Ventricular fibrillation, paroxysmal familial, type 1

Summary

Ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376) is a disease with 14 cohort genes and 183 clinical trials. The dominant Reactome pathway is Cardiac conduction (4 cohort genes). Top therapeutic interventions include ganirelix, cetrorelix, and estradiol valerate.

At a glance

• Cohort genes: 14
• ClinVar variants: 420
• Clinical trials: 183

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ventricular fibrillation, paroxysmal familial, type 1
Mondo ID	MONDO:0011376
MeSH	C567851
OMIM	603829
SNOMED CT	233915000
UMLS	C2751898
MedGen	414502
GARD	0024795
Is cancer (heuristic)	no

Also known as: IVF · ventricular fibrillation, familial, 1 · ventricular fibrillation, paroxysmal familial, 1 · ventricular fibrillation, paroxysmal familial, type 1 · VF1

Data availability: 420 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › ventricular fibrillation › paroxysmal familial ventricular fibrillation › ventricular fibrillation, paroxysmal familial, type 1

Related subtypes (1): ventricular fibrillation, paroxysmal familial, 2

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

420 retrieved; paginated sample, class counts are floors:

218 uncertain significance, 135 conflicting classifications of pathogenicity, 37 benign/likely benign, 13 pathogenic/likely pathogenic, 8 likely benign, 6 pathogenic, 2 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
155775	NM_001167623.2(CACNA1C):c.1204G>A (p.Gly402Ser)	CACNA1C	Pathogenic	criteria provided, multiple submitters, no conflicts
201438	NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
201508	NM_000335.5(SCN5A):c.4242+1G>C	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
201560	NM_000335.5(SCN5A):c.2550_2551dup (p.Phe851fs)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
201572	NM_000335.5(SCN5A):c.4844TCT[1] (p.Phe1616del)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39444	NM_000335.5(SCN5A):c.665G>A (p.Arg222Gln)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
406415	NM_000335.5(SCN5A):c.5414_5417del (p.Thr1805fs)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67633	NM_000335.5(SCN5A):c.1099C>T (p.Arg367Cys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67639	NM_000335.5(SCN5A):c.1127G>A (p.Arg376His)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67778	NM_000335.5(SCN5A):c.310C>T (p.Arg104Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67838	NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67932	NM_000335.5(SCN5A):c.4856C>T (p.Thr1619Met)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67967	NM_000335.5(SCN5A):c.5224G>A (p.Gly1742Arg)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68032	NM_000335.5(SCN5A):c.673C>T (p.Arg225Trp)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9374	NM_000335.5(SCN5A):c.4864C>T (p.Arg1622Ter)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9377	NM_000335.5(SCN5A):c.5347G>A (p.Glu1783Lys)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9383	NM_000335.5(SCN5A):c.5126C>T (p.Ser1709Leu)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9395	NM_000335.5(SCN5A):c.4219G>A (p.Gly1407Arg)	SCN5A	Pathogenic	criteria provided, multiple submitters, no conflicts
9406	NM_000335.5(SCN5A):c.4780G>C (p.Asp1594His)	SCN5A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3252218	NM_000335.5(SCN5A):c.2425_2426del (p.Ser809fs)	SCN5A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383167	NM_000335.5(SCN5A):c.3741T>G (p.Tyr1247Ter)	SCN5A	Likely pathogenic	criteria provided, single submitter
180339	NM_004415.4(DSP):c.6812A>C (p.Lys2271Thr)	DSP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163710	NM_002230.4(JUP):c.2069A>G (p.Asn690Ser)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180376	NM_002230.4(JUP):c.1807G>T (p.Val603Leu)	JUP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178130	NM_000335.5(SCN5A):c.3259G>A (p.Ala1087Thr)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178131	NM_000335.5(SCN5A):c.3246C>T (p.Ser1082=)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
264627	NM_000335.5(SCN5A):c.3315C>T (p.Ala1105=)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520458	NM_000335.5(SCN5A):c.3080G>A (p.Arg1027Gln)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532068	NM_000335.5(SCN5A):c.3301G>A (p.Ala1101Thr)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
67770	NM_000335.5(SCN5A):c.2957G>A (p.Arg986Gln)	LOC110121269	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 67 · 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
SNTA1	Orphanet:101016	Romano-Ward syndrome
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
VCL	Orphanet:154	Familial isolated dilated cardiomyopathy
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
JPH2	Orphanet:154	Familial isolated dilated cardiomyopathy
RBM20	Orphanet:154	Familial isolated dilated cardiomyopathy
DPP6	Orphanet:228140	Idiopathic ventricular fibrillation
DPP6	Orphanet:2514	Autosomal dominant primary microcephaly
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome
JUP	Orphanet:158687	Lethal acantholytic erosive disorder
JUP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant

