Congestive heart failure

Summary

Congestive heart failure (MONDO:0005009) is a disease (an umbrella term covering 5 Mondo subtypes) with 13 cohort genes (55 GWAS associations across 29 studies) and 751 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (4 cohort genes). Top therapeutic interventions include nesiritide, furosemide, and enalapril.

At a glance

• Umbrella term: 5 Mondo subtypes
• Cohort genes: 13
• GWAS associations: 55
• ClinVar variants: 21
• Clinical trials: 751

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congestive heart failure
Mondo ID	MONDO:0005009
EFO	EFO:0000373
DOID	DOID:6000
ICD-11	2136808878
NCIT	C3080
SNOMED CT	42343007
UMLS	C0018802
MedGen	9169
Is cancer (heuristic)	no

Also known as: cardiac failure, congestive · CHF · congestive heart disease · failure, congestive heart · heart failure, congestive

Data availability: 21 ClinVar variants · 55 GWAS associations (29 studies) · 1 HPO phenotype · 1 cell line.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart failure › congestive heart failure

Related subtypes (3): high output heart failure, symptomatic heart failure, cardio-renal syndrome

Subtypes (5): rheumatic congestive heart failure, cor pulmonale, diastolic heart failure, systolic heart failure, left ventricular failure

Genetics & variants

GWAS landscape

55 GWAS associations across 29 studies. Top hits map to 15 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs3176326	2e-33	CDKN1A	G	0.09
rs1421085	1e-31	FTO	T	0.07
rs4977575	4e-25	CDKN2B-AS1	C	0.06
rs62048402	4e-24	FTO	G	0.07
rs10455872	2e-20	LPA	A	0.11
chr9:22093299	2e-19		A	0.1
rs1333047	5e-19	CDKN2B-AS1	A	0.1
chr4:111680202	3e-18		T	0.07
chr4:111669220	4e-17		T	0.08
rs76229004	6e-16	PITX2 - LINC01438	C	0.08
chr10:75583034	9e-16		C	0.07
rs9685830	5e-15	PITX2 - LINC01438	G	0.06
rs7915134	1e-13	SYNPO2L, SYNPO2L-AS1	C	0.06
rs800997	2e-13	GTF2IRD2	T	0.06
rs202209188	4e-13	GTF2IRD2	C	0.07
rs2957657	7e-13	SBF2	G	0.11
chr11:10120228	1e-12		A	0.07
rs12150603	1e-12	PGAP3	G	0.05
chr17:65837193	2e-12		C	0.05
rs945425	2e-12	CLCNKA	T	0.05
chr2:58944760	3e-12		A	0.06
rs7528419	8e-12	CELSR2	A	0.06
chr1:10798552	1e-11		T	0.04
rs7900932	1e-11	SYNPO2L, SYNPO2L-AS1	T	0.06
rs34517439	2e-11	GIPC2, DNAJB4	C	0.07
rs7930218	2e-11	SBF2	G	0.11
chr11:10155041	3e-11		G	0.11
chr1:16305279	3e-11		T	0.04
rs111739575	3e-11	BBS9	C	1.6
rs2517953	3e-11	PGAP3	G	0.05

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475981	Verma A	2024	58,749	370,923	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475982	Verma A	2024	41,922	389,773	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475200	Verma A	2024	19,350	296,318	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475201	Verma A	2024	17,142	298,526	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477955	Verma A	2024	15,405	100,974	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480184	Verma A	2024	15,405	100,974	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477957	Verma A	2024	11,137	105,743	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480181	Verma A	2024	11,137	105,743	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90013686	Ishigaki K	2020	9,413	203,040	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST90652020	Liu TY	2025	6,838	228,337	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	32

