Cardiac conduction defect

Summary

Cardiac conduction defect (MONDO:0100042) is a disease caused by POPDC2 (GenCC Strong), with 21 cohort genes and 10 clinical trials. The dominant Reactome pathway is Muscle contraction (8 cohort genes).

At a glance

• Causal gene: POPDC2 (GenCC Strong)
• Cohort genes: 21
• ClinVar variants: 28
• Clinical trials: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiac conduction defect
Mondo ID	MONDO:0100042
OMIM	115080
NCIT	C78245
UMLS	C0264886
MedGen	78114
Is cancer (heuristic)	no

Also known as: cardiac conduction disorder · conduction disorder · disorder of cardiac conduction · heart conduction disorder

Data availability: 28 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Related subtypes (16): 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, sudden cardiac arrest, cardiac conduction disease with or without cardiomyoopathy, cardiogenetic rhythm disorder

Subtypes (1): atrioventricular dissociation

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

28 retrieved; paginated sample, class counts are floors:

14 conflicting classifications of pathogenicity, 11 uncertain significance, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
978274	NM_001458.5(FLNC):c.5685del (p.Val1896fs)	FLNC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
978276	NM_000719.7(CACNA1C):c.32del (p.Pro11fs)	CACNA1C	Likely pathogenic	criteria provided, single submitter
978366	NM_001035.3(RYR2):c.9848T>A (p.Ile3283Asn)	RYR2	Likely pathogenic	criteria provided, single submitter
45392	NM_020297.4(ABCC9):c.1887G>T (p.Glu629Asp)	ABCC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
457049	NM_001148.6(ANK2):c.7183A>C (p.Thr2395Pro)	ANK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
978365	NM_001232.4(CASQ2):c.289A>G (p.Lys97Glu)	CASQ2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518815	NM_004006.3(DMD):c.8053G>A (p.Glu2685Lys)	DMD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632865	NM_002230.4(JUP):c.412G>A (p.Glu138Lys)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67505	NM_000238.4(KCNH2):c.442C>T (p.Arg148Trp)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239179	NM_002471.4(MYH6):c.5476_5477delinsAA (p.Gly1826Asn)	MYH6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45076	NM_001005242.3(PKP2):c.302G>A (p.Arg101His)	PKP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
229186	NM_001134363.3(RBM20):c.1529T>C (p.Phe510Ser)	RBM20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191483	NM_001035.3(RYR2):c.5923A>G (p.Met1975Val)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
684806	NM_001035.3(RYR2):c.243G>A (p.Met81Ile)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67835	NM_000335.5(SCN5A):c.3908C>T (p.Thr1303Met)	SCN5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
684784	NM_000335.5(SCN5A):c.5894C>G (p.Ser1965Cys)	SCN5A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
381692	NM_017636.4(TRPM4):c.3611C>T (p.Pro1204Leu)	TRPM4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2585217	NM_007202.4(AKAP10):c.1467+5C>A	AKAP10	Uncertain significance	criteria provided, single submitter
684796	NM_001148.6(ANK2):c.9245C>T (p.Thr3082Ile)	ANK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
978369	NM_001148.6(ANK2):c.2735A>G (p.His912Arg)	ANK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
978344	NM_004006.3(DMD):c.1603G>A (p.Val535Ile)	DMD	Uncertain significance	criteria provided, multiple submitters, no conflicts
684795	NM_000218.3(KCNQ1):c.74G>C (p.Arg25Pro)	KCNQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
978280	NM_000257.4(MYH7):c.4543C>G (p.Gln1515Glu)	MHRT	Uncertain significance	criteria provided, multiple submitters, no conflicts
684804	NM_002471.4(MYH6):c.4060G>A (p.Glu1354Lys)	MYH6	Uncertain significance	criteria provided, single submitter
660218	NM_000257.4(MYH7):c.4756G>A (p.Ala1586Thr)	MYH7	Uncertain significance	criteria provided, multiple submitters, no conflicts
229220	NM_001035.3(RYR2):c.5416G>A (p.Ala1806Thr)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
978283	NM_001267550.2(TTN):c.61447_61449del (p.Arg20483del)	TTN	Uncertain significance	criteria provided, single submitter
404412	NM_000371.4(TTR):c.370C>T (p.Arg124Cys)	TTR	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 78 · 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
POPDC2	Strong	Autosomal recessive	cardiac conduction defect