Cohort genes → proteins

14 cohort genes, 14 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

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
SNTA1	HGNC:11167	ENSG00000101400	Q13424	Alpha-1-syntrophin	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
VCL	HGNC:12665	ENSG00000035403	P18206	Vinculin	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
JPH2	HGNC:14202	ENSG00000149596	Q9BR39	Junctophilin-2	clinvar
RBM20	HGNC:27424	ENSG00000203867	Q5T481	RNA-binding protein 20	clinvar
DPP6	HGNC:3010	ENSG00000130226	P42658	A-type potassium channel modulatory protein DPP6	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
JUP	HGNC:6207	ENSG00000173801	P14923	Junction plakoglobin	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	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)
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.
SNTA1	Alpha-1-syntrophin	Adapter protein that binds to and probably organizes the subcellular localization of a variety of membrane proteins.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
VCL	Vinculin	Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion.
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
JPH2	Junctophilin-2	Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes.
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.
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
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.
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: 6 · Difficult: 4 · Unknown: 4 · 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	4	31.9×	3e-05
Scaffold/PPI	3	3.7×	0.131
Protease	1	2.6×	0.603
Kinase	1	2.0×	0.603
Transcription factor	1	0.6×	0.990
Other/Unknown	4	0.5×	0.990

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
SNTA1	Scaffold/PPI	no		PDZ, PH_domain, PH-like_dom_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
VCL	Other/Unknown	no		Vinculin_CS, Vinculin/catenin, Vinculin
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
JPH2	Other/Unknown	no		MORN, Junctophilin
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
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
JUP	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
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: 0.

12 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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	6
left ventricle myocardium	4
heart right ventricle	2
myocardium	2
hindlimb stylopod muscle	2
skeletal muscle tissue of biceps brachii	2
cardiac ventricle	1
heart left ventricle	1
gastrocnemius	1
biceps brachii	1
gluteal muscle	1
blood vessel layer	1
saphenous vein	1
urethra	1
muscle layer of sigmoid colon	1
right coronary artery	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	1
cardiac muscle of right atrium	1
Brodmann (1909) area 23	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
SNTA1	266	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
VCL	300	ubiquitous	marker	saphenous vein, blood vessel layer, urethra
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
JPH2	173	broad	yes	left ventricle myocardium, skeletal muscle tissue of rectus abdominis, tibialis anterior
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
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
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
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: 18.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JUP	4,618
VCL	4,495
TTN	4,237
CACNA1C	3,145
DSP	2,897
MYH7	2,744
RYR2	2,653
DPP6	2,224
SCN5A	2,090
KCNH2	1,932

Intra-cohort edges

A	B	Sources
CACNA1C	JPH2	string_interaction
CACNA1C	KCNH2	string_interaction
CACNA1C	RYR2	biogrid_interaction, string_interaction
DPP6	SCN5A	string_interaction
DSP	JUP	intact, string_interaction
DSP	PKP2	string_interaction
JPH2	RYR2	string_interaction
JUP	PKP2	string_interaction
JUP	RYR2	string_interaction
KCNH2	SCN5A	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
RYR2	SNTA1	intact
SCN5A	SNTA1	biogrid_interaction, string_interaction

