Heart failure

Summary

Heart failure (MONDO:0005252) is a disease with 44 cohort genes (890 GWAS associations across 74 studies) and 4,325 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (3 cohort genes). Top therapeutic interventions include enalapril, furosemide, and bisoprolol.

At a glance

• Cohort genes: 44
• GWAS associations: 890
• ClinVar variants: 26
• Clinical trials: 4,325

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heart failure
Mondo ID	MONDO:0005252
EFO	EFO:0003144
MeSH	D006333
ICD-10-CM	I50
ICD-11	1458683894
NCIT	C50577
SNOMED CT	84114007
UMLS	C0018801
MedGen	6749
Anatomy (UBERON)	UBERON:0000948
Is cancer (heuristic)	no

Also known as: cardiac failure · cardiac insufficiency · failure, heart · heart failure · insufficiency, Cardiac

Data availability: 26 ClinVar variants · 890 GWAS associations (74 studies) · 3 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

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

Subtypes (4): congestive heart failure, high output heart failure, symptomatic heart failure, cardio-renal syndrome

Genetics & variants

GWAS landscape

890 GWAS associations across 74 studies. Top hits map to 29 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs247617	1e-149	HERPUD1 - CETP	?
rs964184	2e-108	ZPR1	?
rs780094	4e-91	GCKR	?
rs8082812	5e-67	THEMIS3P - AKR1B1P6	?
rs3176326	4e-57	CDKN1A	A	0.07
rs78229461	3e-55	PITX2 - LINC01438	T	0.08
rs1906592	8e-54	LINC01438	G	0.1
rs56094641	3e-53	FTO	A	0.06
rs629301	1e-49	CELSR2	?
rs1906596	1e-45	LINC01438	T	0.16
rs765547	2e-44	LPL - RPL30P9	?
rs7859727	3e-40	CDKN2B-AS1	T	0.05
rs55730499	7e-37	LPA	T	0.1
rs261332	2e-35	ALDH1A2, LIPC-AS1, LIPC	?
rs4713999	2e-34	RNU1-88P - Y_RNA	A	0.05
rs1728918	1e-31	PPM1G - NRBP1	?
rs4151702	1e-30	DINOL, CDKN1A	C	0.15
rs2634071	4e-29	PITX2 - LINC01438	T	0.08
rs4833443	6e-29	PITX2 - LINC01438	C	0.08
rs1906595	8e-27	LINC01438	T	0.09
rs2177843	1e-26	SYNPO2L, SYNPO2L-AS1	T	0.05
rs10455872	2e-26	LPA	A	0.1
rs4714001	5e-26	RNU1-88P - Y_RNA	A	0.05
rs12740374	2e-25	CELSR2	G	10.41
rs11642015	3e-25	FTO	T	0.06
rs174547	7e-25	FADS1, FADS2	?
rs59788391	2e-24	PITX2 - LINC01438	G	0.08
rs200854839	9e-24	CASZ1	G	0.04
rs147288039	5e-23	AOPEP	G	0.49
rs4420638	1e-22	APOC1	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90455657	Lee DSM	2025	168,363	1,725,558	Common-variant and rare-variant genetic architecture of heart failure across the allele-frequency spectrum.
GCST90274223	Rasooly D	2023	90,653	1,188,957	Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure.
GCST90399713	Zhou W	2022	52,496	967,945	Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease.
GCST90085925	Zhuang Z	2021	47,309	930,014	Shared genetic etiology and causality between body fat percentage and cardiovascular diseases: a large-scale genome-wide cross-trait analysis.
GCST009541	Shah S	2020	47,309	930,014	Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.
GCST90473575	UK Biobank Whole-Genome Sequencing Consortium	2025	19,629	438,811	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90667912	UK Biobank Whole-Genome Sequencing Consortium	2025	19,629	438,811	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90654629	Enzan N	2025	19,589	258,943	Genome-wide analysis of heart failure yields insights into disease heterogeneity and enables prognostic prediction in the Japanese population.
GCST90654628	Enzan N	2025	19,495	258,943	Genome-wide analysis of heart failure yields insights into disease heterogeneity and enables prognostic prediction in the Japanese population.
GCST90018806	Sakaue S	2021	14,262	471,898	A cross-population atlas of genetic associations for 220 human phenotypes.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	3
Tier 3: regulatory	0
Tier 4: intronic/intergenic	47