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
TTR	Orphanet:597939	Euthyroid dysprealbuminemic hyperthyroxinemia
TTR	Orphanet:85447	ATTRV30M amyloidosis
TTR	Orphanet:85451	ATTRV122I amyloidosis
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
CASQ2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
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
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy
ANK2	Orphanet:101016	Romano-Ward syndrome
ABCC9	Orphanet:130	Brugada syndrome
ABCC9	Orphanet:1517	Cantú syndrome

Cohort genes → proteins

21 cohort genes, 20 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	21

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POPDC2	HGNC:17648	ENSG00000121577	Q9HBU9	Popeye domain-containing protein 2	gencc
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
TTR	HGNC:12405	ENSG00000118271	P02766	Transthyretin	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-2	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
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
AKAP10	HGNC:368	ENSG00000108599	O43572	A-kinase anchor protein 10, mitochondrial	clinvar
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
MHRT	HGNC:51291			myosin heavy chain associated RNA transcript	clinvar
ABCC9	HGNC:60	ENSG00000069431	O60706	ATP-binding cassette sub-family C member 9	clinvar
JUP	HGNC:6207	ENSG00000173801	P14923	Junction plakoglobin	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	clinvar
MYH6	HGNC:7576	ENSG00000197616	P13533	Myosin-6	clinvar
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POPDC2	Popeye domain-containing protein 2	Important for the maintenance of cardiac function.
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.
TTR	Transthyretin	Thyroid hormone-binding protein.
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.
CASQ2	Calsequestrin-2	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.
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.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
AKAP10	A-kinase anchor protein 10, mitochondrial	Differentially targeted protein that binds to type I and II regulatory subunits of protein kinase A and anchors them to the mitochondria or the plasma membrane.
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
ANK2	Ankyrin-2	Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells.
ABCC9	ATP-binding cassette sub-family C member 9	Subunit of ATP-sensitive potassium channels (KATP).
JUP	Junction plakoglobin	Common junctional plaque protein.
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
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.
MYH6	Myosin-6	Muscle contraction.
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

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	6	31.9×	2e-07
Scaffold/PPI	3	2.5×	0.414
Transporter	1	3.7×	0.555
Antibody/Immunoglobulin	1	1.4×	0.753
Kinase	1	1.3×	0.753
Transcription factor	2	0.8×	0.865
Other/Unknown	7	0.6×	0.989

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POPDC2	Other/Unknown	no		POPDC1-3, cNMP-bd_dom_sf, POPDC1-3_dom
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
TTR	Other/Unknown	no		Transthyretin/HIU_hydrolase, Transthyretin/HIU_hydrolase_d, Thyroxine_BS
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
CASQ2	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_sf
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
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
AKAP10	Other/Unknown	no		RGS, RGS_sf, AKAP10_AKB_dom
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
MHRT	Other/Unknown	no
ABCC9	Transporter	yes		ABCC8/9, ABCC9, ABC_transporter-like_ATP-bd
JUP	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
MYH6	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
MYH7	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 1.

17 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)	20
unknown	1

Top tissues across cohort

Tissue	Cohort genes
apex of heart	7
left ventricle myocardium	4
heart right ventricle	3
myocardium	3
hindlimb stylopod muscle	3
heart left ventricle	2
right atrium auricular region	2
skeletal muscle tissue of biceps brachii	2
cardiac muscle of right atrium	2
gastrocnemius	2
cardiac atrium	2
cardiac ventricle	1
biceps brachii	1
gluteal muscle	1
choroid plexus epithelium	1
right lobe of liver	1
type B pancreatic cell	1
muscle layer of sigmoid colon	1
right coronary artery	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POPDC2	190	tissue_specific	yes	apex of heart, right atrium auricular region, heart left ventricle
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
TTR	185	broad	marker	choroid plexus epithelium, type B pancreatic cell, right lobe of liver
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
CASQ2	213	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
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
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
AKAP10	287	ubiquitous	marker	buccal mucosa cell, sural nerve, calcaneal tendon
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
MHRT
ABCC9	195	broad	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
JUP	287	ubiquitous	marker	lower esophagus mucosa, skin of leg, skin of abdomen
KCNH2	211	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex
MYH6	154	tissue_specific	yes	cardiac muscle of right atrium, cardiac atrium, vena cava
MYH7	167	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii
PKP2	237	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 25.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
JUP	4,618
TTR	4,528
TTN	4,237
KCNQ1	3,235
FLNC	3,174
CACNA1C	3,145
MYH6	3,119
MYH7	2,744
RYR2	2,653