Structural data

PDB: 12 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
MYH7	P12883	43
VCL	P18206	37
CACNA1C	Q13936	33
RYR2	Q92736	26
KCNH2	Q12809	24
SCN5A	Q14524	16
DPP6	P42658	8
DSP	P15924	4
JPH2	Q9BR39	2
JUP	P14923	1
PKP2	Q99959	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SNTA1	Q13424	80.00
RBM20	Q5T481	48.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. Enrichment computed across 14 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cardiac conduction	4	43.5×	8e-05	RYR2, SCN5A, CACNA1C, KCNH2
Muscle contraction	4	30.9×	2e-04	RYR2, SCN5A, CACNA1C, KCNH2
Regulation of CDH1 Function	2	190.3×	9e-04	VCL, JUP
Formation of the cornified envelope	3	26.4×	0.003	DSP, JUP, PKP2
Phase 0 - rapid depolarisation	2	69.2×	0.004	SCN5A, CACNA1C
Keratinization	3	16.7×	0.006	DSP, JUP, PKP2
Activation of STAT3 by cadherin engagement	2	32.6×	0.014	VCL, JUP
CDH11 homotypic and heterotypic interactions	1	163.1×	0.042	JUP
Platelet degranulation	2	17.6×	0.042	TTN, VCL
Regulation of CDH19 Expression and Function	1	142.8×	0.042	JUP
Phase 3 - rapid repolarisation	1	114.2×	0.042	KCNH2
Apoptotic cleavage of cell adhesion proteins	1	103.8×	0.042	DSP
Regulation of CDH11 function	1	103.8×	0.042	JUP
Neutrophil degranulation	3	6.9×	0.042	VCL, DSP, JUP
Phase 2 - plateau phase	1	76.1×	0.054	CACNA1C
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	49.6×	0.064	JUP
VEGFR2 mediated vascular permeability	1	40.8×	0.064	JUP
Adrenaline,noradrenaline inhibits insulin secretion	1	39.4×	0.064	CACNA1C
Interaction between L1 and Ankyrins	1	36.8×	0.064	SCN5A
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	35.7×	0.064	VCL
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	33.6×	0.064	JUP
Signaling by high-kinase activity BRAF mutants	1	31.7×	0.064	VCL
Striated Muscle Contraction	1	30.9×	0.064	TTN
RHOH GTPase cycle	1	30.9×	0.064	JUP
Formation of the dystrophin-glycoprotein complex (DGC)	1	30.9×	0.064	SNTA1
MAP2K and MAPK activation	1	28.6×	0.064	VCL
Signaling by RAF1 mutants	1	27.9×	0.064	VCL
NCAM signaling for neurite out-growth	1	27.2×	0.064	CACNA1C
Smooth Muscle Contraction	1	26.6×	0.064	VCL
RND1 GTPase cycle	1	26.6×	0.064	DSP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 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 ventricular cardiac muscle cell action potential	5	501.6×	3e-11	RYR2, CACNA1C, DSP, JUP, PKP2
ventricular cardiac muscle cell action potential	5	354.0×	7e-11	RYR2, SCN5A, SNTA1, KCNH2, PKP2
regulation of heart rate by cardiac conduction	6	160.5×	7e-11	SCN5A, CACNA1C, DSP, JUP, KCNH2, PKP2
cardiac muscle contraction	5	143.3×	7e-09	RYR2, SCN5A, TTN, KCNH2, MYH7
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	3	515.9×	5e-07	DSP, JUP, PKP2
regulation of heart rate	4	133.8×	5e-07	RYR2, SCN5A, SNTA1, MYH7
cell communication by electrical coupling involved in cardiac conduction	3	300.9×	3e-06	RYR2, CACNA1C, PKP2
calcium ion transport into cytosol	3	257.9×	4e-06	RYR2, CACNA1C, JPH2
striated muscle contraction	3	180.6×	1e-05	RYR2, TTN, MYH7
regulation of ventricular cardiac muscle cell membrane repolarization	3	180.6×	1e-05	SCN5A, SNTA1, KCNH2
cardiac muscle cell action potential involved in contraction	3	150.5×	2e-05	SCN5A, CACNA1C, PKP2
membrane depolarization during atrial cardiac muscle cell action potential	2	802.5×	3e-05	SCN5A, CACNA1C
membrane depolarization during AV node cell action potential	2	481.5×	9e-05	SCN5A, CACNA1C
desmosome assembly	2	343.9×	2e-04	JUP, PKP2
desmosome organization	2	300.9×	2e-04	DSP, PKP2
cardiac muscle hypertrophy	2	240.7×	3e-04	RYR2, TTN
membrane depolarization during action potential	2	240.7×	3e-04	SCN5A, KCNH2
muscle contraction	3	44.6×	4e-04	SNTA1, TTN, MYH7
membrane depolarization during cardiac muscle cell action potential	2	200.6×	4e-04	SCN5A, CACNA1C
regulation of cardiac muscle contraction by calcium ion signaling	2	185.2×	5e-04	RYR2, JPH2
epithelial cell-cell adhesion	2	172.0×	5e-04	VCL, DSP
muscle filament sliding	2	150.5×	6e-04	TTN, MYH7
regulation of sodium ion transmembrane transport	2	150.5×	6e-04	SCN5A, SNTA1
positive regulation of sodium ion transport	2	120.4×	9e-04	SCN5A, PKP2
ventricular cardiac muscle tissue morphogenesis	2	100.3×	0.001	MYH7, PKP2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	2	96.3×	0.001	RYR2, CACNA1C
regulation of potassium ion transmembrane transport	2	89.2×	0.002	DPP6, KCNH2
protein localization to plasma membrane	3	23.3×	0.002	DPP6, JUP, PKP2
cell-cell adhesion	3	21.8×	0.002	DSP, JUP, PKP2
skeletal muscle contraction	2	73.0×	0.002	TTN, MYH7