MAF distribution

Bucket	Variants
common (>=0.05)	33
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intron_variant	15
unknown	11
intergenic_variant	6
regulatory_region_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3176326	6	36679512	G>A	0.203	intron_variant	CDKN1A	2e-33	Tier 4: intronic/intergenic
rs1421085	16	53767042	T>C	0.407	intron_variant	FTO	1e-31	Tier 4: intronic/intergenic
rs4977575	9	22124745	C>G,T	0.496	regulatory_region_variant	CDKN2B-AS1	4e-25	Tier 3: regulatory
rs62048402	16	53769311	G>A,T	0.329	intron_variant	FTO	4e-24	Tier 4: intronic/intergenic
rs10455872	6	160589086	A>G	0.069	intron_variant	LPA	2e-20	Tier 4: intronic/intergenic
chr9:22093299				0.487			2e-19	Tier 4: intronic/intergenic
rs1333047	9	22124505	A>C,G,T	0.446	intergenic_variant	CDKN2B-AS1	5e-19	Tier 4: intronic/intergenic
chr4:111680202				0.234			3e-18	Tier 4: intronic/intergenic
chr4:111669220				0.204			4e-17	Tier 4: intronic/intergenic
rs76229004	4	110737902	C>G,T	0.128	intergenic_variant	PITX2 - LINC01438	6e-16	Tier 4: intronic/intergenic
chr10:75583034				0.141			9e-16	Tier 4: intronic/intergenic
rs9685830	4	110761735	G>A,C,T	0.306	intergenic_variant	PITX2 - LINC01438	5e-15	Tier 4: intronic/intergenic
rs7915134	10	73660422	C>A,T	0.161	intron_variant	SYNPO2L, SYNPO2L-AS1	1e-13	Tier 4: intronic/intergenic
rs800997	7	74813359	T>A,C	0.397	intron_variant	GTF2IRD2	2e-13	Tier 4: intronic/intergenic
rs202209188	7	74813118	C>T	0.356	intron_variant	GTF2IRD2	4e-13	Tier 4: intronic/intergenic
rs2957657	11	10266263	G>A	0.116	intron_variant	SBF2	7e-13	Tier 4: intronic/intergenic
chr11:10120228				0.119			1e-12	Tier 4: intronic/intergenic
rs12150603	17	39678462	G>A	0.44	intron_variant	PGAP3	1e-12	Tier 4: intronic/intergenic
chr17:65837193				0.203			2e-12	Tier 4: intronic/intergenic
rs945425	1	16021917	T>A,C	0.316	intergenic_variant	CLCNKA	2e-12	Tier 4: intronic/intergenic
chr2:58944760				0.137			3e-12	Tier 4: intronic/intergenic
rs7528419	1	109274570	A>G	0.219	3_prime_UTR_variant	CELSR2	8e-12	Tier 2: splice/UTR
chr1:10798552				0.385			1e-11	Tier 4: intronic/intergenic
rs7900932	10	73660812	T>A,C	0.173	intron_variant	SYNPO2L, SYNPO2L-AS1	1e-11	Tier 4: intronic/intergenic
rs34517439	1	77984833	C>A	0.111	intron_variant	GIPC2, DNAJB4	2e-11	Tier 4: intronic/intergenic
rs7930218	11	10213165	G>A,C,T	0.126	intron_variant	SBF2	2e-11	Tier 4: intronic/intergenic
chr11:10155041				0.117			3e-11	Tier 4: intronic/intergenic
chr1:16305279				0.321			3e-11	Tier 4: intronic/intergenic
rs111739575	7	33797968	C>T	0.002	intron_variant	BBS9	3e-11	Tier 4: intronic/intergenic
rs2517953	17	39684958	G>A,C	0.447	intron_variant	PGAP3	3e-11	Tier 4: intronic/intergenic