Intra-cohort edges

A	B	Sources
ABCC9	RBM20	string_interaction
ABCC9	SCN5A	string_interaction
ANK2	DMD	intact
ANK2	POPDC2	biogrid_interaction, intact
ANK2	TTN	string_interaction
CACNA1C	CASQ2	string_interaction
CACNA1C	KCNH2	string_interaction
CACNA1C	RYR2	biogrid_interaction, string_interaction
CASQ2	KCNH2	string_interaction
CASQ2	RYR2	string_interaction
CASQ2	SCN5A	string_interaction
DMD	FLNC	string_interaction
JUP	PKP2	string_interaction
JUP	RYR2	string_interaction
KCNH2	KCNQ1	string_interaction
KCNH2	SCN5A	string_interaction
KCNQ1	SCN5A	string_interaction
MYH6	TTN	string_interaction
MYH7	RBM20	string_interaction
MYH7	TTN	string_interaction
PKP2	RYR2	string_interaction
PKP2	SCN5A	string_interaction
RBM20	SCN5A	string_interaction
RBM20	TTN	string_interaction
SCN5A	TRPM4	string_interaction

Structural data

PDB: 16 · AlphaFold-only: 4 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTR	P02766	462
TTN	Q8WZ42	64
MYH7	P12883	43
CACNA1C	Q13936	33
TRPM4	Q8TD43	29
KCNQ1	P51787	28
RYR2	Q92736	26
KCNH2	Q12809	24
SCN5A	Q14524	16
FLNC	Q14315	14
ANK2	Q01484	11
DMD	P11532	6
CASQ2	O14958	4
AKAP10	O43572	2
JUP	P14923	1
PKP2	Q99959	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ABCC9	O60706	81.72
POPDC2	Q9HBU9	76.07
MYH6	P13533	74.91
RBM20	Q5T481	48.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 71. Enrichment computed across 21 evidence-associated genes (17 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Muscle contraction	8	36.3×	1e-09	RYR2, SCN5A, CACNA1C, CASQ2, ABCC9, KCNH2, KCNQ1, MYH6
Cardiac conduction	7	44.8×	3e-09	RYR2, SCN5A, CACNA1C, CASQ2, ABCC9, KCNH2, KCNQ1
Striated Muscle Contraction	3	54.5×	5e-04	TTN, DMD, MYH6
Ion homeostasis	3	36.0×	0.001	RYR2, CASQ2, ABCC9
Phase 3 - rapid repolarisation	2	134.3×	0.001	KCNH2, KCNQ1
Phase 2 - plateau phase	2	89.6×	0.003	CACNA1C, KCNQ1
Potassium Channels	3	23.7×	0.003	ABCC9, KCNH2, KCNQ1
Interaction between L1 and Ankyrins	2	43.3×	0.008	SCN5A, ANK2
Phase 0 - rapid depolarisation	2	40.7×	0.008	SCN5A, CACNA1C
Voltage gated Potassium channels	2	28.6×	0.015	KCNH2, KCNQ1
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	335.9×	0.019	ABCC9
Defective visual phototransduction due to STRA6 loss of function	1	223.9×	0.026	TTR
ATP sensitive Potassium channels	1	167.9×	0.027	ABCC9
Non-integrin membrane-ECM interactions	2	18.2×	0.027	TTR, DMD
Stimuli-sensing channels	2	16.0×	0.027	RYR2, CASQ2
Axon guidance	3	8.0×	0.027	SCN5A, CACNA1C, ANK2
Neuronal System	3	7.8×	0.027	ABCC9, KCNH2, KCNQ1
Nervous system development	3	7.6×	0.027	SCN5A, CACNA1C, ANK2
L1CAM interactions	2	14.1×	0.032	SCN5A, ANK2
CDH11 homotypic and heterotypic interactions	1	96.0×	0.037	JUP
Regulation of CDH19 Expression and Function	1	84.0×	0.040	JUP
Ion channel transport	2	11.3×	0.043	RYR2, CASQ2
Regulation of CDH11 function	1	61.1×	0.048	JUP
Formation of the cornified envelope	2	10.3×	0.048	JUP, PKP2
Regulation of CDH1 Function	1	56.0×	0.050	JUP