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	26
intergenic_variant	17
3_prime_UTR_variant	3
non_coding_transcript_exon_variant	3
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs247617	16	56956804	C>A	0.05	intergenic_variant	HERPUD1 - CETP	1e-149	Tier 4: intronic/intergenic
rs964184	11	116778201	G>C	0.05	3_prime_UTR_variant	ZPR1	2e-108	Tier 2: splice/UTR
rs780094	2	27518370	T>A,C,G	0.05	intron_variant	GCKR	4e-91	Tier 4: intronic/intergenic
rs8082812	18	8522684	C>A	0.05	intergenic_variant	THEMIS3P - AKR1B1P6	5e-67	Tier 4: intronic/intergenic
rs3176326	6	36679512	G>A	0.191	intron_variant	CDKN1A	4e-57	Tier 4: intronic/intergenic
rs78229461	4	110776497	C>A,G,T	0.174	intergenic_variant	PITX2 - LINC01438	3e-55	Tier 4: intronic/intergenic
rs1906592	4	110787848	T>G	0.237	intron_variant	LINC01438	8e-54	Tier 4: intronic/intergenic
rs56094641	16	53772541	A>G,T	0.387	intron_variant	FTO	3e-53	Tier 4: intronic/intergenic
rs629301	1	109275684	G>A,C,T	0.05	3_prime_UTR_variant	CELSR2	1e-49	Tier 2: splice/UTR
rs1906596	4	110791080	C>A,G,T	0.341	intron_variant	LINC01438	1e-45	Tier 4: intronic/intergenic
rs765547	8	20008763	G>A,C,T	0.05	intergenic_variant	LPL - RPL30P9	2e-44	Tier 4: intronic/intergenic
rs7859727	9	22102166	C>T	0.494	intron_variant	CDKN2B-AS1	3e-40	Tier 4: intronic/intergenic
rs55730499	6	160584578	C>T	0.064	intron_variant	LPA	7e-37	Tier 4: intronic/intergenic
rs261332	15	58435126	A>G	0.05	non_coding_transcript_exon_variant	ALDH1A2, LIPC-AS1, LIPC	2e-35	Tier 4: intronic/intergenic
rs4713999	6	36665292	A>C,G,T	0.334	intron_variant	RNU1-88P - Y_RNA	2e-34	Tier 4: intronic/intergenic
rs1728918	2	27412596	A>C,G,T	0.05	intron_variant	PPM1G - NRBP1	1e-31	Tier 4: intronic/intergenic
rs4151702	6	36678211	G>A,C	0.196	non_coding_transcript_exon_variant	DINOL, CDKN1A	1e-30	Tier 4: intronic/intergenic
rs2634071	4	110748064	T>A,C,G	0.05	intergenic_variant	PITX2 - LINC01438	4e-29	Tier 4: intronic/intergenic
rs4833443	4	110763487	C>T	0.161	intergenic_variant	PITX2 - LINC01438	6e-29	Tier 4: intronic/intergenic
rs1906595	4	110791028	G>C,T	0.132	intron_variant	LINC01438	8e-27	Tier 4: intronic/intergenic
rs2177843	10	73650119	C>T	0.175	intron_variant	SYNPO2L, SYNPO2L-AS1	1e-26	Tier 4: intronic/intergenic
rs10455872	6	160589086	A>G	0.069	intron_variant	LPA	2e-26	Tier 4: intronic/intergenic
rs4714001	6	36670398	G>A	0.368	intergenic_variant	RNU1-88P - Y_RNA	5e-26	Tier 4: intronic/intergenic
rs12740374	1	109274968	G>T	0.209	3_prime_UTR_variant	CELSR2	2e-25	Tier 2: splice/UTR
rs11642015	16	53768582	C>G,T	0.05	intron_variant	FTO	3e-25	Tier 4: intronic/intergenic
rs174547	11	61803311	T>C	0.05	intron_variant	FADS1, FADS2	7e-25	Tier 4: intronic/intergenic
rs59788391	4	110780277	A>G	0.189	intergenic_variant	PITX2 - LINC01438	2e-24	Tier 4: intronic/intergenic
rs200854839	1	10737371	G>C,T	0.354	intron_variant	CASZ1	9e-24	Tier 4: intronic/intergenic
rs147288039	9	95006476	A>G	0.013	intron_variant	AOPEP	5e-23	Tier 4: intronic/intergenic
rs4420638	19	44919689	A>G	0.05	intergenic_variant	APOC1	1e-22	Tier 4: intronic/intergenic

ClinVar germline variants

26 retrieved; paginated sample, class counts are floors:

12 conflicting classifications of pathogenicity, 8 benign/likely benign, 4 uncertain significance, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
42693	NC_000011.10:g.47333332dup	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1018253	NM_144573.4(NEXN):c.1302del (p.Ile435fs)	NEXN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
497501	NM_004006.3(DMD):c.8083C>T (p.Pro2695Ser)	DMD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31819	NM_032578.4(MYPN):c.3481C>A (p.Leu1161Ile)	MYPN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
281070	NM_006790.3(MYOT):c.323A>C (p.Asn108Thr)	PKD2L2-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533010	NM_006790.3(MYOT):c.398C>T (p.Pro133Leu)	PKD2L2-DT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45711	NM_016203.4(PRKAG2):c.247C>T (p.Pro83Ser)	PRKAG2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18156	NM_000021.4(PSEN1):c.998A>G (p.Asp333Gly)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
470608	NM_001134363.3(RBM20):c.3169C>T (p.Arg1057Trp)	RBM20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178157	NM_001267550.2(TTN):c.102271C>T (p.Arg34091Trp)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
46614	NM_001267550.2(TTN):c.16303G>A (p.Val5435Met)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
47184	NM_001267550.2(TTN):c.5479G>T (p.Ala1827Ser)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691751	NM_001267550.2(TTN):c.33611A>C (p.Glu11204Ala)	TTN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13427	NM_000371.4(TTR):c.328C>A (p.His110Asn)	TTR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4070286	NM_001792.5(CDH2):c.1956G>C (p.Trp652Cys)	CDH2	Uncertain significance	criteria provided, single submitter
642106	NM_000257.4(MYH7):c.2641C>A (p.Leu881Met)	LOC126861898	Uncertain significance	criteria provided, multiple submitters, no conflicts
180947	NM_000256.3(MYBPC3):c.1720C>T (p.Arg574Trp)	MYBPC3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3769653	NM_000335.5(SCN5A):c.682A>G (p.Lys228Glu)	SCN5A	Uncertain significance	criteria provided, single submitter
191549	NM_005751.5(AKAP9):c.139C>T (p.His47Tyr)	AKAP9	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
519379	NM_005751.5(AKAP9):c.7208A>G (p.Glu2403Gly)	AKAP9	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
44541	NM_002471.4(MYH6):c.622G>A (p.Asp208Asn)	LOC114827851	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
95440	NM_006790.3(MYOT):c.445G>C (p.Glu149Gln)	MYOT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
46595	NM_001267550.2(TTN):c.14984C>G (p.Pro4995Arg)	TTN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
47437	NM_001267550.2(TTN):c.84461C>T (p.Pro28154Leu)	TTN	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
47160	NM_001267550.2(TTN):c.60232G>A (p.Val20078Met)	TTN-AS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
47189	NM_001267550.2(TTN):c.63026G>A (p.Arg21009Gln)	TTN-AS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 63 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
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
SURF1	Orphanet:391351	SURF1-related Charcot-Marie-Tooth disease type 4
MYOT	Orphanet:268129	Spheroid body myopathy
MYOT	Orphanet:98911	Distal myotilinopathy
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
PRICKLE1	Orphanet:308	Progressive myoclonic epilepsy type 1
CDH2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
MYPN	Orphanet:154	Familial isolated dilated cardiomyopathy
MYPN	Orphanet:171439	Childhood-onset nemaline myopathy
MYPN	Orphanet:171881	Cap myopathy
MYPN	Orphanet:75249	Familial isolated restrictive cardiomyopathy
FTO	Orphanet:210144	Lethal polymalformative syndrome, Boissel type
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
NEXN	Orphanet:154	Familial isolated dilated cardiomyopathy
AKAP9	Orphanet:101016	Romano-Ward syndrome
AKAP9	Orphanet:130	Brugada syndrome
KLHL3	Orphanet:300525	Pseudohypoaldosteronism type 2D
MYBPC3	Orphanet:154	Familial isolated dilated cardiomyopathy
MYBPC3	Orphanet:54260	Left ventricular noncompaction
PITX2	Orphanet:334	Hereditary atrial fibrillation
PITX2	Orphanet:708	Peters anomaly