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

10 conflicting classifications of pathogenicity, 3 uncertain significance, 3 benign, 3 benign/likely benign, 1 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
523361	NM_000352.6(ABCC8):c.1793G>A (p.Arg598Gln)	ABCC8	Likely pathogenic	criteria provided, single submitter
691721	NM_001103.4(ACTN2):c.1727T>C (p.Met576Thr)	ACTN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190573	NM_001148.6(ANK2):c.10693G>A (p.Glu3565Lys)	ANK2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
166769	NM_000719.7(CACNA1C):c.3049-10C>T	CACNA1C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41926	NM_001289808.2(CRYAB):c.460G>A (p.Gly154Ser)	CRYAB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355443	NM_004100.5(EYA4):c.347C>T (p.Ala116Val)	EYA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
412788	NM_005477.3(HCN4):c.1243G>A (p.Val415Met)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191714	NM_002471.4(MYH6):c.3988G>A (p.Ala1330Thr)	MYH6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
137827	NM_001267550.2(TTN):c.8902+14T>A	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
47441	NM_001267550.2(TTN):c.84923A>C (p.Gln28308Pro)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505024	NM_014000.3(VCL):c.1490T>C (p.Ile497Thr)	VCL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
35609	NM_000352.6(ABCC8):c.3517G>A (p.Val1173Met)	ABCC8	Uncertain significance	criteria provided, multiple submitters, no conflicts
181485	NM_016203.4(PRKAG2):c.431C>T (p.Pro144Leu)	PRKAG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
201305	NM_001035.3(RYR2):c.10640C>T (p.Thr3547Met)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
347321	NM_001148.6(ANK2):c.4123-13T>C	ANK2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
43474	NM_000432.4(MYL2):c.4-14C>T	LOC114827850	Benign	criteria provided, multiple submitters, no conflicts
31771	NM_000432.4(MYL2):c.132T>C (p.Ile44=)	MYL2	Benign	criteria provided, multiple submitters, no conflicts
31772	NM_000432.4(MYL2):c.353+20del	MYL2	Benign	criteria provided, multiple submitters, no conflicts
47188	NM_001267550.2(TTN):c.63023C>T (p.Thr21008Ile)	TTN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
47265	NM_001267550.2(TTN):c.69130C>T (p.Pro23044Ser)	TTN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
691754	NM_001267550.2(TTN):c.23363C>T (p.Ser7788Phe)	TTN	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 50 · 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
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
ACTN2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTN2	Orphanet:708129	Autosomal recessive ACTN2-related distal myopathy
ACTN2	Orphanet:708133	Autosomal dominant ACTN2-related distal myopathy
HCN4	Orphanet:130	Brugada syndrome
HCN4	Orphanet:166282	Hereditary sick sinus syndrome
CRYAB	Orphanet:154	Familial isolated dilated cardiomyopathy
CRYAB	Orphanet:280553	Fatal infantile hypertonic myofibrillar myopathy
CRYAB	Orphanet:399058	Alpha-B crystallin-related late-onset myopathy
CRYAB	Orphanet:441452	Early-onset lamellar cataract
CRYAB	Orphanet:98991	Early-onset nuclear cataract
CRYAB	Orphanet:98993	Early-onset posterior polar cataract
EYA4	Orphanet:217622	Sensorineural deafness with dilated cardiomyopathy
EYA4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ANK2	Orphanet:101016	Romano-Ward syndrome
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus
MYH6	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH6	Orphanet:166282	Hereditary sick sinus syndrome
MYH6	Orphanet:99103	Atrial septal defect, ostium secundum type
MYL2	Orphanet:2020	Congenital fiber-type disproportion myopathy
PRKAG2	Orphanet:439854	Fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	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
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	clinvar
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	clinvar
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	clinvar
EYA4	HGNC:3522	ENSG00000112319	O95677	Protein phosphatase EYA4	clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	clinvar
MYH6	HGNC:7576	ENSG00000197616	P13533	Myosin-6	clinvar
MYL2	HGNC:7583	ENSG00000111245	P10916	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	clinvar
PRKAG2	HGNC:9386	ENSG00000106617	Q9UGJ0	5’-AMP-activated protein kinase subunit gamma-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.
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.
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
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.
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.
EYA4	Protein phosphatase EYA4	Tyrosine phosphatase that specifically dephosphorylates ‘Tyr-142’ of histone H2AX (H2AXY142ph). ‘Tyr-142’ phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair…
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.
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.
MYH6	Myosin-6	Muscle contraction.
MYL2	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	Contractile protein that plays a role in heart development and function.
PRKAG2	5’-AMP-activated protein kinase subunit gamma-2	AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.38

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	3	25.7×	9e-04
Transporter	1	6.0×	0.285
Scaffold/PPI	2	2.7×	0.285
Kinase	1	2.1×	0.475
Other/Unknown	6	0.8×	0.837

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
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
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
EYA4	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
MYH6	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
MYL2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
PRKAG2	Other/Unknown	no		CBS_dom, CBS_dom_sf, AMPK_gamma/SDS23_families

Expression context

Cohort genes with no expression data: 0.

