Pulmonary arterial hypertension

Summary

Pulmonary arterial hypertension (MONDO:0015924) is a disease (an umbrella term covering 5 Mondo subtypes) caused by variants in ATP13A3, GDF2, KCNK3, and 3 other genes, with 37 cohort genes (14 GWAS associations across 4 studies) and 577 clinical trials. The dominant Reactome pathway is Signaling by BMP (8 cohort genes). Top therapeutic interventions include treprostinil, sildenafil, and macitentan.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal genes: ATP13A3 (GenCC Definitive), GDF2 (GenCC Definitive), KCNK3 (GenCC Definitive), ABCC8 (GenCC Strong) (+2 more)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 37
• GWAS associations: 14
• ClinVar variants: 385
• Phenotypes (HPO): 13
• Clinical trials: 577

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.11	United States	Validated
Annual incidence	1-9 / 1 000 000	0.1	France	Validated
Annual incidence	1-9 / 1 000 000	0.62	Czech Republic	Validated
Point prevalence	1-9 / 1 000 000	0.65	France	Validated
Point prevalence	1-9 / 100 000	1.4	Czech Republic	Validated
Point prevalence	1-9 / 100 000	6.25	China	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002092	Pulmonary arterial hypertension	Very frequent (80-99%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0011025	Abnormality of cardiovascular system physiology	Frequent (30-79%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001962	Palpitations	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0005133	Right ventricular dilatation	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0030148	Heart murmur	Occasional (5-29%)
HP:0030848	Elevated jugular venous pressure	Occasional (5-29%)
HP:0100749	Chest pain	Occasional (5-29%)
HP:0010741	Pedal edema	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary arterial hypertension
Mondo ID	MONDO:0015924
EFO	EFO:0001361
MeSH	D000081029
Orphanet	182090, 422
ICD-11	1931148955
SNOMED CT	11399002
UMLS	C2973725
MedGen	425404
GARD	0007501
MedDRA	10064911
NORD	1634
Is cancer (heuristic)	no

Also known as: idiopathic pulmonary hypertension · PAH · PAH with overt features of venous/capillaries involvement · PPH · pulmonary arterial hypertension · PVOD/PCH

Data availability: 385 ClinVar variants · 83 ClinGen variant curations · 14 GWAS associations (4 studies) · 22 GenCC gene-disease records · 24 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › arterial disorder › hypertensive disorder › pulmonary hypertension › pulmonary arterial hypertension

Related subtypes (5): Braddock syndrome, chronic thromboembolic pulmonary hypertension, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, pulmonary hypertension owing to lung disease and/or hypoxia, pulmonary hypertension, neonatal

Subtypes (5): idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, drug- or toxin-induced pulmonary arterial hypertension, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis, Eisenmenger syndrome

Genetics & variants

GWAS landscape

14 GWAS associations across 4 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2856830	8e-20	HLA-DPA1, HLA-DPB1	C	1.56
rs10103692	5e-15	RNU105C - RN7SL250P	G	1.8
rs13266183	2e-12	RNU105C - RN7SL250P	C	1.36
rs183926708	2e-10	PIM1 - TMEM217	?	4
rs2217560	7e-10	LINC01899 - CBLN2	G	1.97
rs370775256	2e-09	PKIA-AS1, PKIA	?	3.12
rs573886591	3e-09	Y_RNA - CARS1P2	?	3.2
rs187386578	5e-09	RPL12P2 - PIM1	?	3.63
rs71427857	8e-09	PDE1A - DNAJC10	A	5.76
rs193148583	2e-08	LINC02691 - RNU6-684P	?	3.81
rs145733648	2e-08	LINC01491 - SLC24A5	?	3.3
rs567757955	4e-08	RNU6-699P - RNU1-63P	?	3.88
rs4764961	4e-08	C12orf42	?	2.11
rs147444776	4e-08	FBN1	?	3.42

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST007228	Rhodes CJ	2018	2,085	9,659	Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
GCST90270938	Pu A	2023	493	24,650	Identification of novel genetic variants, including PIM1 and LINC01491, with ICD-10 based diagnosis of pulmonary arterial hypertension in the UK Biobank cohort.
GCST001908	Germain M	2013	340	1,068	Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension.
GCST004947	Kimura M	2017	23	2,002	A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	14

MAF distribution

Bucket	Variants
common (>=0.05)	5
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	8

