrome
HCN4	Orphanet:166282	Hereditary sick sinus syndrome
TRPM4	Orphanet:130	Brugada syndrome
TRPM4	Orphanet:316	Progressive symmetric erythrokeratodermia
TRPM4	Orphanet:871	Hereditary progressive cardiac conduction defect
RBM20	Orphanet:154	Familial isolated dilated cardiomyopathy
DPP6	Orphanet:228140	Idiopathic ventricular fibrillation
DPP6	Orphanet:2514	Autosomal dominant primary microcephaly
DSC2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSC2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSC2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSC3	Orphanet:217407	Hereditary hypotrichosis with recurrent skin vesicles
DSG2	Orphanet:154	Familial isolated dilated cardiomyopathy
DSG2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSG2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSG2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome

Cohort genes → proteins

21 cohort genes, 21 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	21

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
CACNA2D1	HGNC:1399	ENSG00000153956	P54289	Voltage-dependent calcium channel subunit alpha-2/delta-1	clinvar
CACNB2	HGNC:1402	ENSG00000165995	Q08289	Voltage-dependent L-type calcium channel subunit beta-2	clinvar
SLMAP	HGNC:16643	ENSG00000163681	Q14BN4	Sarcolemmal membrane-associated protein	clinvar
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	clinvar
NEBL	HGNC:16932	ENSG00000078114	O76041	Nebulette	clinvar
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	clinvar
RBM20	HGNC:27424	ENSG00000203867	Q5T481	RNA-binding protein 20	clinvar
DPP6	HGNC:3010	ENSG00000130226	P42658	A-type potassium channel modulatory protein DPP6	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
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
KCNJ8	HGNC:6269	ENSG00000121361	Q15842	ATP-sensitive inward rectifier potassium channel 8	clinvar
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	clinvar
MYOM1	HGNC:7613	ENSG00000101605	P52179	Myomesin-1	clinvar
PLN	HGNC:9080	ENSG00000198523	P26678	Phospholamban	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.
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.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
CACNA2D1	Voltage-dependent calcium channel subunit alpha-2/delta-1	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
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.
SLMAP	Sarcolemmal membrane-associated protein	Associates with the striatin-interacting phosphatase and kinase (STRIPAK) core complex, forming the extended (SIKE1:SLMAP)STRIPAK complex.
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.
NEBL	Nebulette	Binds to actin and plays an important role in the assembly of the Z-disk.
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.
RBM20	RNA-binding protein 20	RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes encoding key structural proteins involved in cardiac development, such as TTN (Titin), CACNA1C, CAMK2D or PDLIM5/ENH.
DPP6	A-type potassium channel modulatory protein DPP6	Promotes cell surface expression of the potassium channel KCND2.
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.
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.
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.
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
MYOM1	Myomesin-1	Major component of the vertebrate myofibrillar M band.
PLN	Phospholamban	Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+).

Protein-family classification

Druggable: 9 · Difficult: 5 · Unknown: 7 · Druggable fraction: 0.43

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	5	26.6×	7e-06
Scaffold/PPI	4	3.3×	0.106
Antibody/Immunoglobulin	2	2.8×	0.375
Protease	1	1.7×	0.753
Kinase	1	1.3×	0.753
Other/Unknown	7	0.6×	0.989
Transcription factor	1	0.4×	0.989

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
CACNA2D1	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
CACNB2	Scaffold/PPI	no		VDCC_L_bsu, SH3_domain, VDCC_L_b2su
SLMAP	Other/Unknown	no		FHA_dom, SMAD_FHA_dom_sf, Cent_Immune-Sig_Mod
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
NEBL	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulette_SH3
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM
RBM20	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
DPP6	Protease	yes		Peptidase_S9_cat, Peptidase_S9B_N, AB_hydrolase_fold
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
AKAP9	Other/Unknown	no		ELK_dom, PACT_domain, AKAP9/Pericentrin
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
KCNJ8	Ion channel	yes		K_chnl_inward-rec_Kir6.1, K_chnl_inward-rec_Kir_cyto, Ig_E-set
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
MYOM1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
PLN	Other/Unknown	no		PLB

Expression context

Cohort genes with no expression data: 0.