11 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skeletal muscle tissue of biceps brachii	3
cardiac atrium	3
heart right ventricle	2
left ventricle myocardium	2
biceps brachii	2
apex of heart	2
right atrium auricular region	2
cardiac muscle of right atrium	2
myocardium	1
gluteal muscle	1
blood vessel layer	1
saphenous vein	1
urethra	1
muscle layer of sigmoid colon	1
right coronary artery	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1
tibialis anterior	1
cardiac ventricle	1
middle frontal gyrus	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
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
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
CRYAB	289	ubiquitous	marker	middle frontal gyrus, left ventricle myocardium, cardiac ventricle
EYA4	208	broad	marker	biceps brachii, skeletal muscle tissue of biceps brachii, seminal vesicle
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
MYH6	154	tissue_specific	yes	cardiac muscle of right atrium, cardiac atrium, vena cava
MYL2	179	tissue_specific	marker	heart right ventricle, diaphragm, apex of heart
PRKAG2	258	ubiquitous	marker	right atrium auricular region, cardiac atrium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANK2	6,423
VCL	4,495
TTN	4,237
CRYAB	3,368
PRKAG2	3,212
CACNA1C	3,145
MYH6	3,119
MYL2	3,119
ABCC8	2,826
ACTN2	2,781

Intra-cohort edges

A	B	Sources
ACTN2	CACNA1C	biogrid_interaction
ACTN2	MYH6	biogrid_interaction, string_interaction
ACTN2	TTN	string_interaction
ACTN2	VCL	string_interaction
ANK2	TTN	string_interaction
CACNA1C	HCN4	string_interaction
CACNA1C	RYR2	biogrid_interaction, string_interaction
CRYAB	TTN	string_interaction
MYH6	MYL2	string_interaction
MYH6	PRKAG2	intact
MYH6	TTN	string_interaction
MYL2	PRKAG2	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
VCL	P18206	37
CACNA1C	Q13936	33
RYR2	Q92736	26
CRYAB	P02511	21
ACTN2	P35609	16
ANK2	Q01484	11
HCN4	Q9Y3Q4	8
ABCC8	Q09428	8
MYL2	P10916	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MYH6	P13533	74.91
PRKAG2	Q9UGJ0	67.24
EYA4	O95677	63.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 96. Enrichment computed across 13 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	4	95.0×	6e-06	TTN, ACTN2, MYH6, MYL2
Muscle contraction	5	29.7×	2e-05	RYR2, CACNA1C, ACTN2, MYH6, MYL2
Integration of energy metabolism	3	40.5×	0.002	CACNA1C, ABCC8, PRKAG2
Platelet degranulation	3	20.3×	0.009	TTN, VCL, ACTN2
Defective ABCC8 can cause hypo- and hyper-glycemias	1	439.2×	0.027	ABCC8
Regulation of insulin secretion	2	33.8×	0.027	CACNA1C, ABCC8
Post NMDA receptor activation events	2	31.4×	0.027	ACTN2, PRKAG2
Activation of NMDA receptors and postsynaptic events	2	28.3×	0.027	ACTN2, PRKAG2
Neuronal System	3	10.2×	0.029	ACTN2, ABCC8, PRKAG2
ATP sensitive Potassium channels	1	219.6×	0.040	ABCC8
HCN channels	1	219.6×	0.040	HCN4
Cardiac conduction	2	16.7×	0.049	RYR2, CACNA1C
Neurotransmitter receptors and postsynaptic signal transmission	2	15.4×	0.053	ACTN2, PRKAG2
AMPK inhibits chREBP transcriptional activation activity	1	109.8×	0.062	PRKAG2
Lipophagy	1	97.6×	0.065	PRKAG2