Functional consequences

Consequence	Count
intron_variant	7
intergenic_variant	6
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2856830	6	33073957	T>C	0.12	intron_variant	HLA-DPA1, HLA-DPB1	8e-20	Tier 4: intronic/intergenic
rs10103692	8	54345567	A>G	0.1	intergenic_variant	RNU105C - RN7SL250P	5e-15	Tier 4: intronic/intergenic
rs13266183	8	54355052	C>T	0.27	non_coding_transcript_exon_variant	RNU105C - RN7SL250P	2e-12	Tier 4: intronic/intergenic
rs183926708	6	37181977	T>G		intron_variant	PIM1 - TMEM217	2e-10	Tier 4: intronic/intergenic
rs2217560	18	72483704	G>A,C,T	0.069	intergenic_variant	LINC01899 - CBLN2	7e-10	Tier 4: intronic/intergenic
rs370775256	8	78537084	AG>A		intron_variant	PKIA-AS1, PKIA	2e-09	Tier 4: intronic/intergenic
rs573886591	8	114163877	C>A,T		intergenic_variant	Y_RNA - CARS1P2	3e-09	Tier 4: intronic/intergenic
rs187386578	6	37113836	C>T		intron_variant	RPL12P2 - PIM1	5e-09	Tier 4: intronic/intergenic
rs71427857	2	182633113	G>A,T	0.042	intergenic_variant	PDE1A - DNAJC10	8e-09	Tier 4: intronic/intergenic
rs193148583	14	104362487	G>A		intergenic_variant	LINC02691 - RNU6-684P	2e-08	Tier 4: intronic/intergenic
rs145733648	15	47905103	A>C		intron_variant	LINC01491 - SLC24A5	2e-08	Tier 4: intronic/intergenic
rs567757955	4	67297593	T>G		intergenic_variant	RNU6-699P - RNU1-63P	4e-08	Tier 4: intronic/intergenic
rs4764961	12	103436015	T>A,C,G	0.05	intron_variant	C12orf42	4e-08	Tier 4: intronic/intergenic
rs147444776	15	48457002	G>A		intron_variant	FBN1	4e-08	Tier 4: intronic/intergenic

ClinVar germline variants

385 retrieved; paginated sample, class counts are floors:

133 pathogenic, 70 likely pathogenic, 58 uncertain significance, 51 not provided, 25 conflicting classifications of pathogenicity, 19 likely benign, 12 benign/likely benign, 12 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
813263	Single allele	ABI2	Pathogenic	no assertion criteria provided
813264	Single allele	ABI2	Pathogenic	no assertion criteria provided
212796	NM_000020.3(ACVRL1):c.1451G>A (p.Arg484Gln)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
426037	NM_000020.3(ACVRL1):c.1450C>G (p.Arg484Gly)	ACVRL1	Pathogenic/Likely pathogenic	no assertion criteria provided
656236	NM_000020.3(ACVRL1):c.1030T>C (p.Cys344Arg)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812852	NM_000020.3(ACVRL1):c.334C>T (p.Gln112Ter)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
812855	NM_000020.3(ACVRL1):c.1451G>T (p.Arg484Leu)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8252	NM_000020.3(ACVRL1):c.1450C>T (p.Arg484Trp)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1195990	NM_001367549.1(ATP13A3):c.2549dup (p.Met850fs)	ATP13A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1195992	NM_001367549.1(ATP13A3):c.3079dup (p.Trp1027fs)	ATP13A3	Pathogenic	criteria provided, single submitter
1069537	NM_001204.7(BMPR2):c.2450_2451del (p.Asn817fs)	BMPR2	Pathogenic	criteria provided, single submitter
1069660	NM_001204.7(BMPR2):c.1748dup (p.Asn583fs)	BMPR2	Pathogenic	criteria provided, single submitter
1339409	NM_001204.7(BMPR2):c.1524G>A (p.Trp508Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1706628	NM_001204.7(BMPR2):c.1169del (p.Gly390fs)	BMPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1706632	NM_001204.7(BMPR2):c.189dup (p.Ser64Ter)	BMPR2	Pathogenic	criteria provided, single submitter
1706633	NM_001204.7(BMPR2):c.2530C>T (p.Gln844Ter)	BMPR2	Pathogenic	no assertion criteria provided
1706634	NM_001204.7(BMPR2):c.1644del (p.Ser549fs)	BMPR2	Pathogenic	no assertion criteria provided
1706635	NM_001204.7(BMPR2):c.978del (p.Lys326fs)	BMPR2	Pathogenic	no assertion criteria provided
212809	NM_001204.7(BMPR2):c.846T>G (p.Tyr282Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
212811	NM_001204.7(BMPR2):c.1128+1G>A	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
212814	NM_001204.7(BMPR2):c.186dup (p.Gly63fs)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
212815	NM_001204.7(BMPR2):c.853-2A>G	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
212817	NM_001204.7(BMPR2):c.377A>G (p.Asn126Ser)	BMPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222513	NM_001204.7(BMPR2):c.439C>T (p.Arg147Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
228460	NM_001204.7(BMPR2):c.901T>C (p.Ser301Pro)	BMPR2	Pathogenic	reviewed by expert panel
264650	NM_001204.7(BMPR2):c.16C>T (p.Gln6Ter)	BMPR2	Pathogenic	no assertion criteria provided
280019	NM_001204.7(BMPR2):c.637C>T (p.Arg213Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
280837	NM_001204.7(BMPR2):c.1128+1G>C	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
409813	NM_001204.7(BMPR2):c.1398G>A (p.Trp466Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
409826	NM_001204.7(BMPR2):c.961C>T (p.Arg321Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 117 · Orphanet: 69 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
SOX17	SOX17	GWAS, GenCC, Orphanet