Cohort genes → proteins

44 cohort genes, 41 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	29
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SH3GL2	HGNC:10831	ENSG00000107295	Q99962	Endophilin-A1	gwas
BTG1	HGNC:1130	ENSG00000133639	P62324	Protein BTG1	gwas
SURF1	HGNC:11474	ENSG00000148290	Q15526	Surfeit locus protein 1	gwas
MYOT	HGNC:12399	ENSG00000120729	Q9UBF9	Myotilin	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
TTR	HGNC:12405	ENSG00000118271	P02766	Transthyretin	clinvar
USP3	HGNC:12626	ENSG00000140455	Q9Y6I4	Ubiquitin carboxyl-terminal hydrolase 3	gwas
SNX16	HGNC:14980	ENSG00000104497	P57768	Sorting nexin-16	gwas
PRICKLE1	HGNC:17019	ENSG00000139174	Q96MT3	Prickle-like protein 1	gwas
CDH2	HGNC:1759	ENSG00000170558	P19022	Cadherin-2	clinvar
CH25H	HGNC:1907	ENSG00000138135	O95992	Cholesterol 25-hydroxylase	gwas
TBC1D4	HGNC:19165	ENSG00000136111	O60343	TBC1 domain family member 4	gwas
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
AGAP5	HGNC:23467	ENSG00000172650	A6NIR3	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 5	gwas
SYNPO2L	HGNC:23532	ENSG00000166317	Q9H987	Synaptopodin 2-like protein	gwas
MOB3B	HGNC:23825	ENSG00000120162	Q86TA1	MOB kinase activator 3B	gwas
TMTC1	HGNC:24099	ENSG00000133687	Q8IUR5	Protein O-mannosyl-transferase TMTC1	gwas
FTO	HGNC:24678	ENSG00000140718	Q9C0B1	Alpha-ketoglutarate-dependent dioxygenase FTO	gwas
RPUSD4	HGNC:25898	ENSG00000165526	Q96CM3	Pseudouridylate synthase RPUSD4, mitochondrial	gwas
FAM241A	HGNC:26813	ENSG00000174749	Q8N8J7	Uncharacterized protein FAM241A	gwas
RBM20	HGNC:27424	ENSG00000203867	Q5T481	RNA-binding protein 20	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
SHTN1	HGNC:29319	ENSG00000187164	A0MZ66	Shootin-1	gwas
NEXN	HGNC:29557	ENSG00000162614	Q0ZGT2	Nexilin	clinvar
LRIG3	HGNC:30991	ENSG00000139263	Q6UXM1	Leucine-rich repeats and immunoglobulin-like domains protein 3	gwas
CELSR2	HGNC:3231	ENSG00000143126	Q9HCU4	Cadherin EGF LAG seven-pass G-type receptor 2	gwas
CDPF1	HGNC:33710	ENSG00000205643	Q6NVV7	Cysteine-rich DPF motif domain-containing protein 1	gwas
CDKN2B-AS1	HGNC:34341	ENSG00000240498		CDKN2B and CDKN2A antisense cis and trans regulatory RNA 1	gwas
EVX1	HGNC:3506	ENSG00000106038	P49640	Homeobox even-skipped homolog protein 1	gwas
AKAP9	HGNC:379	ENSG00000127914	Q99996	A-kinase anchor protein 9	clinvar
GNA15	HGNC:4383	ENSG00000060558	P30679	Guanine nucleotide-binding protein subunit alpha-15	gwas
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
PKD2L2-DT	HGNC:55557	ENSG00000250159		PKD2L2 divergent transcript	clinvar
KLHL3	HGNC:6354	ENSG00000146021	Q9UH77	Kelch-like protein 3	gwas
LPA	HGNC:6667	ENSG00000198670	P08519	Apolipoprotein(a)	gwas
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	clinvar
ABO	HGNC:79	ENSG00000175164	P16442	Histo-blood group ABO system transferase	gwas
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	gwas
PRKAG2	HGNC:9386	ENSG00000106617	Q9UGJ0	5’-AMP-activated protein kinase subunit gamma-2	clinvar
BAG3	HGNC:939	ENSG00000151929	O95817	BAG family molecular chaperone regulator 3	gwas
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	clinvar
BCHE	HGNC:983	ENSG00000114200	P06276	Cholinesterase	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
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.
SH3GL2	Endophilin-A1	Implicated in synaptic vesicle endocytosis.
BTG1	Protein BTG1	Anti-proliferative protein.
SURF1	Surfeit locus protein 1	Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.
MYOT	Myotilin	Component of a complex of multiple actin cross-linking proteins.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
TTR	Transthyretin	Thyroid hormone-binding protein.
USP3	Ubiquitin carboxyl-terminal hydrolase 3	Deubiquitinase that plays a role in several cellular processes including transcriptional regulation, cell cycle progression or innate immunity.
SNX16	Sorting nexin-16	May be involved in several stages of intracellular trafficking.
PRICKLE1	Prickle-like protein 1	Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure.
CDH2	Cadherin-2	Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell.
CH25H	Cholesterol 25-hydroxylase	Catalyzes the formation of 25-hydroxycholesterol from cholesterol, leading to repress cholesterol biosynthetic enzymes.
TBC1D4	TBC1 domain family member 4	May act as a GTPase-activating protein for RAB2A, RAB8A, RAB10 and RAB14.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
AGAP5	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 5	Putative GTPase-activating protein.
SYNPO2L	Synaptopodin 2-like protein	Actin-associated protein that may play a role in modulating actin-based shape.
MOB3B	MOB kinase activator 3B	Modulates LATS1 expression in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.
TMTC1	Protein O-mannosyl-transferase TMTC1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.
FTO	Alpha-ketoglutarate-dependent dioxygenase FTO	RNA demethylase that mediates oxidative demethylation of different RNA species, such as mRNAs, tRNAs and snRNAs, and acts as a regulator of fat mass, adipogenesis and energy homeostasis.
RPUSD4	Pseudouridylate synthase RPUSD4, mitochondrial	Catalyzes uridine to pseudouridine isomerization (pseudouridylation) of different mitochondrial RNA substrates.
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.
SHTN1	Shootin-1	Involved in the generation of internal asymmetric signals required for neuronal polarization and neurite outgrowth.
NEXN	Nexilin	Involved in regulating cell migration through association with the actin cytoskeleton.
LRIG3	Leucine-rich repeats and immunoglobulin-like domains protein 3	May play a role in craniofacial and inner ear morphogenesis during embryonic development.
CELSR2	Cadherin EGF LAG seven-pass G-type receptor 2	Receptor that may have an important role in cell/cell signaling during nervous system formation.
EVX1	Homeobox even-skipped homolog protein 1	May play a role in the specification of neuronal cell types.
AKAP9	A-kinase anchor protein 9	Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus.
GNA15	Guanine nucleotide-binding protein subunit alpha-15	Member of the G-protein alpha subunit family that plays a crucial role in intracellular signaling.
KLHL3	Kelch-like protein 3	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron.
LPA	Apolipoprotein(a)	Apo(a) is the main constituent of lipoprotein(a) (Lp(a)).
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
ABO	Histo-blood group ABO system transferase	This protein is the basis of the ABO blood group system.
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.
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.
BAG3	BAG family molecular chaperone regulator 3	Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g.
PSEN1	Presenilin-1	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).
BCHE	Cholinesterase	Esterase with broad substrate specificity.