Activation of PPARGC1A (PGC-1alpha) by phosphorylation	1	87.8×	0.068	PRKAG2
Transmission across Chemical Synapses	2	11.7×	0.069	ACTN2, PRKAG2
Regulation of CDH1 Function	1	73.2×	0.072	VCL
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	67.6×	0.074	ACTN2
Carnitine shuttle	1	58.6×	0.077	PRKAG2
Phase 2 - plateau phase	1	58.6×	0.077	CACNA1C
Inwardly rectifying K+ channels	1	54.9×	0.079	ABCC8
Ras activation upon Ca2+ influx through NMDA receptor	1	43.9×	0.091	ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	1	41.8×	0.091	ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	41.8×	0.091	ACTN2
Nephrin family interactions	1	36.6×	0.096	ACTN2
Long-term potentiation	1	36.6×	0.096	ACTN2
ABC transporter disorders	1	33.8×	0.098	ABCC8
Energy dependent regulation of mTOR by LKB1-AMPK	1	30.3×	0.098	PRKAG2
Adrenaline,noradrenaline inhibits insulin secretion	1	30.3×	0.098	CACNA1C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 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 SA node cell action potential	3	648.1×	1e-06	RYR2, HCN4, ANK2
regulation of heart rate	4	144.0×	1e-06	RYR2, HCN4, ANK2, MYH6
cardiac muscle contraction	4	123.5×	2e-06	RYR2, TTN, MYH6, MYL2
regulation of cardiac muscle contraction	3	204.7×	1e-05	RYR2, HCN4, ANK2
striated muscle contraction	3	194.4×	1e-05	RYR2, TTN, MYH6
muscle contraction	4	64.0×	1e-05	TTN, HCN4, CRYAB, MYH6
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	3	155.6×	3e-05	RYR2, CACNA1C, ANK2
cardiac muscle cell development	3	144.0×	3e-05	TTN, ACTN2, MYH6
regulation of atrial cardiac muscle cell action potential	2	864.2×	4e-05	RYR2, ANK2
sarcoplasmic reticulum calcium ion transport	2	518.5×	9e-05	RYR2, ANK2
membrane depolarization during SA node cell action potential	2	518.5×	9e-05	HCN4, ANK2
positive regulation of the force of heart contraction	2	518.5×	9e-05	RYR2, MYL2
sarcomere organization	3	88.4×	9e-05	TTN, ACTN2, MYH6
regulation of heart rate by cardiac conduction	3	86.4×	9e-05	CACNA1C, HCN4, ANK2
SA node cell action potential	2	432.1×	1e-04	HCN4, ANK2
positive regulation of potassium ion transport	2	324.1×	2e-04	ACTN2, ABCC8
cardiac muscle hypertrophy	2	259.3×	3e-04	RYR2, TTN
membrane depolarization during cardiac muscle cell action potential	2	216.1×	4e-04	CACNA1C, HCN4
cell communication by electrical coupling involved in cardiac conduction	2	216.1×	4e-04	RYR2, CACNA1C
regulation of ventricular cardiac muscle cell action potential	2	216.1×	4e-04	RYR2, CACNA1C
regulation of cardiac muscle contraction by calcium ion signaling	2	199.4×	4e-04	RYR2, ANK2
cardiac myofibril assembly	2	199.4×	4e-04	TTN, MYL2
calcium ion transport into cytosol	2	185.2×	5e-04	RYR2, CACNA1C
muscle filament sliding	2	162.0×	6e-04	TTN, MYH6
regulation of the force of heart contraction	2	152.5×	6e-04	MYH6, MYL2
ventricular cardiac muscle cell action potential	2	152.5×	6e-04	RYR2, ANK2
ventricular cardiac muscle tissue morphogenesis	2	108.0×	0.001	MYH6, MYL2
protein localization to cell surface	2	76.2×	0.002	VCL, ANK2
cellular response to nutrient levels	2	72.0×	0.003	ABCC8, PRKAG2
potassium ion import across plasma membrane	2	56.4×	0.004	HCN4, ABCC8