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ATP13A3	Definitive	Semidominant	pulmonary arterial hypertension	2
GDF2	Definitive	Autosomal dominant	pulmonary arterial hypertension	8
KCNK3	Definitive	Autosomal dominant	pulmonary arterial hypertension	4
ABCC8	Strong	Autosomal dominant	pulmonary arterial hypertension	32
KDR	Strong	Autosomal dominant	pulmonary arterial hypertension	3
SOX17	Strong	Autosomal dominant	pulmonary arterial hypertension	6
AQP1	Moderate	Autosomal dominant	pulmonary arterial hypertension	2
BMP10	Moderate	Autosomal dominant	pulmonary arterial hypertension	4
BMPR1B	Moderate	Autosomal dominant	pulmonary arterial hypertension	17
TET2	Moderate	Autosomal dominant	pulmonary arterial hypertension	3
BRAP	Limited	Autosomal dominant	pulmonary arterial hypertension
FBLN2	Limited	Autosomal dominant	pulmonary arterial hypertension	3
KLF2	Limited	Autosomal dominant	pulmonary arterial hypertension
KLK1	Limited	Autosomal dominant	pulmonary arterial hypertension
PDGFD	Limited	Autosomal dominant	pulmonary arterial hypertension
BMPR1A	Disputed Evidence	Unknown	pulmonary arterial hypertension	12
SMAD1	Disputed Evidence	Autosomal dominant	pulmonary arterial hypertension	3
SMAD4	Disputed Evidence	Autosomal dominant	pulmonary arterial hypertension	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX17	Orphanet:275777	Heritable pulmonary arterial hypertension
SOX17	Orphanet:289365	Familial vesicoureteral reflux
BMPR1A	Orphanet:157794	Hereditary mixed polyposis syndrome
BMPR1A	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
BMPR1A	Orphanet:440437	Familial colorectal cancer Type X
BMPR1A	Orphanet:79076	Juvenile polyposis of infancy
BMPR1B	Orphanet:2098	Acromesomelic dysplasia, Grebe type
BMPR1B	Orphanet:2639	Fibular aplasia-complex brachydactyly syndrome
BMPR1B	Orphanet:93384	Brachydactyly type C
BMPR1B	Orphanet:93388	Brachydactyly type A1
BMPR1B	Orphanet:93396	Brachydactyly type A2
ATP13A3	Orphanet:275777	Heritable pulmonary arterial hypertension
GDF2	Orphanet:275777	Heritable pulmonary arterial hypertension
GDF2	Orphanet:774	Hereditary hemorrhagic telangiectasia
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
KCNK3	Orphanet:275777	Heritable pulmonary arterial hypertension
SMAD4	Orphanet:1333	Familial pancreatic carcinoma
SMAD4	Orphanet:2588	Myhre syndrome
SMAD4	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
SMAD4	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TET2	Orphanet:100019	Myelodysplastic neoplasm with increased blasts type 1
TET2	Orphanet:100020	Myelodysplastic neoplasm with increased blasts type 2
TET2	Orphanet:3318	Essential thrombocythemia
TET2	Orphanet:664729	EBV-induced lymphoproliferative disease due to TET2 deficiency
TET2	Orphanet:75564	Acquired idiopathic sideroblastic anemia
TET2	Orphanet:824	Primary myelofibrosis
TET2	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
TET2	Orphanet:98826	Myelodysplastic neoplasm with low blasts
TET2	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
TET2	Orphanet:98850	Aggressive systemic mastocytosis
KDR	Orphanet:3303	Tetralogy of Fallot
BMPR2	Orphanet:275777	Heritable pulmonary arterial hypertension
BMPR2	Orphanet:275786	Drug- or toxin-induced pulmonary arterial hypertension
BMPR2	Orphanet:31837	Pulmonary venoocclusive disease
TBX4	Orphanet:1509	Coxopodopatellar syndrome
TBX4	Orphanet:238578	Familial clubfoot due to 17q23.1q23.2 microduplication
TBX4	Orphanet:261279	17q23.1q23.2 microdeletion syndrome
TBX4	Orphanet:275777	Heritable pulmonary arterial hypertension
TBX4	Orphanet:3301	Tetraamelia-multiple malformations syndrome
ACVRL1	Orphanet:275777	Heritable pulmonary arterial hypertension
ACVRL1	Orphanet:774	Hereditary hemorrhagic telangiectasia
PHF6	Orphanet:127	Borjeson-Forssman-Lehmann syndrome
EIF2AK4	Orphanet:199241	Pulmonary capillary hemangiomatosis