Protein-family classification

Druggable: 18 · Difficult: 9 · Unknown: 17 · Druggable fraction: 0.41

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
Antibody/Immunoglobulin	5	3.3×	0.151
Protease	3	2.5×	0.471
Enzyme (other)	6	1.6×	0.471
Scaffold/PPI	4	1.6×	0.560
Ion channel	1	2.5×	0.589
Kinase	2	1.3×	0.712
Transcription factor	5	0.9×	0.809
GPCR	1	0.5×	0.953
Other/Unknown	17	0.7×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SH3GL2	Scaffold/PPI	no		SH3_domain, BAR_dom, AH/BAR_dom_sf
BTG1	Other/Unknown	no		Anti_prolifrtn, BTG, BTG-like_sf
SURF1	Other/Unknown	no		Surf1/Shy1, Surf1/Surf4
MYOT	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
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
USP3	Protease	yes		Peptidase_C19_UCH, Znf_UBP, Znf_RING/FYVE/PHD
SNX16	Other/Unknown	no		PX_dom, PX_dom_sf, SNX16_PX
PRICKLE1	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
CDH2	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
CH25H	Enzyme (other)	yes	1.14.99.38	Fatty_acid_hydroxylase, Sterol_desaturase-rel
TBC1D4	Other/Unknown	no		Rab-GAP-TBC_dom, PTB/PI_dom, PH-like_dom_sf
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
AGAP5	Scaffold/PPI	no		ArfGAP_dom, PH_domain, Ankyrin_rpt
SYNPO2L	Scaffold/PPI	no		PDZ, PDZ_sf, Synaptopodin_domain
MOB3B	Kinase	yes		MOB_kinase_act_fam, MOB_kinase_act_sf
TMTC1	Other/Unknown	no		HAT, TPR-like_helical_dom_sf, TPR_2
FTO	Enzyme (other)	yes	1.14.11.53	FTO_C, FTO_cat_dom, FTO
RPUSD4	Enzyme (other)	yes	5.4.99.B22	PsdUridine_synth_RsuA/RluA, PsdUridine_synth_RluA-like_CS, PsdUridine_synth_cat_dom_sf
FAM241A	Other/Unknown	no		DUF4605, FAM241_domain
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
SHTN1	Other/Unknown	no		Shootin-1
NEXN	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_I-set
LRIG3	Antibody/Immunoglobulin	yes		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
CELSR2	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF
CDPF1	Other/Unknown	no		CDPF1_dom, CDPF1
CDKN2B-AS1	Other/Unknown	no
EVX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
AKAP9	Other/Unknown	no		ELK_dom, PACT_domain, AKAP9/Pericentrin
GNA15	Enzyme (other)	yes	3.6.5.1	Gprotein_alpha_Q, Gprotein_alpha_su, GproteinA_insert
TTN-AS1	Other/Unknown	no
PKD2L2-DT	Other/Unknown	no
KLHL3	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
LPA	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ABO	Enzyme (other)	yes	2.4.1.37	Glyco_trans_6, Nucleotide-diphossugar_trans
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
PRKAG2	Other/Unknown	no		CBS_dom, CBS_dom_sf, AMPK_gamma/SDS23_families
BAG3	Scaffold/PPI	no		WW_dom, BAG_domain, WW_dom_sf
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP
BCHE	Enzyme (other)	yes	3.1.1.8	Cholinesterase, CarbesteraseB, AChE_tetra

Expression context

Cohort genes with no expression data: 0.