Therapeutics

Drugs indicated for this disease

25 approved, 25 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acetazolamide	Approved (phase 4)
Alteplase	Approved (phase 4)
Bumetanide	Approved (phase 4)
Candesartan Cilexetil	Approved (phase 4)
Captopril	Approved (phase 4)
Carvedilol	Approved (phase 4)
Chlorothiazide	Approved (phase 4)
Chlorthalidone	Approved (phase 4)
Digoxin	Approved (phase 4)
Eplerenone	Approved (phase 4)
Ethacrynic Acid	Approved (phase 4)
Furosemide	Approved (phase 4)
Hydrochlorothiazide	Approved (phase 4)
Indapamide	Approved (phase 4)
Ivabradine	Approved (phase 4)
Metolazone	Approved (phase 4)
Nitroglycerin	Approved (phase 4)
Ramipril	Approved (phase 4)
Sacubitril	Approved (phase 4)
Sodium Chloride	Approved (phase 4)
Spironolactone	Approved (phase 4)
Tolvaptan	Approved (phase 4)
Torsemide	Approved (phase 4)
Triamterene	Approved (phase 4)
Valsartan	Approved (phase 4)
Albuterol	Phase 3 (in late-stage trials)
Aliskiren	Phase 3 (in late-stage trials)
Amiodarone	Phase 3 (in late-stage trials)
Amlodipine	Phase 3 (in late-stage trials)
Candesartan	Phase 3 (in late-stage trials)
Dextrose	Phase 3 (in late-stage trials)
Digitalis	Phase 3 (in late-stage trials)
Dronedarone	Phase 3 (in late-stage trials)
Enalapril	Phase 3 (in late-stage trials)
Enoximone	Phase 3 (in late-stage trials)
Icodextrin	Phase 3 (in late-stage trials)
Insulin Human	Phase 3 (in late-stage trials)
Irbesartan	Phase 3 (in late-stage trials)
Levosimendan	Phase 3 (in late-stage trials)
Lisinopril Anhydrous	Phase 3 (in late-stage trials)
Metoprolol	Phase 3 (in late-stage trials)
Nesiritide	Phase 3 (in late-stage trials)
Pantoprazole	Phase 3 (in late-stage trials)
Potassium Chloride	Phase 3 (in late-stage trials)
Prednisone	Phase 3 (in late-stage trials)
Rolofylline	Phase 3 (in late-stage trials)
Rosuvastatin	Phase 3 (in late-stage trials)
Sildenafil	Phase 3 (in late-stage trials)
Tonapofylline	Phase 3 (in late-stage trials)
Ularitide	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Albiglutide, Allopurinol, Azimilide, Dexamethasone, Elamipretide, Hydralazine, Isosorbide Dinitrate, Lixivaptan, Nitric Oxide, Nitrogen, Relaxin, Ursodiol.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 8

Druggability breadth: 10 of 13 evidence-associated genes (77%) 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
CACNA1C	REMIFENTANIL
HCN4	IVABRADINE
ABCC8	REPAGLINIDE
PRKAG2	ADENOSINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1C	85	4
PRKAG2	19	4
ABCC8	6	4
HCN4	2	4
RYR2	1	2
TTN	0	0
VCL	0	0
ACTN2	0	0
CRYAB	0	0
EYA4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NIMODIPINE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
SILDENAFIL	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C
OLICERIDINE	4	CACNA1C
PROPRANOLOL	4	CACNA1C
ALVIMOPAN	4	CACNA1C
ASTEMIZOLE	4	CACNA1C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
PRKAG2	266	Binding:265, Functional:1
ABCC8	84	Functional:52, Binding:32
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
RYR2	15	Binding:15
CRYAB	13	Binding:13
VCL	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
CACNA1C	575
PRKAG2	266