Cohort genes → proteins

37 cohort genes, 37 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	5
multi_evidence	32

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX17	HGNC:18122	ENSG00000164736	Q9H6I2	Transcription factor SOX-17	gwas,gencc,clinvar
BMPR1A	HGNC:1076	ENSG00000107779	P36894	Bone morphogenetic protein receptor type-1A	gencc,clinvar
BMPR1B	HGNC:1077	ENSG00000138696	O00238	Bone morphogenetic protein receptor type-1B	gencc,clinvar
ATP13A3	HGNC:24113	ENSG00000133657	Q9H7F0	Polyamine-transporting ATPase 13A3	gencc,clinvar
FBLN2	HGNC:3601	ENSG00000163520	P98095	Fibulin-2	gencc,clinvar
GDF2	HGNC:4217	ENSG00000263761	Q9UK05	Growth/differentiation factor 2	gencc,clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	gencc,clinvar
KCNK3	HGNC:6278	ENSG00000171303	O14649	Potassium channel subfamily K member 3	gencc,clinvar
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	gencc,clinvar
BRAP	HGNC:1099	ENSG00000089234	Q7Z569	BRCA1-associated protein	gencc
BMP10	HGNC:20869	ENSG00000163217	O95393	Bone morphogenetic protein 10	gencc
TET2	HGNC:25941	ENSG00000168769	Q6N021	Methylcytosine dioxygenase TET2	gencc
PDGFD	HGNC:30620	ENSG00000170962	Q9GZP0	Platelet-derived growth factor D	gencc
KDR	HGNC:6307	ENSG00000128052	P35968	Vascular endothelial growth factor receptor 2	gencc
AQP1	HGNC:633	ENSG00000240583	P29972	Aquaporin-1	gencc
KLF2	HGNC:6347	ENSG00000127528	Q9Y5W3	Krueppel-like factor 2	gencc
KLK1	HGNC:6357	ENSG00000167748	P06870	Kallikrein-1	gencc
SMAD1	HGNC:6767	ENSG00000170365	Q15797	SMAD family member 1	gencc
BMPR2	HGNC:1078	ENSG00000204217	Q13873	Bone morphogenetic protein receptor type-2	clinvar
TBX4	HGNC:11603	ENSG00000121075	P57082	T-box transcription factor TBX4	clinvar
CBLN2	HGNC:1544	ENSG00000141668	Q8IUK8	Cerebellin-2	gwas
TOPBP1	HGNC:17008	ENSG00000163781	Q92547	DNA topoisomerase 2-binding protein 1	clinvar
ACVRL1	HGNC:175	ENSG00000139567	P37023	Activin receptor type-1-like	clinvar
PHF6	HGNC:18145	ENSG00000156531	Q8IWS0	PHD finger protein 6	clinvar
EIF2AK4	HGNC:19687	ENSG00000128829	Q9P2K8	eIF-2-alpha kinase GCN2	clinvar
ABI2	HGNC:24011	ENSG00000138443	Q9NYB9	Abl interactor 2	clinvar
DNAJC10	HGNC:24637	ENSG00000077232	Q8IXB1	Endoplasmic reticulum disulfide reductase DNAJC10	gwas
FLCN	HGNC:27310	ENSG00000154803	Q8NFG4	Folliculin	clinvar
DIPK1A	HGNC:32213	ENSG00000154511	Q5T7M9	Divergent protein kinase domain 1A	clinvar
ENG	HGNC:3349	ENSG00000106991	P17813	Endoglin	clinvar
HLA-DPA1	HGNC:4938	ENSG00000231389	P20036	HLA class II histocompatibility antigen, DP alpha 1 chain	gwas
HLA-DPB1	HGNC:4940	ENSG00000223865	P04440	HLA class II histocompatibility antigen, DP beta 1 chain	gwas
HNMT	HGNC:5028	ENSG00000150540	P50135	Histamine N-methyltransferase	clinvar
KCNA5	HGNC:6224	ENSG00000130037	P22460	Potassium voltage-gated channel subfamily A member 5	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	clinvar
PDE1A	HGNC:8774	ENSG00000115252	P54750	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1A	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX17	Transcription factor SOX-17	Acts as a transcription regulator that binds target promoter DNA.
BMPR1A	Bone morphogenetic protein receptor type-1A	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
BMPR1B	Bone morphogenetic protein receptor type-1B	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
ATP13A3	Polyamine-transporting ATPase 13A3	ATP-driven pump involved in endocytosis-dependent polyamine transport.
FBLN2	Fibulin-2	Its binding to fibronectin and some other ligands is calcium dependent.