37 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)	44
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skeletal muscle tissue of rectus abdominis	6
apex of heart	5
right lobe of liver	4
gastrocnemius	4
hindlimb stylopod muscle	4
buccal mucosa cell	3
ventricular zone	3
left ventricle myocardium	3
right atrium auricular region	3
olfactory bulb	2
middle temporal gyrus	2
body of pancreas	2
biceps brachii	2
skeletal muscle tissue of biceps brachii	2
type B pancreatic cell	2
lateral nuclear group of thalamus	2
tendon of biceps brachii	2
heart right ventricle	2
male germ line stem cell (sensu Vertebrata) in testis	2
inferior vagus X ganglion	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SH3GL2	193	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, endothelial cell
BTG1	306	ubiquitous	marker	lower lobe of lung, nipple, pericardium
SURF1	183	ubiquitous	marker	apex of heart, body of pancreas, right lobe of liver
MYOT	176	tissue_specific	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
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
USP3	284	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
SNX16	257	ubiquitous	yes	sperm, male germ cell, secondary oocyte
PRICKLE1	243	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral nuclear group of thalamus
CDH2	233	ubiquitous	marker	heart right ventricle, ventricular zone, stromal cell of endometrium
CH25H	226	broad	marker	mucosa of paranasal sinus, mucosa of stomach, vena cava
TBC1D4	290	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, renal medulla, diaphragm
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
AGAP5	134		yes	body of pancreas, right testis, male germ line stem cell (sensu Vertebrata) in testis
SYNPO2L	167	tissue_specific	yes	skeletal muscle tissue of rectus abdominis, apex of heart, skeletal muscle tissue of biceps brachii
MOB3B	260	ubiquitous	marker	inferior vagus X ganglion, ventricular zone, lateral globus pallidus
TMTC1	257	ubiquitous	marker	dorsal root ganglion, lateral nuclear group of thalamus, trigeminal ganglion
FTO	294	ubiquitous	marker	cortical plate, bronchial epithelial cell, Brodmann (1909) area 10
RPUSD4	252	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, tibialis anterior, deltoid
FAM241A	243	ubiquitous	marker	parietal pleura, heart right ventricle, left ventricle myocardium
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
SHTN1	281	ubiquitous	marker	medial globus pallidus, inferior vagus X ganglion, globus pallidus
NEXN	229	ubiquitous	marker	left ventricle myocardium, skeletal muscle tissue of rectus abdominis, myocardium
LRIG3	218	ubiquitous	marker	calcaneal tendon, right lobe of thyroid gland, skin of leg
CELSR2	248	ubiquitous	marker	ganglionic eminence, ventricular zone, right frontal lobe
CDPF1	174	ubiquitous	yes	pancreatic ductal cell, tibialis anterior, apex of heart
CDKN2B-AS1	169	ubiquitous	marker	mucosa of transverse colon, rectum, transverse colon

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH2	5,623
BAG3	4,957
TTR	4,528
TTN	4,237
PSEN1	3,732
AKAP9	3,537
ATXN2	3,360
PRKAG2	3,212
FTO	2,496
DMD	2,479

Intra-cohort edges

A	B	Sources
AGAP5	FAM241A	string_interaction
AGAP5	SYNPO2L	string_interaction
ATXN2	SH3GL2	intact, string_interaction
BAG3	MYOT	string_interaction
CDH2	PSEN1	biogrid_interaction, string_interaction
DMD	MYOT	string_interaction
FAM241A	KLHL3	string_interaction
MYBPC3	PRKAG2	string_interaction
MYBPC3	RBM20	string_interaction
MYBPC3	TTN	string_interaction
MYPN	TTN	biogrid_interaction, string_interaction
NEXN	RBM20	string_interaction
PITX2	SYNPO2L	string_interaction
RBM20	SCN5A	string_interaction
RBM20	TTN	string_interaction

Structural data

PDB: 18 · AlphaFold-only: 23 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTR	P02766	462
ABO	P16442	151
BCHE	P06276	109
TTN	Q8WZ42	64
FTO	Q9C0B1	28
PSEN1	P49768	27
MYBPC3	Q14896	17
SCN5A	Q14524	16
LPA	P08519	16
DMD	P11532	6
SH3GL2	Q99962	4
KLHL3	Q9UH77	3
PITX2	Q99697	3
MYOT	Q9UBF9	2
SNX16	P57768	2
TBC1D4	O60343	2
ATXN2	Q99700	1
RPUSD4	Q96CM3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CH25H	O95992	92.40
GNA15	P30679	90.74
MOB3B	Q86TA1	90.13
TMTC1	Q8IUR5	88.13
CDPF1	Q6NVV7	87.30
SURF1	Q15526	82.62
BTG1	P62324	81.91
CDH2	P19022	79.68
USP3	Q9Y6I4	79.40
LRIG3	Q6UXM1	73.40
SHTN1	A0MZ66	72.03
NEXN	Q0ZGT2	70.78
PRKAG2	Q9UGJ0	67.24
AGAP5	A6NIR3	62.80
FAM241A	Q8N8J7	58.47
BAG3	O95817	57.98
EVX1	P49640	57.95
PRICKLE1	Q96MT3	55.55
SYNPO2L	Q9H987	53.10
MYPN	Q86TC9	52.71
RBM20	Q5T481	48.52
CELSR2	Q9HCU4
AKAP9	Q99996