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
REMIFENTANIL	4	CACNA1C
BEPRIDIL	4	CACNA1C
CLOTRIMAZOLE	4	CACNA1C
PROPIVERINE	4	CACNA1C
DIBUCAINE	4	CACNA1C
IMIPRAMINE	4	CACNA1C
DULOXETINE	4	CACNA1C
QUINIDINE	4	CACNA1C
ESTRADIOL	4	CACNA1C
TOLTERODINE	4	CACNA1C
PIMOZIDE	4	CACNA1C
NIMODIPINE	4	CACNA1C
NICARDIPINE	4	CACNA1C
AMLODIPINE	4	CACNA1C
VARDENAFIL	4	CACNA1C
CLEMASTINE	4	CACNA1C
ISRADIPINE	4	CACNA1C
TERFENADINE	4	CACNA1C
NISOLDIPINE	4	CACNA1C
SOLIFENACIN	4	CACNA1C
PINAVERIUM	4	CACNA1C
NIFEDIPINE	4	CACNA1C
XANOMELINE	4	CACNA1C
DILTIAZEM	4	CACNA1C
PRENYLAMINE	4	CACNA1C
OLICERIDINE	4	CACNA1C
PROPRANOLOL	4	CACNA1C
ALVIMOPAN	4	CACNA1C
ASTEMIZOLE	4	CACNA1C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	CACNA1C, HCN4, ABCC8, PRKAG2
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	1	TTN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	VCL, ACTN2, CRYAB, EYA4, ANK2, MYH6, MYL2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TTN	1	—
VCL	2	—
ACTN2	0	—
CRYAB	13	—
EYA4	0	—
ANK2	0	—
MYH6	0	—
MYL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 751.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	461
PHASE3	76
PHASE4	62
PHASE2	62
PHASE1	41
PHASE1/PHASE2	25
PHASE2/PHASE3	19
EARLY_PHASE1	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05276219	PHASE4	RECRUITING	Optimized Treatment of Pulmonary Edema or Congestion
NCT06218199	PHASE4	RECRUITING	Diuretics vs. Afterload Reduction for Treatment of HeartLogic Alerts
NCT06495892	PHASE4	RECRUITING	PVP-Guided Decongestive Therapy in HF 2
NCT00013221	PHASE4	COMPLETED	Exercise Effect on Aerobic Capacity and QOL in Heart Failure
NCT00047775	PHASE4	COMPLETED	African-American Heart Failure Trial
NCT00082589	PHASE4	COMPLETED	The Purpose of This Study is to Determine if Eplerenone is Effective in Treatment of Mild to Moderate Heart Failure
NCT00083772	PHASE4	TERMINATED	Use of Nesiritide in the Management of Acute Diastolic Heart Failure
NCT00108251	PHASE4	COMPLETED	Aldosterone Antagonism in Diastolic Heart Failure
NCT00115726	PHASE4	COMPLETED	Trial Assessing the Effect of Preoperative Furosemide on Intraoperative Blood Pressure
NCT00133328	PHASE4	UNKNOWN	A Morbidity-Mortality and Remodeling Study With Valsartan
NCT00141856	PHASE4	COMPLETED	Health E Heart Study (South Texas Veterans Health Care System Heart Failure Disease Management Program/Study)
NCT00149227	PHASE4	COMPLETED	Add-on Effects of Valsartan on Morbi- Mortality (KYOTO HEART Study)
NCT00157846	PHASE4	TERMINATED	X-Change HF - Exchange of the Existing Pacemaker/ICD in Bradycardia Patients Suffering From Heart Failure
NCT00162565	PHASE4	COMPLETED	Beta-Blocker Continuation Versus Interruption in Heart Failure Worsening
NCT00180531	PHASE4	COMPLETED	Monitoring of Arrhythmias and HRV in Patients With Heart Failure Treated With the CRT Pacemaker Renewal TR2
NCT00233480	PHASE4	COMPLETED	Statin Therapy in Heart Failure: Potential Mechanisms of Benefit
NCT00241098	PHASE4	COMPLETED	The VALIDATE Study of Valsartan for Patients With Early Stage Heart Failure