GDF2	Growth/differentiation factor 2	Potent circulating inhibitor of angiogenesis.
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.
KCNK3	Potassium channel subfamily K member 3	K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.
BRAP	BRCA1-associated protein	Negatively regulates MAP kinase activation by limiting the formation of Raf/MEK complexes probably by inactivation of the KSR1 scaffold protein.
BMP10	Bone morphogenetic protein 10	Required for maintaining the proliferative activity of embryonic cardiomyocytes by preventing premature activation of the negative cell cycle regulator CDKN1C/p57KIP and maintaining the required expression levels of cardiogenic factors suc…
TET2	Methylcytosine dioxygenase TET2	Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation.
PDGFD	Platelet-derived growth factor D	Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis.
KDR	Vascular endothelial growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD.
AQP1	Aquaporin-1	Forms a water channel that facilitates the transport of water across cell membranes, playing a crucial role in water homeostasis in various tissues.
KLF2	Krueppel-like factor 2	Transcription factor that binds to the CACCC box in the promoter of target genes such as HBB/beta globin or NOV and activates their transcription.
KLK1	Kallikrein-1	Glandular kallikreins cleave Met-Lys and Arg-Ser bonds in kininogen to release Lys-bradykinin.
SMAD1	SMAD family member 1	Transcriptional modulator that plays a role in various cellular processes, including embryonic development, cell differentiation, and tissue homeostasis.
BMPR2	Bone morphogenetic protein receptor type-2	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.
TBX4	T-box transcription factor TBX4	Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.
CBLN2	Cerebellin-2	Acts as a synaptic organizer in specific subsets of neurons in the brain.
TOPBP1	DNA topoisomerase 2-binding protein 1	Scaffold protein that acts as a key protein-protein adapter in DNA replication and DNA repair.
ACVRL1	Activin receptor type-1-like	Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development.
PHF6	PHD finger protein 6	Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription.
EIF2AK4	eIF-2-alpha kinase GCN2	Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability.
ABI2	Abl interactor 2	Regulator of actin cytoskeleton dynamics underlying cell motility and adhesion.
DNAJC10	Endoplasmic reticulum disulfide reductase DNAJC10	Endoplasmic reticulum disulfide reductase that collaborates directly with the chaperone BIP/HSPA5 (GRP78) to maintain protein quality control by facilitating either the correct folding or the targeted degradation of misfolded proteins.
FLCN	Folliculin	Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis.
ENG	Endoglin	Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis.
HLA-DPA1	HLA class II histocompatibility antigen, DP alpha 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DPB1	HLA class II histocompatibility antigen, DP beta 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HNMT	Histamine N-methyltransferase	Inactivates histamine by N-methylation.
KCNA5	Potassium voltage-gated channel subfamily A member 5	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
PDE1A	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1A	Calcium/calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cGMP and cAMP, which are key regulators of many important physiological processes.