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 10

Druggability breadth: 9 of 14 evidence-associated genes (64%) 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
CACNA1C	REMIFENTANIL
KCNH2	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
SCN5A	108	4
CACNA1C	85	4
RYR2	1	2
SNTA1	0	0
TTN	0	0
VCL	0	0
JPH2	0	0
RBM20	0	0
DPP6	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, SCN5A
PALONOSETRON	4	KCNH2, 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, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	CACNA1C, KCNH2, 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
RYR2	15	Binding:15
VCL	2	Binding:2
DSP	2	Binding:2
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
CACNA1C	575
KCNH2	4,851

Pharmacogenomics

Cohort genes with a PharmGKB record: 14; 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, SCN5A
PALONOSETRON	4	KCNH2, 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, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	CACNA1C, KCNH2, 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)	3	SCN5A, CACNA1C, KCNH2
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	2	TTN, DPP6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	SNTA1, VCL, JPH2, RBM20, DSP, JUP, MYH7, PKP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SNTA1	0	SCN5A
JPH2	0	RYR2
DPP6	0	SCN5A
PKP2	0	SCN5A
TTN	1	—
VCL	2	—
RBM20	0	—
DSP	2	—
JUP	1	—
MYH7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 183.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	152
PHASE4	14
PHASE3	6
PHASE2	5
PHASE2/PHASE3	3
PHASE1	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04487925	PHASE4	RECRUITING	Controlled Ovarian Stimulation Versus Modified Natural Cycles in Poor Responders
NCT06396390	PHASE4	NOT_YET_RECRUITING	Comparison of Progestin Primed Ovarian Stimulation (PPOS) vs.GnRH Antagonist Methods on IVF Outcomes
NCT07499804	PHASE4	RECRUITING	Effect of Tadalafil on Endometrial Thickness and Frozen Embryo Transfer Outcomes
NCT02201914	PHASE4	UNKNOWN	Clomiphene Citrate Plus Gonadotropins and GnRH Antagonist Versus Flexible GnRH Antagonist Protocol Versus Microdose GnRH Agonist Protocol in Poor Responders Undergoing IVF
NCT02651285	PHASE4	UNKNOWN	Use of G-CSF Supplemented IVF Medium in Patients Undergoing IVF
NCT04002635	PHASE4	WITHDRAWN	Letrozole for Frozen Embryo Transfer (FET) in Patients With Polycystic Ovary Syndrome (PCOS)
NCT04385342	PHASE4	UNKNOWN	FSH Followed by HMG vs FSH Plus HMG in IVF
NCT04654741	PHASE4	UNKNOWN	The Rate of Embryo Euploidy in Progestin-primed Ovarian Stimulation Cycles
NCT04728659	PHASE4	UNKNOWN	Desogestrel Versus GnRH Antagonist in IVF/ICSI
NCT04993924	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment in the Early Follicular Phase for Resolution of a Baseline Functional Ovarian Cyst
NCT05071339	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment for the Prevention of Asynchronous Follicular Growth
NCT05321511	PHASE4	UNKNOWN	Comparison of Triggers in Double Ovarian Stimulation (DuoStim).
NCT05954962	PHASE4	COMPLETED	Efficacy of Micronized Natural Progesterone vs GnRH Antagonist in the Prevention of LH Peak During Ovarian Stimulation.
NCT06181305	PHASE4	UNKNOWN	Endometrial Preparation in Frozen Embryo Transfer Cycles
NCT06405204	PHASE3	NOT_YET_RECRUITING	of Myo-inositol, Melatonin and Co-enzyme q10 on Ovarian Reserve
NCT07499817	PHASE3	RECRUITING	Effect of Pentoxyfilline on Endometrial Thickness and Frozen Embryo Transfer Outcomes