19 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)	21
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	4
left ventricle myocardium	4
myocardium	4
apex of heart	3
cardiac ventricle	2
biceps brachii	2
gluteal muscle	2
skeletal muscle tissue of biceps brachii	2
skeletal muscle tissue of rectus abdominis	2
cardiac muscle of right atrium	2
cardiac atrium	2
right atrium auricular region	2
gingiva	2
gingival epithelium	2
upper leg skin	2
jejunal mucosa	2
heart left ventricle	1
adrenal tissue	1
buccal mucosa cell	1
mucosa of stomach	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
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
CACNA2D1	261	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis
CACNB2	237	broad	marker	adrenal tissue, mucosa of stomach, buccal mucosa cell
SLMAP	260	ubiquitous	marker	saphenous vein, cauda epididymis, cardiac muscle of right atrium
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
NEBL	282	broad	marker	heart right ventricle, myocardium, cranial nerve II
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart
RBM20	191	broad	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
DPP6	221	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
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
AKAP9	292	ubiquitous	marker	jejunal mucosa, bronchial epithelial cell, cortical plate
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
KCNJ8	233	broad	marker	heart right ventricle, left ventricle myocardium, cardiac ventricle
MYBPC3	149	tissue_specific	marker	apex of heart, right atrium auricular region, cardiac atrium
MYOM1	215	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gluteal muscle
PLN	243	broad	marker	heart right ventricle, myocardium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 31.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
TTN	4,237
AKAP9	3,537
DSP	2,897
RYR2	2,653
DPP6	2,224
SLMAP	2,144
SCN5A	2,090
DSG2	2,033
CACNA2D1	2,002

Intra-cohort edges

A	B	Sources
ANK2	CACNA2D1	intact
ANK2	TTN	string_interaction
CACNA2D1	CACNB2	string_interaction
CACNA2D1	KCNJ8	string_interaction
CACNA2D1	SCN5A	string_interaction
CACNB2	HCN4	string_interaction
CACNB2	KCNJ8	string_interaction
CACNB2	SCN5A	string_interaction
DPP6	SCN5A	string_interaction
DSC2	DSG2	intact, string_interaction
DSC2	DSP	string_interaction
DSC2	RYR2	string_interaction
DSC3	DSG2	intact, string_interaction
DSC3	DSP	string_interaction
DSC3	RYR2	string_interaction
DSG2	DSP	string_interaction
DSG2	MYBPC3	string_interaction
DSG2	RBM20	string_interaction
DSG2	RYR2	string_interaction
DSG2	SCN5A	string_interaction
HCN4	SCN5A	string_interaction
KCNJ8	SCN5A	string_interaction
MYBPC3	RBM20	string_interaction
MYBPC3	TTN	string_interaction
MYOM1	TTN	intact, string_interaction
NEBL	TTN	string_interaction
PLN	RYR2	string_interaction
PLN	SCN5A	string_interaction
RBM20	SCN5A	string_interaction
RBM20	TTN	string_interaction
SCN5A	TRPM4	string_interaction