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 153. Enrichment computed across 44 evidence-associated genes (25 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 25 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	3	37.0×	0.010	TTN, DMD, MYBPC3
L1CAM interactions	3	14.4×	0.086	SCN5A, SH3GL2, SHTN1
Defective visual phototransduction due to STRA6 loss of function	1	152.3×	0.146	TTR
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	114.2×	0.146	PITX2
LDL remodeling	1	76.1×	0.146	LPA
Reversal of alkylation damage by DNA dioxygenases	1	65.3×	0.146	FTO
AMPK inhibits chREBP transcriptional activation activity	1	57.1×	0.146	PRKAG2
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	1	57.1×	0.146	GNA15
Noncanonical activation of NOTCH3	1	57.1×	0.146	PSEN1
Neurotransmitter clearance	1	50.8×	0.146	BCHE
Lipophagy	1	50.8×	0.146	PRKAG2
Activation of PPARGC1A (PGC-1alpha) by phosphorylation	1	45.7×	0.146	PRKAG2
Acetylcholine regulates insulin secretion	1	45.7×	0.146	GNA15
Phase 3 - rapid repolarisation	1	45.7×	0.146	AKAP9
Regulated proteolysis of p75NTR	1	41.5×	0.146	PSEN1
Listeria monocytogenes entry into host cells	1	41.5×	0.146	SH3GL2
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	41.5×	0.146	PSEN1
Mitochondrial mRNA modification	1	41.5×	0.146	RPUSD4
Recycling pathway of L1	2	17.9×	0.146	SH3GL2, SHTN1
Translocation of SLC2A4 (GLUT4) to the plasma membrane	2	12.3×	0.146	TBC1D4, PRKAG2
Non-integrin membrane-ECM interactions	2	12.3×	0.146	TTR, DMD
Muscle contraction	3	9.3×	0.146	SCN5A, AKAP9, MYBPC3
Cardiac conduction	2	8.7×	0.146	SCN5A, AKAP9
Axon guidance	3	5.4×	0.146	SCN5A, SH3GL2, SHTN1
Nervous system development	3	5.2×	0.146	SCN5A, SH3GL2, SHTN1
TGFBR3 PTM regulation	1	38.1×	0.150	PSEN1
rRNA modification in the mitochondrion	1	35.1×	0.150	RPUSD4
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	35.1×	0.150	CDH2
Retrograde neurotrophin signalling	1	32.6×	0.150	SH3GL2
Carnitine shuttle	1	30.4×	0.150	PRKAG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 38 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	4	42.2×	6e-04	SCN5A, TTN, DMD, MYBPC3
sarcomere organization	4	40.3×	6e-04	TTN, MYPN, SYNPO2L, MYBPC3
homophilic cell-cell adhesion	5	18.5×	0.001	MYOT, CDH2, MYPN, NEXN, CELSR2
detection of muscle stretch	2	126.7×	0.011	TTN, CDH2
sterol biosynthetic process	2	88.7×	0.019	CH25H, PRKAG2
regulation of cardiac muscle cell contraction	2	59.1×	0.032	SCN5A, MYBPC3
dendrite self-avoidance	2	55.4×	0.032	MYPN, NEXN
regulation of sodium ion transmembrane transport	2	55.4×	0.032	SCN5A, DMD
striated muscle cell apoptotic process	1	443.5×	0.038	BAG3
subthalamic nucleus development	1	443.5×	0.038	PITX2
superior vena cava morphogenesis	1	443.5×	0.038	PITX2
endoplasmic reticulum polarization	1	443.5×	0.038	SHTN1
actin filament bundle retrograde transport	1	443.5×	0.038	SHTN1
regulation of white fat cell proliferation	1	443.5×	0.038	FTO
negative regulation of cholesterol metabolic process	1	443.5×	0.038	CH25H
regulation of muscle system process	1	443.5×	0.038	DMD
regulation of cellular response to growth factor stimulus	1	443.5×	0.038	DMD
spinal cord interneuron axon guidance	1	443.5×	0.038	EVX1
negative regulation of fusion of virus membrane with host plasma membrane	1	443.5×	0.038	CH25H
positive regulation of L-glutamate import across plasma membrane	1	221.7×	0.038	PSEN1
acetylcholine catabolic process	1	221.7×	0.038	BCHE
hypothalamus cell migration	1	221.7×	0.038	PITX2
Cajal-Retzius cell differentiation	1	221.7×	0.038	PSEN1
negative regulation of vesicle fusion	1	221.7×	0.038	TBC1D4
regulation of muscle filament sliding	1	221.7×	0.038	MYBPC3
cocaine catabolic process	1	221.7×	0.038	BCHE
smooth endoplasmic reticulum calcium ion homeostasis	1	221.7×	0.038	PSEN1
prolactin secreting cell differentiation	1	221.7×	0.038	PITX2
left lung morphogenesis	1	221.7×	0.038	PITX2
pulmonary vein morphogenesis	1	221.7×	0.038	PITX2

Therapeutics

Drugs indicated for this disease

29 approved, 58 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)
Dapagliflozin	Approved (phase 4)
Digoxin	Approved (phase 4)
Empagliflozin	Approved (phase 4)
Eplerenone	Approved (phase 4)
Furosemide	Approved (phase 4)
Hydrochlorothiazide	Approved (phase 4)
Ivabradine	Approved (phase 4)
Metolazone	Approved (phase 4)
Nitroglycerin	Approved (phase 4)
Olmesartan Medoxomil	Approved (phase 4)
Ramipril	Approved (phase 4)
Reteplase	Approved (phase 4)
Sacubitril	Approved (phase 4)
Sodium Chloride	Approved (phase 4)
Sotagliflozin	Approved (phase 4)
Spironolactone	Approved (phase 4)
Tolvaptan	Approved (phase 4)
Torsemide	Approved (phase 4)
Trandolapril	Approved (phase 4)
Valsartan	Approved (phase 4)
Vericiguat	Approved (phase 4)
Albuterol	Phase 3 (in late-stage trials)
Aliskiren	Phase 3 (in late-stage trials)
Alprostadil	Phase 3 (in late-stage trials)
Amiodarone	Phase 3 (in late-stage trials)
Amlodipine	Phase 3 (in late-stage trials)
Arginine	Phase 3 (in late-stage trials)
Ascorbic Acid	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Atenolol	Phase 3 (in late-stage trials)
Candesartan	Phase 3 (in late-stage trials)
Cholecalciferol	Phase 3 (in late-stage trials)
Clopidogrel	Phase 3 (in late-stage trials)
Colchicine	Phase 3 (in late-stage trials)
Dextrose	Phase 3 (in late-stage trials)
Digitalis	Phase 3 (in late-stage trials)
Diltiazem	Phase 3 (in late-stage trials)
Disopyramide	Phase 3 (in late-stage trials)
Dobutamine	Phase 3 (in late-stage trials)
Doconexent	Phase 3 (in late-stage trials)
Dofetilide	Phase 3 (in late-stage trials)
Doxazosin	Phase 3 (in late-stage trials)
Enalapril	Phase 3 (in late-stage trials)
Epinephrine	Phase 3 (in late-stage trials)
Ferrous Sulfate	Phase 3 (in late-stage trials)
Finerenone	Phase 3 (in late-stage trials)
HUMAN NEUREGULIN-1 RECOMBINANT (177-237)	Phase 3 (in late-stage trials)
Hawthorn Leaf With Flower	Phase 3 (in late-stage trials)
Icosapent	Phase 3 (in late-stage trials)
Indacaterol	Phase 3 (in late-stage trials)
Iobenguane	Phase 3 (in late-stage trials)
Levosimendan	Phase 3 (in late-stage trials)
Lisinopril Anhydrous	Phase 3 (in late-stage trials)
Losartan	Phase 3 (in late-stage trials)
Metoprolol	Phase 3 (in late-stage trials)
Milrinone	Phase 3 (in late-stage trials)
Nesiritide	Phase 3 (in late-stage trials)
Nicotine	Phase 3 (in late-stage trials)
OMEGA-3-ACID ETHYL ESTERS	Phase 3 (in late-stage trials)
Omecamtiv Mecarbil	Phase 3 (in late-stage trials)
Oxygen	Phase 3 (in late-stage trials)
Potassium Chloride	Phase 3 (in late-stage trials)
Pravastatin	Phase 3 (in late-stage trials)
Prednisone	Phase 3 (in late-stage trials)
Procainamide	Phase 3 (in late-stage trials)
Propafenone	Phase 3 (in late-stage trials)
Rolofylline	Phase 3 (in late-stage trials)
Rosuvastatin	Phase 3 (in late-stage trials)
Serelaxin	Phase 3 (in late-stage trials)
Sildenafil	Phase 3 (in late-stage trials)
Somatropin	Phase 3 (in late-stage trials)
Sotalol	Phase 3 (in late-stage trials)
Tezosentan	Phase 3 (in late-stage trials)
Thyroid	Phase 3 (in late-stage trials)
Tonapofylline	Phase 3 (in late-stage trials)
Triglycerides, Medium-Chain	Phase 3 (in late-stage trials)
Ularitide	Phase 3 (in late-stage trials)
Verapamil	Phase 3 (in late-stage trials)
Warfarin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acipimox, Allopurinol, Anakinra, Apixaban, Atorvastatin, Biotin, Calcium, Cilostazol, Conivaptan, Cyanocobalamin, Dexamethasone, Dopamine, Elamipretide, Ergocalciferol, Ertugliflozin, Evolocumab, Firibastat, Folic Acid, Glutamine, Hydralazine, Hydrocortisone, Icatibant, Iodine, Isosorbide Dinitrate, Isosorbide Mononitrate, Levocarnitine, Liraglutide, Macitentan, Mavacamten, Metformin, Mirabegron, Niacin, Nicotinamide Riboside, Pantothenic Acid, Patiromer, Perhexiline, Pirfenidone, Probenecid, Pyridoxine, Retinol, Riboflavin, Rituximab, Sodium Zirconium Cyclosilicate, Teprenone, Testosterone, Ubidecarenone, Vepoloxamer, Vitamin E.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 7 · Phased (≥1): 7 · Undrugged: 37