Protein-family classification

Druggable: 15 · Difficult: 10 · Unknown: 12 · 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
Kinase	7	5.2×	0.003
Ion channel	2	6.0×	0.217
Complement	1	7.2×	0.384
Transcription factor	7	1.6×	0.384
Transporter	1	2.1×	0.544
Antibody/Immunoglobulin	2	1.6×	0.544
Scaffold/PPI	3	1.4×	0.544
Protease	1	1.0×	0.802
Other/Unknown	12	0.6×	0.999
Enzyme (other)	1	0.3×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX17	Transcription factor	no		HMG_box_dom, Sox_C, Sox7/17/18_central
BMPR1A	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
BMPR1B	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
ATP13A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_TPase_V
FBLN2	Complement	yes		Anaphylatoxin/fibulin, EGF-type_Asp/Asn_hydroxyl_site, EGF
GDF2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
KCNK3	Ion channel	yes		2pore_dom_K_chnl_TASK, 2pore_dom_K_chnl, KCNK3
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
BRAP	Transcription factor	no		Znf_UBP, Znf_RING, BRAP2/ETP1_RRM
BMP10	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
TET2	Other/Unknown	no		2OGFeDO_JBP1/TET_oxygenase_dom, TET1/2/3, TET_oxygenase
PDGFD	Other/Unknown	no		PDGF/VEGF_dom, CUB_dom, Cystine-knot_cytokine
KDR	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
AQP1	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
KLF2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
KLK1	Protease	yes	3.4.21.35	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
SMAD1	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
BMPR2	Kinase	yes		TGFB_receptor, Activin_recp, Prot_kinase_dom
TBX4	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
CBLN2	Other/Unknown	no		C1q_dom, Tumour_necrosis_fac-like_dom, Cerebellin_Synaptic_Org
TOPBP1	Other/Unknown	no		BRCT_dom, Secretoglobin_sf, BRCT_dom_sf
ACVRL1	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
PHF6	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD
EIF2AK4	Kinase	yes		Prot_kinase_dom, RWD_dom, Ser/Thr_kinase_AS
ABI2	Scaffold/PPI	no		T_SNARE_dom, SH3_domain, Abl-interactor_HHR_dom
DNAJC10	Other/Unknown	no		DnaJ_domain, Thioredoxin_domain, Thioredoxin_CS
FLCN	Other/Unknown	no		Folliculin, Folliculin_DENN, Folliculin/SMCR8_longin
DIPK1A	Kinase	yes		FAM69_kinase_dom, FAM69_N
ENG	Other/Unknown	no		TGFBR3/Endoglin-like_N
HLA-DPA1	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DPB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
HNMT	Enzyme (other)	yes	2.1.1.8	HHMT-like, SAM-dependent_MTases_sf
KCNA5	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
PDE1A	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, HD/PDEase_dom, PDE1_N

Expression context

Cohort genes with no expression data: 0.