Inwardly rectifying K+ channels	1	42.0×	0.064	ABCC9
Cell-extracellular matrix interactions	1	39.5×	0.066	FLNC
Transport of small molecules	3	4.4×	0.071	RYR2, CASQ2, ABCC9
The canonical retinoid cycle in rods (twilight vision)	1	30.5×	0.079	TTR
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	29.2×	0.080	JUP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle contraction	9	180.6×	7e-17	RYR2, SCN5A, TTN, CASQ2, DMD, KCNH2, KCNQ1, MYH6 (+1 more)
regulation of heart rate	8	187.2×	3e-15	RYR2, SCN5A, CASQ2, POPDC2, DMD, ANK2, MYH6, MYH7
regulation of heart rate by cardiac conduction	8	149.8×	2e-14	SCN5A, CACNA1C, TRPM4, ANK2, JUP, KCNH2, KCNQ1, PKP2
ventricular cardiac muscle cell action potential	6	297.4×	1e-12	RYR2, SCN5A, ANK2, KCNH2, KCNQ1, PKP2
regulation of ventricular cardiac muscle cell action potential	5	351.1×	6e-11	RYR2, CACNA1C, TRPM4, JUP, PKP2
striated muscle contraction	5	210.7×	1e-09	RYR2, TTN, CASQ2, MYH6, MYH7
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	5	168.5×	3e-09	RYR2, CACNA1C, CASQ2, DMD, ANK2
regulation of ventricular cardiac muscle cell membrane repolarization	4	168.5×	2e-07	SCN5A, ANK2, KCNH2, KCNQ1
membrane depolarization during AV node cell action potential	3	505.6×	5e-07	SCN5A, CACNA1C, TRPM4
atrial cardiac muscle cell action potential	3	252.8×	5e-06	SCN5A, ANK2, KCNQ1
cell communication by electrical coupling involved in cardiac conduction	3	210.7×	8e-06	RYR2, CACNA1C, PKP2
regulation of membrane repolarization	3	194.4×	1e-05	CASQ2, KCNH2, KCNQ1
muscle filament sliding	3	158.0×	2e-05	TTN, MYH6, MYH7
Purkinje myocyte to ventricular cardiac muscle cell signaling	2	842.6×	3e-05	RYR2, CASQ2
positive regulation of heart rate	3	105.3×	5e-05	RYR2, TRPM4, KCNQ1
ventricular cardiac muscle tissue morphogenesis	3	105.3×	5e-05	MYH6, MYH7, PKP2
cardiac muscle cell action potential involved in contraction	3	105.3×	5e-05	SCN5A, CACNA1C, PKP2
membrane depolarization during Purkinje myocyte cell action potential	2	561.7×	5e-05	SCN5A, TRPM4
membrane depolarization during bundle of His cell action potential	2	561.7×	5e-05	SCN5A, TRPM4
regulation of atrial cardiac muscle cell action potential	2	561.7×	5e-05	RYR2, ANK2
membrane depolarization during atrial cardiac muscle cell action potential	2	561.7×	5e-05	SCN5A, CACNA1C
ATP metabolic process	3	70.2×	1e-04	ABCC9, MYH6, MYH7
sarcoplasmic reticulum calcium ion transport	2	337.0×	2e-04	RYR2, ANK2
membrane depolarization during SA node cell action potential	2	337.0×	2e-04	SCN5A, ANK2
sarcomere organization	3	57.5×	2e-04	TTN, FLNC, MYH6
SA node cell action potential	2	280.9×	2e-04	SCN5A, ANK2
regulation of SA node cell action potential	2	280.9×	2e-04	RYR2, ANK2
potassium ion import across plasma membrane	3	55.0×	2e-04	ABCC9, KCNH2, KCNQ1
desmosome assembly	2	240.7×	3e-04	JUP, PKP2
regulation of atrial cardiac muscle cell membrane repolarization	2	240.7×	3e-04	SCN5A, KCNQ1