Druggability breadth: 14 of 44 evidence-associated genes (32%) 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
FTO	FLUORESCEIN
PRKAG2	ADENOSINE PHOSPHATE
PSEN1	NIROGACESTAT
BCHE	PYRIDOSTIGMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
BCHE	36	4
TTR	29	4
PRKAG2	19	4
FTO	18	4
PSEN1	8	4
GNA15	2	3
ATXN2	0	0
SH3GL2	0	0
BTG1	0	0

Drugs targeting cohort genes (top 30)

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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
BCHE	1,172	Binding:1162, ADMET:9, Functional:1
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
PSEN1	557	Binding:538, Functional:12, ADMET:6, Unclassified:1
TTR	423	Binding:391, Functional:32
PRKAG2	266	Binding:265, Functional:1
FTO	153	Binding:153
BAG3	8	Binding:8
ABO	6	Binding:6
ATXN2	5	Binding:3, Functional:2
CDH2	4	Binding:3, Functional:1
USP3	3	Binding:3
GNA15	3	Binding:2, Functional:1
KLHL3	3	Binding:3
TTN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
CH25H	1.14.99.38	cholesterol 25-monooxygenase
FTO	1.14.11.53	mRNA N6-methyladenine demethylase
RPUSD4	5.4.99.B22
GNA15	3.6.5.1	heterotrimeric G-protein GTPase
ABO	2.4.1.37, 2.4.1.40, 2.4.1.88	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase, globoside alpha-N-acetylgalactosaminyltransferase
BCHE	3.1.1.8	cholinesterase

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
FTO	153
PRKAG2	266
PSEN1	557
BCHE	1,172

Pharmacogenomics

Cohort genes with a PharmGKB record: 42; 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	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	SCN5A
IMIPRAMINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	SCN5A
FEDRATINIB	4	SCN5A
QUINIDINE	4	BCHE, SCN5A
DARUNAVIR	4	SCN5A
DARIFENACIN	4	SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	SCN5A
RANOLAZINE	4	SCN5A
PIMOZIDE	4	SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	SCN5A
AMLODIPINE	4	SCN5A
PHENYTOIN	4	SCN5A
PALIPERIDONE	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	SCN5A, TTR, FTO, PRKAG2, PSEN1, BCHE
B	Phased (≥1) drug, not yet approved	1	GNA15
C	Druggable family + PDB, no drug	6	MYOT, TTN, RPUSD4, LPA, MYBPC3, ABO
D	Druggable family + AlphaFold only, no drug	7	USP3, CH25H, MYPN, MOB3B, NEXN, LRIG3, CELSR2
E	Difficult family or no structure, no drug	24	ATXN2, SH3GL2, BTG1, SURF1, SNX16, PRICKLE1, CDH2, TBC1D4, AGAP5, SYNPO2L (+14 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATXN2	5	—
SH3GL2	0	—
BTG1	0	—
SURF1	0	—
MYOT	0	—
TTN	1	—
USP3	3	—
SNX16	0	—
PRICKLE1	0	—
CDH2	4	—
CH25H	0	—
TBC1D4	0	—
MYPN	0	—
AGAP5	0	—
SYNPO2L	0	—
MOB3B	0	—
TMTC1	0	—
RPUSD4	0	—
FAM241A	0	—
RBM20	0	—
DMD	0	—
SHTN1	0	—
NEXN	0	—
LRIG3	0	—
CELSR2	0	—
CDPF1	0	—
CDKN2B-AS1	0	—
EVX1	0	—
AKAP9	0	—
TTN-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4,325.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	325
PHASE2	280
PHASE3	236
PHASE1	118
PHASE1/PHASE2	64
PHASE2/PHASE3	60
EARLY_PHASE1	17