35 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)	1
broad (>20)	36
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	4
cardiac atrium	4
calcaneal tendon	3
secondary oocyte	3
right atrium auricular region	3
ventricular zone	3
corpus epididymis	3
right lung	3
middle temporal gyrus	3
Brodmann (1909) area 23	3
bronchial epithelial cell	2
amniotic fluid	2
right coronary artery	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
ganglionic eminence	2
cardiac muscle of right atrium	2
germinal epithelium of ovary	2
lower lobe of lung	2
visceral pleura	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX17	190	broad	marker	endothelial cell, omental fat pad, peritoneum
BMPR1A	284	ubiquitous	marker	secondary oocyte, calcaneal tendon, saphenous vein
BMPR1B	239	broad	marker	calcaneal tendon, bronchial epithelial cell, cauda epididymis
ATP13A3	291	ubiquitous	marker	decidua, secondary oocyte, amniotic fluid
FBLN2	242	ubiquitous	marker	right atrium auricular region, cardiac atrium, right coronary artery
GDF2	17	tissue_specific	yes	cervix squamous epithelium, diaphragm, skeletal muscle tissue of biceps brachii
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
KCNK3	203	broad	marker	left adrenal gland, adrenal cortex, left adrenal gland cortex
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
BRAP	286	ubiquitous	marker	left testis, right testis, testis
BMP10	90	tissue_specific	marker	cardiac muscle of right atrium, right atrium auricular region, cardiac atrium
TET2	249	ubiquitous	marker	palpebral conjunctiva, amniotic fluid, epithelium of nasopharynx
PDGFD	252	ubiquitous	marker	periodontal ligament, germinal epithelium of ovary, seminal vesicle
KDR	267	broad	marker	germinal epithelium of ovary, lower lobe of lung, parietal pleura
AQP1	283	broad	marker	descending thoracic aorta, ascending aorta, thoracic aorta
KLF2	278	ubiquitous	marker	urethra, vena cava, trachea
KLK1	176	broad	marker	body of pancreas, pancreas, mucosa of transverse colon
SMAD1	297	ubiquitous	marker	secondary oocyte, nipple, corpus epididymis
BMPR2	271	ubiquitous	marker	visceral pleura, lower lobe of lung, tendon of biceps brachii
TBX4	116	tissue_specific	yes	right lung, upper lobe of left lung, upper lobe of lung
CBLN2	164	tissue_specific	marker	superior frontal gyrus, endothelial cell, middle temporal gyrus
TOPBP1	291	ubiquitous	marker	sperm, ventricular zone, ganglionic eminence
ACVRL1	221	broad	marker	right lung, upper lobe of left lung, upper lobe of lung
PHF6	254	ubiquitous	marker	corpus epididymis, oocyte, endothelial cell
EIF2AK4	258	ubiquitous	marker	adenohypophysis, pituitary gland, bone marrow cell
ABI2	286	ubiquitous	marker	Brodmann (1909) area 23, entorhinal cortex, middle temporal gyrus
DNAJC10	287	ubiquitous	marker	corpus epididymis, right uterine tube, bronchial epithelial cell
FLCN	261	ubiquitous	marker	buccal mucosa cell, right hemisphere of cerebellum, cerebellar hemisphere
DIPK1A	275	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ENG	265	ubiquitous	marker	right lung, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 38.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
SMAD4	7,320
DNAJC10	6,825
TOPBP1	5,342
KDR	4,960
NOTCH3	4,403
AQP1	4,259
BMPR1A	3,316
ENG	3,236
EIF2AK4	3,193

Intra-cohort edges

A	B	Sources
ACVRL1	ATP13A3	string_interaction
ACVRL1	BMP10	string_interaction
ACVRL1	BMPR2	string_interaction
ACVRL1	ENG	intact, string_interaction
ACVRL1	GDF2	biogrid_interaction, intact, string_interaction
ACVRL1	KCNK3	string_interaction
ACVRL1	SMAD1	biogrid_interaction
ACVRL1	SMAD4	string_interaction
ACVRL1	TBX4	string_interaction
AQP1	ATP13A3	string_interaction
ATP13A3	BMPR2	string_interaction
ATP13A3	EIF2AK4	string_interaction
ATP13A3	GDF2	string_interaction
ATP13A3	KCNA5	string_interaction
ATP13A3	KCNK3	string_interaction
ATP13A3	SOX17	string_interaction
ATP13A3	TBX4	string_interaction
BMP10	BMPR1A	string_interaction
BMP10	BMPR2	string_interaction
BMP10	ENG	string_interaction
BMPR1A	BMPR2	string_interaction
BMPR1A	GDF2	string_interaction
BMPR1A	SMAD1	string_interaction
BMPR1A	SMAD4	string_interaction
BMPR2	CBLN2	string_interaction
BMPR2	ENG	string_interaction
BMPR2	GDF2	string_interaction
BMPR2	KCNK3	string_interaction
BMPR2	TBX4	string_interaction
CBLN2	KCNK3	string_interaction
CBLN2	TBX4	string_interaction
ENG	GDF2	biogrid_interaction, intact, string_interaction
GDF2	SMAD4	string_interaction
HLA-DPA1	HLA-DPB1	intact
KCNA5	KCNK3	string_interaction
KCNK3	TBX4	string_interaction
KDR	PDGFD	string_interaction
SMAD1	SMAD4	biogrid_interaction, intact, string_interaction