NCT04414761	PHASE3	COMPLETED	Live Birth Rate Between PPOS and GnRH Antagonist Protocol in Patients With Anticipated High Ovarian Response
NCT04806919	PHASE3	COMPLETED	Luteal Support in Artificial Vitrified/Warmed Cycles With Low Progesterone
NCT05951400	PHASE2/PHASE3	COMPLETED	Progesterone Primed Protocol Versus GnRH Antagonist in With PCO Undergoing ICSI
NCT05951413	PHASE2/PHASE3	UNKNOWN	The Effect of Sildenafil Citrate on Frozen Embryo Transfer Cycles
NCT05971667	PHASE2/PHASE3	UNKNOWN	Effect of Tadalafil, Sildenafil and Pentoxyfylline on Frozen Embryo Transfer Outcomes
NCT05972902	PHASE3	UNKNOWN	Dydrogesterone, Cetrorelix Acetate and Triptorelin in Intra Cytoplasmic Sperm Injection Outcomes
NCT06048666	PHASE3	UNKNOWN	Platelet Rich Plasma on Ovarian Reserve Parameters and Intra Cytoplasmic Sperm Injection Outcomes in Patients With Diminished Ovarian Reserve
NCT06555575	PHASE2	RECRUITING	Ubiquinone vs. Ubiquinol Supplementation
NCT06997900	PHASE2	RECRUITING	Menopur And Rekovelle Combination Study Version 2.0
NCT02677259	PHASE2	UNKNOWN	Luteal Phase Estradiol Support for In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles
NCT04524026	PHASE2	COMPLETED	RIOTC: Reducing the Impact of Ovarian Stimulation. Novel Approaches to Luteal Support in IVF-Study 2
NCT04778358	PHASE2	COMPLETED	Higher Dose of Rekovelle in Oocyte Donors
NCT04175990	PHASE1	COMPLETED	IVF Outcome Following Progestogen Ovarian Stimulation
NCT04283435	PHASE1	UNKNOWN	Endometrial Effects of Sildenafil in Frozen-Thawed Cycles in Women With Thin Endometrium
NCT06870266	EARLY_PHASE1	NOT_YET_RECRUITING	Comparison of Pregnancy Rates in Modified Natural Frozen Embryo Transfer (FET) Cycle After Luteal Support with GnRH Agonist Versus Progesterone
NCT04371783	Not specified	ACTIVE_NOT_RECRUITING	A Randomized Trial Comparing the Live Birth Rate of Immediate Versus Delayed FET Following a Freeze-all Strategy
NCT04381299	Not specified	ACTIVE_NOT_RECRUITING	Will Autologous Platelet Rich Plasma Able To Restore Ovarian Function?
NCT04390308	Not specified	RECRUITING	Is There A Role For Mechanical Stimulation In Ovarian Follicular Activation?
NCT04477863	Not specified	RECRUITING	Follow-up With Preimplantation Genetic Testing Patients
NCT04619524	Not specified	RECRUITING	Biomarkers of Endometrial Receptivity
NCT04748874	Not specified	ACTIVE_NOT_RECRUITING	Immediate Versus Postponed Single Blastocyst Transfer in mNC-FET
NCT04751084	Not specified	ACTIVE_NOT_RECRUITING	Buscopan in Patients Undergoing IVF/Intracytoplasmic Sperm Injection Treatment
NCT05017740	Not specified	ACTIVE_NOT_RECRUITING	PICSI RCT in Couples With a Previous Poor Fertilisation Cycle in IVF
NCT05332769	Not specified	ACTIVE_NOT_RECRUITING	Cumulus Cell Mitochondrial Activity as a Non-invasive Marker of Embryo Quality (FLIM)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GANIRELIX	4	6
CETRORELIX	4	5
ESTRADIOL VALERATE	4	4
CLOMIPHENE	4	3
DYDROGESTERONE	4	3
GONADORELIN ACETATE	4	3
DIENOGEST	4	2
FOLLITROPIN DELTA	4	2
LETROZOLE	4	2
PENTOXIFYLLINE	4	2
PROGESTERONE	4	2
TADALAFIL	4	2
TRIPTORELIN	4	2
DESOGESTREL	4	1
FOLIC ACID	4	1
FOLLITROPIN	4	1
FOLLITROPIN ALFA	4	1
GONADOTROPIN, CHORIONIC	4	1
MEDROXYPROGESTERONE ACETATE	4	1
MENOTROPINS	4	1
SCOPOLAMINE	4	1
ENCLOMIPHENE CITRATE	3	2
BUTYLSCOPOLAMINE BROMIDE	3	1
UBIDECARENONE	3	1
CHEMBL2370644	0	3
CHEMBL139521	0	2
CHEMBL177542	0	2
CHEMBL4244897	0	2
CHEMBL4792718	0	2
CHEMBL5439651	0	2