Structural data

PDB: 17 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
CACNA2D1	P54289	30
TRPM4	Q8TD43	29
RYR2	Q92736	26
MYBPC3	Q14896	17
SCN5A	Q14524	16
DSG2	Q14126	12
ANK2	Q01484	11
MYOM1	P52179	9
HCN4	Q9Y3Q4	8
DPP6	P42658	8
PLN	P26678	7
DSP	P15924	4
CACNB2	Q08289	3
SLMAP	Q14BN4	3
DSC2	Q02487	3
NEBL	O76041	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNJ8	Q15842	84.00
DSC3	Q14574	75.53
RBM20	Q5T481	48.52
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 75. Enrichment computed across 21 evidence-associated genes (16 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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Muscle contraction	5	24.1×	1e-04	RYR2, SCN5A, CACNB2, AKAP9, MYBPC3
Cardiac conduction	4	27.2×	4e-04	RYR2, SCN5A, CACNB2, AKAP9
Formation of the cornified envelope	4	22.0×	7e-04	DSC2, DSC3, DSG2, DSP
Apoptotic cleavage of cell adhesion proteins	2	129.8×	0.002	DSG2, DSP
Keratinization	4	13.9×	0.002	DSC2, DSC3, DSG2, DSP
Phase 2 - plateau phase	2	95.2×	0.002	CACNB2, AKAP9
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	2	84.0×	0.003	CACNA2D1, CACNB2
Interaction between L1 and Ankyrins	2	46.0×	0.008	SCN5A, ANK2
Phase 0 - rapid depolarisation	2	43.3×	0.008	SCN5A, CACNB2
Striated Muscle Contraction	2	38.6×	0.009	TTN, MYBPC3
Cellular responses to mechanical stimuli	2	32.4×	0.011	CACNA2D1, CACNB2
Ion homeostasis	2	25.5×	0.017	RYR2, PLN
ATP sensitive Potassium channels	1	178.4×	0.026	KCNJ8
HCN channels	1	178.4×	0.026	HCN4
Axon guidance	3	8.5×	0.026	SCN5A, CACNB2, ANK2
Nervous system development	3	8.1×	0.026	SCN5A, CACNB2, ANK2
L1CAM interactions	2	15.0×	0.034	SCN5A, ANK2
Phase 3 - rapid repolarisation	1	71.4×	0.058	AKAP9
Presynaptic depolarization and calcium channel opening	1	59.5×	0.066	CACNB2
Inwardly rectifying K+ channels	1	44.6×	0.083	KCNJ8
TRP channels	1	25.5×	0.136	TRPM4
Adrenaline,noradrenaline inhibits insulin secretion	1	24.6×	0.136	CACNB2
Sensory processing of sound	1	19.3×	0.151	CACNB2
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	17.4×	0.151	TRPM4
NCAM signaling for neurite out-growth	1	17.0×	0.151	CACNB2
RND1 GTPase cycle	1	16.6×	0.151	DSP
RND3 GTPase cycle	1	16.2×	0.151	DSP
Centrosome maturation	1	15.9×	0.151	AKAP9
NCAM1 interactions	1	15.5×	0.151	CACNB2
Oncogenic MAPK signaling	1	15.5×	0.151	AKAP9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 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	10	178.3×	6e-19	SCN5A, CACNA2D1, CACNB2, HCN4, TRPM4, DSC2, DSG2, DSP (+2 more)
regulation of ventricular cardiac muscle cell action potential	5	334.4×	2e-10	RYR2, TRPM4, DSC2, DSG2, DSP
regulation of heart rate	5	111.5×	6e-08	RYR2, SCN5A, HCN4, ANK2, KCNJ8
membrane depolarization during bundle of His cell action potential	3	802.5×	1e-07	SCN5A, CACNA2D1, TRPM4
regulation of cardiac muscle cell contraction	4	214.0×	1e-07	SCN5A, ANK2, MYBPC3, PLN
regulation of ventricular cardiac muscle cell membrane repolarization	4	160.5×	4e-07	SCN5A, CACNA2D1, AKAP9, ANK2
membrane depolarization during AV node cell action potential	3	481.5×	6e-07	SCN5A, CACNB2, TRPM4
membrane depolarization during SA node cell action potential	3	481.5×	6e-07	SCN5A, HCN4, ANK2
SA node cell action potential	3	401.2×	9e-07	SCN5A, HCN4, ANK2
regulation of SA node cell action potential	3	401.2×	9e-07	RYR2, HCN4, ANK2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	3	343.9×	1e-06	DSC2, DSG2, DSP
cardiac muscle contraction	4	76.4×	4e-06	RYR2, SCN5A, TTN, MYBPC3
ventricular cardiac muscle cell action potential	3	141.6×	2e-05	RYR2, SCN5A, ANK2
regulation of cardiac muscle contraction	3	126.7×	3e-05	RYR2, HCN4, ANK2
regulation of calcium ion transport	3	114.6×	4e-05	CACNA2D1, ANK2, PLN
membrane depolarization during Purkinje myocyte cell action potential	2	535.0×	6e-05	SCN5A, TRPM4
regulation of atrial cardiac muscle cell action potential	2	535.0×	6e-05	RYR2, ANK2
membrane depolarization during atrial cardiac muscle cell action potential	2	535.0×	6e-05	SCN5A, CACNB2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	3	96.3×	6e-05	RYR2, ANK2, PLN
calcium ion transport	4	34.5×	6e-05	RYR2, CACNA2D1, CACNB2, PLN
sarcoplasmic reticulum calcium ion transport	2	321.0×	2e-04	RYR2, ANK2
sarcomere organization	3	54.7×	3e-04	TTN, MYBPC3, MYOM1
protein localization to plasma membrane	4	20.7×	4e-04	CACNB2, SLMAP, DPP6, ANK2
desmosome organization	2	200.6×	5e-04	DSG2, DSP
cell-cell adhesion	4	19.3×	5e-04	DSC2, DSC3, DSG2, DSP
regulation of cardiac muscle cell action potential involved in regulation of contraction	2	178.3×	5e-04	HCN4, AKAP9
cardiac muscle hypertrophy	2	160.5×	6e-04	RYR2, TTN
atrial cardiac muscle cell action potential	2	160.5×	6e-04	SCN5A, ANK2
obsolete protein kinase A signaling	2	133.8×	9e-04	TTN, MYOM1
membrane depolarization during cardiac muscle cell action potential	2	133.8×	9e-04	SCN5A, HCN4