NCT00262119	PHASE4	COMPLETED	MINERVA: MINimizE Right Ventricular Pacing to Prevent Atrial Fibrillation and Heart Failure
NCT00270829	PHASE4	TERMINATED	Renal Effects of Intrarenal Nesiritide
NCT00288587	PHASE4	COMPLETED	Extracorporeal Ultrafiltration (UF) vs. Usual and Customary Care for Patients With Severe Heart Failure (HF)
NCT00328809	PHASE4	WITHDRAWN	Spironolactone Safety in Dialysis Patients
NCT00344513	PHASE4	COMPLETED	Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure (OPTIMIZE-HF)
NCT00345592	PHASE4	COMPLETED	TReatment of Atrial Fibrillation With Dual dEfibrillator in Heart Failure Patients
NCT00351676	PHASE4	COMPLETED	Capturing Outcomes of Clinical Activities Performed by a Rounding Pharmacist Practising in a Team Environment
NCT00355667	PHASE4	COMPLETED	Comparison of Long- and Short-acting Diuretics in Congestive Heart Failure
NCT00360958	PHASE4	COMPLETED	Treatment of Severe Heart Failure by Ultrafiltration
NCT00370526	PHASE4	TERMINATED	HEAL-HF: A Cardiac Resynchronization Therapy (CRT) Outcomes Study
NCT00381030	PHASE4	COMPLETED	Effects of Carvedilol on Health Outcomes in Heart Failure
NCT00395642	PHASE4	COMPLETED	TRIAGE-CRT Telemonitoring in Patients With CHF and Indication of CRT-D
NCT00396136	PHASE4	COMPLETED	COSMO Post Approval Registry: Corox OTW Steroid LV Lead Monitoring
NCT00409916	PHASE4	UNKNOWN	PREVENT-HF: Prevention of Heart Failure Events With Impedance Cardiography Testing
NCT00409942	PHASE4	COMPLETED	Effect of a New Formulation of Torasemide (Prolonged Release)on Myocardial Fibrosis in Patients With Heart Failure.
NCT00433043	PHASE4	TERMINATED	BOAT: Beta Blocker Uptitration With OptiVol After Cardiac Resynchronization Therapy (CRT)
NCT00453453	PHASE4	TERMINATED	BNP Therapy Observation Unit Outcomes STudy (BOOST)
NCT00473876	PHASE4	COMPLETED	Metformin in Insulin Resistant Left Ventricular (LV) Dysfunction (TAYSIDE Trial)
NCT00490958	PHASE4	COMPLETED	Telmisartan in Haemodialysis Patients With Chronic Heart Failure
NCT00505791	PHASE4	WITHDRAWN	Double Blind Randomized Placebo Controlled Trial of Natrecor in Acute Decompensated Heart Failure With Normal EF
NCT00538356	PHASE4	COMPLETED	Influence of Home Monitoring on the Clinical Status of Heart Failure Patients With an Impaired Left Ventricular Function
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00597077	PHASE4	COMPLETED	Atrial Fibrillation and Congestive Heart Failure Trial

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NESIRITIDE	4	23
FUROSEMIDE	4	12
ENALAPRIL	4	9
SILDENAFIL	4	6
TOLVAPTAN	4	6
VALSARTAN	4	5
DARBEPOETIN ALFA	4	3
HYDRALAZINE	4	3
ISOSORBIDE DINITRATE	4	3
METOLAZONE	4	3
SPIRONOLACTONE	4	3
ALISKIREN	4	2
ALLOPURINOL	4	2
BUMETANIDE	4	2
CARVEDILOL	4	2
DOBUTAMINE	4	2
ENOXIMONE	4	2
EPLERENONE	4	2
ICODEXTRIN	4	2
IVABRADINE	4	2
LOSARTAN	4	2
METOPROLOL SUCCINATE	4	2
SACUBITRIL	4	2
ACETAZOLAMIDE	4	1
ACETYLCYSTEINE	4	1
ALBIGLUTIDE	4	1
AMIODARONE	4	1
AMIODARONE HYDROCHLORIDE	4	1
ATORVASTATIN	4	1
BOSENTAN	4	1