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 14

Druggability breadth: 13 of 21 evidence-associated genes (62%) 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
TTR	TRICLABENDAZOLE
CACNA1C	REMIFENTANIL
ABCC9	PINACIDIL ANHYDROUS
KCNH2	CETIRIZINE
KCNQ1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
SCN5A	108	4
CACNA1C	85	4
TTR	29	4
KCNQ1	15	4
ABCC9	5	4
RYR2	1	2
POPDC2	0	0
TTN	0	0
CASQ2	0	0

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, KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNH2, KCNQ1, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	CACNA1C, KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	CACNA1C, KCNH2, SCN5A
DARUNAVIR	4	KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNH2, KCNQ1, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	CACNA1C, KCNH2, KCNQ1, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	CACNA1C, KCNH2, SCN5A
NIMODIPINE	4	CACNA1C, 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): 1.

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
TTR	423	Binding:391, Functional:32
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
ABCC9	61	Functional:46, Binding:15
RYR2	15	Binding:15
TRPM4	14	Binding:13, Functional:1
TTN	1	Binding:1
JUP	1	Binding:1

Cohort enzymes (BRENDA EC)

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594
TTR	423
CACNA1C	575
KCNH2	4,851
KCNQ1	179

Pharmacogenomics

Cohort genes with a PharmGKB record: 20; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	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, KCNH2, KCNQ1, SCN5A
PALONOSETRON	4	KCNH2, KCNQ1, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	CACNA1C, KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	CACNA1C, KCNH2, SCN5A
DARUNAVIR	4	KCNH2, KCNQ1, SCN5A
DARIFENACIN	4	KCNH2, KCNQ1, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	CACNA1C, KCNH2, KCNQ1, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	CACNA1C, KCNH2, SCN5A
NIMODIPINE	4	CACNA1C, 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)	6	SCN5A, TTR, CACNA1C, ABCC9, KCNH2, KCNQ1
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	3	TTN, TRPM4, FLNC
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	11	POPDC2, CASQ2, RBM20, DMD, AKAP10, ANK2, MHRT, JUP, MYH6, MYH7 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CASQ2	0	RYR2, CACNA1C
RBM20	0	ABCC9
PKP2	0	SCN5A
POPDC2	0	—
TTN	1	—
TRPM4	14	—
DMD	0	—
AKAP10	0	—
FLNC	0	—
ANK2	0	—
MHRT	0	—
JUP	1	—
MYH6	0	—
MYH7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	10

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04776642	Not specified	RECRUITING	Biobank for Arrhythmia and Conduction Disorders: TowArd Pathophysiology Based Treatment
NCT06278844	Not specified	RECRUITING	Exercise Capacity Improvement by Conduction System Pacing in heArt Failure patieNts Without Compelling CRT inDication
NCT06620237	Not specified	ACTIVE_NOT_RECRUITING	BIO|MASTER.CSP Study
NCT07201363	Not specified	RECRUITING	Biomarkers of Inflammation and Fibrosis in Conduction Disorders After TAVI
NCT01609738	Not specified	COMPLETED	Left Ventricular Septum Pacing in Patients by Transvenous Approach Through the Inter-ventricular Septum
NCT02881671	Not specified	UNKNOWN	Identification of Genetic Basis of Atrioventricular Conduction Defects: From Congenital Forms to Degenerative Forms
NCT03024047	Not specified	UNKNOWN	Cohort Description of Younger With AV-block
NCT03947021	Not specified	UNKNOWN	Developing Methods for Reconstructing Electrical Heart Activity
NCT06371846	Not specified	UNKNOWN	Comparative Study of the Surface Electrocardiogram Signals During the Implantation of Conduction System Pacing Devices
NCT06857201	Not specified	WITHDRAWN	RAFT-TAVR PACE: LBBAP vs. RVP Post-TAVR in Patients Requiring PPI