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Epinephrine	Approved (phase 4)

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

Drug	Highest phase
Amiodarone	Phase 3
Cyclosporine	Phase 3
Epoetin Alfa	Phase 3
Hydrocortisone	Phase 3
Lidocaine	Phase 3
Methylprednisolone	Phase 3
Sodium Chloride	Phase 3
Vasopressin	Phase 3
Ascorbic Acid	Phase 2
Atropine	Phase 2
Calcium Chloride	Phase 2
Iloprost	Phase 2
Metoprolol	Phase 2
Nitric Oxide	Phase 2
Potassium Chloride	Phase 2
Rocuronium	Phase 2
Ubidecarenone	Phase 2

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 6 · Undrugged: 15

Druggability breadth: 9 of 21 evidence-associated genes (43%) 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
CACNA2D1	PREGABALIN
CACNB2	NIMODIPINE
HCN4	IVABRADINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
CACNA2D1	5	4
CACNB2	2	4
HCN4	2	4
RYR2	1	2
KCNJ8	1	2
TTN	0	0
SLMAP	0	0
NEBL	0	0
TRPM4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	CACNA2D1, CACNB2, SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
CACNA2D1	47	Binding:45, ADMET:1, Toxicity:1
KCNJ8	43	Functional:38, Binding:5
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
CACNB2	22	Binding:20, ADMET:1, Toxicity:1
RYR2	15	Binding:15
TRPM4	14	Binding:13, Functional:1
DSP	2	Binding:2
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; 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	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	CACNA2D1, CACNB2, SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SCN5A, CACNA2D1, CACNB2, HCN4
B	Phased (≥1) drug, not yet approved	2	RYR2, KCNJ8
C	Druggable family + PDB, no drug	5	TTN, TRPM4, DPP6, MYBPC3, MYOM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	10	SLMAP, NEBL, RBM20, DSC2, DSC3, DSG2, DSP, AKAP9, ANK2, PLN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DPP6	0	SCN5A
TTN	1	—
SLMAP	0	—
NEBL	0	—
TRPM4	14	—
RBM20	0	—
DSC2	0	—
DSC3	0	—
DSG2	0	—
DSP	2	—
AKAP9	0	—
ANK2	0	—
MYBPC3	0	—
MYOM1	0	—
PLN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 646.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	537
PHASE2	31
PHASE3	26
PHASE4	25
PHASE1	12
PHASE1/PHASE2	6
EARLY_PHASE1	5
PHASE2/PHASE3	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05173740	PHASE4	RECRUITING	Rehabilitation for Survivors of Out-of-hospital Cardiac Arrest
NCT05205031	PHASE4	ACTIVE_NOT_RECRUITING	Intravenous Vs. Intraosseous Vascular Access During Out-of-Hospital
NCT05564130	PHASE4	ACTIVE_NOT_RECRUITING	Bicarbonate for In-Hospital Cardiac Arrest
NCT06353334	PHASE4	RECRUITING	Butylphthalide’s Safety and Efficacy for Improving Neurological Function Prognosis in Patients With Cardiac Arrest (BNCA Trial)
NCT06530641	PHASE4	RECRUITING	Evaluation of Clinical Impact of the Type of Cardioplegia Used in the Patient Undergoing Major Cardiac Surgery.
NCT06572085	PHASE4	RECRUITING	Neuroprotective Effect of Butylphthalide for Cardiac Arrest Patients
NCT00101881	PHASE4	COMPLETED	Transthoracic Incremental Monophasic Versus Biphasic by Emergency Responders (TIMBER)
NCT00127907	PHASE4	COMPLETED	Vasopressin and Epinephrine Versus Epinephrine Alone in Cardiac Arrest
NCT00180362	PHASE4	COMPLETED	Quick ICD Study: Is Extensive Electrophysiological Testing Before, During and After ICD-Implantation Still Necessary ?
NCT00392639	PHASE4	COMPLETED	Clinical and Economical Interest of Endovascular Cooling in the Management of Cardiac Arrest (ICEREA Study)