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04160000	PHASE4	RECRUITING	Treatment Of Atrial Fibrillation In Preserved Cardiac Function Heart Failure
NCT04323189	PHASE4	ACTIVE_NOT_RECRUITING	Effects of Sitagliptin in Individuals With Genetically Decreased DPP4
NCT04654988	PHASE4	RECRUITING	Study to Evaluate the Efficacy of Immunosuppression in Myocarditis or Inflammatory Cardiomyopathy.
NCT04691700	PHASE4	ACTIVE_NOT_RECRUITING	GOREISAN for Heart Failure (GOREISAN-HF) Trial
NCT04707261	PHASE4	RECRUITING	Association Between Dapagliflozin-induced Improvement and Anemia in Heart Failure Patients (ADIDAS)
NCT04899479	PHASE4	RECRUITING	Peri-treatment of SGLT-2 Inhibitor on Myocardial Infarct Size and Remodeling Index in Patients With Acute Myocardial Infarction and High Risk of Heart Failure Undergoing Percutaneous Coronary Intervention
NCT05164653	PHASE4	ACTIVE_NOT_RECRUITING	Program of Angiotensin-Neprilysin Inhibition in Admitted Patients With Worsening Heart Failure (PREMIER)
NCT05276219	PHASE4	RECRUITING	Optimized Treatment of Pulmonary Edema or Congestion
NCT05465031	PHASE4	RECRUITING	Sacubitril/Valsartan in PriMAry preventIoN of the Cardiotoxicity of Systematic breaST canceR trEAtMent (MAINSTREAM)
NCT05583773	PHASE4	RECRUITING	SHengXIaN-QuYu DEcoction in Heart Failure With Reduced and Mildly Reduced Ejection Fraction
NCT05585125	PHASE4	ENROLLING_BY_INVITATION	A Preliminary Study for INFORMED
NCT05672836	PHASE4	RECRUITING	ENAVOgliflozin Outcome Trial in Patients With Severe Aortic Stenosis After Transcatheter Aortic Valve Replacement
NCT05704478	PHASE4	ACTIVE_NOT_RECRUITING	Impact of Vericiguat on Hemodynamics of Heart Failure
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT05741658	PHASE4	ENROLLING_BY_INVITATION	The Fontan Dapagliflozin Pilot Study
NCT05793996	PHASE4	RECRUITING	The Prevalence of Iron Deficiency and the Effectiveness of Ferinject® in Patients With HFpEF (ID-HFpEF)
NCT05802849	PHASE4	RECRUITING	Acetazolamide Per os for Decompensation of Heart Failure
NCT05816265	PHASE4	ENROLLING_BY_INVITATION	Effects of IV Iron Replacement on Exercise Capacity in Individuals With Heart Failure
NCT06166654	PHASE4	RECRUITING	Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload
NCT06183437	PHASE4	RECRUITING	The STOP-MED CTRCD Trial
NCT06260059	PHASE4	RECRUITING	Efficacy Of Sodium Glucose Transporter Inhibitor (SGLT2I) In Adult Patients With Congenital Heart Disease
NCT06270498	PHASE4	RECRUITING	Effect of Oral sucRosomIal Iron on exerciSE Capacity and Quality of Life in Patients With Heart Failure
NCT06286423	PHASE4	RECRUITING	Colchicine in Acutely Decompensated HFREF
NCT06427343	PHASE4	RECRUITING	The Effects of Low-Dose Versus High-Dose Intravenous IRON Therapy With Ferric DerisomaltOSE in Patients With Chronic Heart Failure and Iron Deficiency
NCT06442280	PHASE4	NOT_YET_RECRUITING	SGLT-2 Inhibitor and High-Dose Furosemide Plus Small-Volume Hypertonic Saline Solution in Acute HF
NCT06495892	PHASE4	RECRUITING	PVP-Guided Decongestive Therapy in HF 2
NCT06578520	PHASE4	RECRUITING	Effect of the Use of Dapagliflozin in Patients With Refractory Heart Failure
NCT06604611	PHASE4	NOT_YET_RECRUITING	Colchicine in Patients With Heart Failure With Preserved Ejection Fraction and Inflammation
NCT06642272	PHASE4	RECRUITING	A Pragmatic Trial Comparing Empagliflozin and Dapagliflozin Through Cluster Randomization Embedded in the Electronic Health Record
NCT06651970	PHASE4	RECRUITING	Acalabrutinib Monotherapy vs Investigator’s Choice of Treatment in Patients With CL Leukaemia and Heart Failure
NCT06671990	PHASE4	NOT_YET_RECRUITING	The CardioMEMS Vericiguat Heart Failure Trial
NCT06704633	PHASE4	NOT_YET_RECRUITING	Sacubitril-valsartan in Patients With Heart Failure With Reduced Ejection Fraction From Rural Tanzania
NCT06706791	PHASE4	RECRUITING	Effect of Empagliflozin on Quality of Life in Chronic Heart Failure Patients With Diabetes Mellitus Type II
NCT06725927	PHASE4	ACTIVE_NOT_RECRUITING	Vaccination Against Influenza Pre-discharge in Heart Failure
NCT06793670	PHASE4	RECRUITING	Landiolol in Mitral Valve Surgery
NCT06812546	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Early Initiation of Vericiguat in Heart Failure After Acute Myocardial Infarction
NCT06979726	PHASE4	RECRUITING	Gator SCALES-WHF: SubCutaneous Administration of Lasix to Eliminate Symptoms of Worsening Heart Failure
NCT07053475	PHASE4	RECRUITING	IRONICA: IRON Repletion In Heart Failure - A Comparison of Oral and IV Approaches
NCT07243119	PHASE4	ENROLLING_BY_INVITATION	PRIMA-HF: Predicting Myocardial Recovery in Heart Failure Using Cardiac Imaging HAI-HF: High Dosing vs. Standard Dosing Adenosine During Myocardial Perfusion in Heart Failure
NCT07252310	PHASE4	ENROLLING_BY_INVITATION	Pilot Study of StudyU for N-of-1 Trials in HFrEF Patients (N-of-1 App)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ENALAPRIL	4	33
FUROSEMIDE	4	29
BISOPROLOL	4	21
SPIRONOLACTONE	4	21
FINERENONE	4	15
SACUBITRIL	4	15
VERICIGUAT	4	13
AMIODARONE	4	12
FERRIC CARBOXYMALTOSE	4	10
IVABRADINE	4	10
CARVEDILOL	4	9
EMPAGLIFLOZIN	4	9
THIAMINE ION	4	9
ACETAZOLAMIDE	4	8
DIGOXIN	4	8
METOLAZONE	4	8
TOLVAPTAN	4	8
DAPAGLIFLOZIN	4	7
NESIRITIDE	4	7
TORSEMIDE	4	7
EPLERENONE	4	6
LISINOPRIL ANHYDROUS	4	6
VALSARTAN	4	6
SOTAGLIFLOZIN	4	5
ALISKIREN	4	4
ALLOPURINOL	4	4
DOBUTAMINE	4	4
FERRIC DERISOMALTOSE	4	4
LEVOTHYROXINE	4	4
METFORMIN HYDROCHLORIDE	4	4