NCT00644722	PHASE4	COMPLETED	Out-of-Hospital Intubation With Metal Single Use Laryngoscope Blades
NCT00827957	PHASE4	COMPLETED	Comparing Therapeutic Hypothermia Using External and Internal Cooling for Post-Cardiac Arrest Patients
NCT00843297	PHASE4	COMPLETED	COOL-Trial: Outcome With Invasive and Non-invasive Cooling After Cardiac Arrest
NCT01009606	PHASE4	COMPLETED	Cardiopulmonary Resuscitation Witnessing by a Relative
NCT01083784	PHASE4	UNKNOWN	The Benefit of Prophylactic Anticonvulsant in Post Cardiac Arrest Syndrome With Induced Mild Hypothermia
NCT01155622	PHASE4	COMPLETED	Trial of Different Hypothermia Temperatures in Patients Recovered From Out-of-hospital Cardiac Arrest
NCT01374061	PHASE4	WITHDRAWN	Pre Hospital Evaluation of Video Laryngoscopy
NCT02088736	PHASE4	COMPLETED	Intraosseous vs Intravenous Access for Cardiac Arrest Treatment
NCT02224274	PHASE4	COMPLETED	Antiplatelet Therapy After Cardiac Arrest
NCT02367755	PHASE4	UNKNOWN	Therapeutic Hypothermia With Propofol in Survival and Neurological Prognoses After Cardiac Arrest
NCT03317197	PHASE4	UNKNOWN	Effect of Vasopressin, Steroid, and Epinephrine Treatment in Patients With Out-of-hospital Cardiac Arrest
NCT04287842	PHASE4	WITHDRAWN	Impact if Desflurane Preconditioning on the Content of the Phospho-GSK-3b in the Rat’s Neurons in the Model of I/R
NCT05956431	PHASE4	UNKNOWN	RCT Study of Levosimendan Improving Prognosis of Cardiac Arrest
NCT06081283	PHASE4	TERMINATED	Antiseizure Medication in Seizure Networks at Early Acute Brain Injury
NCT06156059	PHASE4	UNKNOWN	Oral Bedtime Melatonin in Critically Ill Patients
NCT05283850	PHASE2/PHASE3	RECRUITING	Surviving PEA in Roanoke (SPEAR) Study
NCT06503016	PHASE3	RECRUITING	The Effect of phoSPHocreatine on mEdical Emergency Team (Met) tREated Patients
NCT06526533	PHASE3	RECRUITING	RECOMMEND Platform Trial
NCT06680869	PHASE3	RECRUITING	Early Amiodarone in Shockable Cardiac Arrest
NCT06939335	PHASE3	RECRUITING	The Application of Positive End-Expiratory Pressure in Out-of-Hospital Cardiac Arrest: The Lazarus-PEEP Trial.
NCT00000464	PHASE3	COMPLETED	Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE)
NCT00000502	PHASE3	COMPLETED	Evaluation of SC-V Versus Conventional CPR
NCT00000525	PHASE3	COMPLETED	Diuretics, Hypertension, and Arrhythmias Clinical Trial
NCT00000526	PHASE3	COMPLETED	Cardiac Arrhythmia Suppression Trial (CAST)
NCT00004560	PHASE3	COMPLETED	Public Access Defibrillation (PAD) Community Trial
NCT00120965	PHASE3	TERMINATED	AutoPulse Assisted Prehospital International Resuscitation Trial (ASPIRE)
NCT00139542	PHASE3	COMPLETED	AED Use in Out-of-Hospital Cardiac Arrest: A New Algorithm Named One Shock Per Minute
NCT00157261	PHASE3	TERMINATED	Thrombolysis Using Tenecteplase (Metalyse®) in Cardiac Arrest - The TROICA Trial
NCT00212992	PHASE3	COMPLETED	Biphasic Defibrillation Study: Trial to Compare Fixed Versus Escalating Energy
NCT00219687	PHASE3	COMPLETED	Dispatcher-Assisted Resuscitation Trial (DART)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMIODARONE	4	18
VASOPRESSIN	4	5
THIAMINE ION	4	4
EPINEPHRINE	4	3
FLECAINIDE	4	3
SODIUM BICARBONATE	4	3
IMIPRAMINE	4	2
METOPROLOL	4	2
PERAMPANEL	4	2
AMANTADINE	4	1
ATROPINE	4	1
CHLORTHALIDONE	4	1
DESFLURANE	4	1
ENCAINIDE	4	1
FLUMAZENIL	4	1
FOSPHENYTOIN	4	1
HYDROCHLOROTHIAZIDE	4	1
HYDROCORTISONE	4	1
ILOPROST	4	1
LANDIOLOL	4	1
LEVETIRACETAM	4	1
LORAZEPAM	4	1
MELATONIN	4	1
MEXILETINE	4	1
MORICIZINE	4	1
NITROUS ACID	4	1
PHENOBARBITAL	4	1
PROCAINAMIDE	4	1
PROPAFENONE	4	1
QUINIDINE	4	1