Structural data

PDB: 26 · AlphaFold-only: 11 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KDR	P35968	54
NOTCH1	P46531	29
GDF2	Q9UK05	20
TOPBP1	Q92547	16
SMAD4	Q13485	12
BMPR1A	P36894	11
AQP1	P29972	10
SMAD1	Q15797	10
HLA-DPA1	P20036	10
HLA-DPB1	P04440	10
ABCC8	Q09428	8
BMP10	O95393	8
EIF2AK4	Q9P2K8	8
BMPR2	Q13873	7
ACVRL1	P37023	7
HNMT	P50135	7
TET2	Q6N021	6
ABI2	Q9NYB9	6
NOTCH3	Q9UM47	6
KCNK3	O14649	4
FLCN	Q8NFG4	4
ENG	P17813	3
SOX17	Q9H6I2	2
KLK1	P06870	2
PHF6	Q8IWS0	2
BMPR1B	O00238	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC10	Q8IXB1	89.42
DIPK1A	Q5T7M9	83.20
PDE1A	P54750	81.12
ATP13A3	Q9H7F0	77.96
CBLN2	Q8IUK8	77.19
BRAP	Q7Z569	76.92
PDGFD	Q9GZP0	73.85
KCNA5	P22460	72.64
FBLN2	P98095	67.85
TBX4	P57082	60.96
KLF2	Q9Y5W3	57.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 172. Enrichment computed across 37 evidence-associated genes (31 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 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by BMP	8	92.1×	2e-12	BMPR1A, BMPR1B, GDF2, SMAD4, BMPR2, ACVRL1, BMP10, SMAD1
Signaling by TGFB family members	7	26.1×	6e-07	BMPR1A, BMPR1B, SMAD4, BMPR2, ACVRL1, BMP10, SMAD1
Defective LFNG causes SCDO3	2	147.3×	0.004	NOTCH1, NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	2	122.8×	0.005	NOTCH1, NOTCH3
Transcriptional regulation of brown and beige adipocyte differentiation	2	73.7×	0.011	SMAD4, SMAD1
Specification of primordial germ cells	2	56.7×	0.013	SOX17, TET2
Signal Transduction	10	3.3×	0.013	SOX17, BMPR1A, BMPR1B, SMAD4, BMPR2, BRAP, ACVRL1, BMP10 (+2 more)
RUNX2 regulates bone development	2	52.6×	0.014	SMAD4, SMAD1
Formation of definitive endoderm	2	46.0×	0.016	SOX17, SMAD4
Pre-NOTCH Processing in Golgi	2	40.9×	0.017	NOTCH1, NOTCH3
Translocation of ZAP-70 to Immunological synapse	2	40.9×	0.017	HLA-DPA1, HLA-DPB1
Phosphorylation of CD3 and TCR zeta chains	2	35.1×	0.020	HLA-DPA1, HLA-DPB1
Co-inhibition by PD-1	2	33.5×	0.020	HLA-DPA1, HLA-DPB1
Potassium Channels	3	13.0×	0.020	ABCC8, KCNK3, KCNA5
NOTCH3 Intracellular Domain Regulates Transcription	2	28.3×	0.026	NOTCH1, NOTCH3
Cardiogenesis	2	27.3×	0.026	SMAD4, SMAD1
Notch-HLH transcription pathway	2	26.3×	0.026	NOTCH1, NOTCH3
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	2	24.6×	0.028	SMAD4, SMAD1
Generation of second messenger molecules	2	22.3×	0.032	HLA-DPA1, HLA-DPB1
Molecules associated with elastic fibres	2	19.9×	0.039	FBLN2, BMP10
Developmental Lineage of Pancreatic Acinar Cells	2	19.4×	0.039	SOX17, KLK1
TWIK-releated acid-sensitive K+ channel (TASK)	1	184.2×	0.041	KCNK3
Defective ABCC8 can cause hypo- and hyper-glycemias	1	184.2×	0.041	ABCC8
Gastrulation	2	16.7×	0.045	SOX17, SMAD4
Transcriptional regulation by RUNX2	2	16.4×	0.045	SMAD4, SMAD1
Loss of Function of SMAD4 in Cancer	1	122.8×	0.050	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	122.8×	0.050	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	122.8×	0.050	SMAD4
Developmental Cell Lineages	2	14.4×	0.050	SOX17, KLK1
Cam-PDE 1 activation	1	92.1×	0.056	PDE1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 36 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
BMP signaling pathway	9	50.1×	7e-11	BMPR1A, BMPR1B, GDF2, SMAD4, BMPR2, ACVRL1, BMP10, ENG (+1 more)
positive regulation of SMAD protein signal transduction	7	74.5×	1e-09	BMPR1A, GDF2, SMAD4, BMPR2, ACVRL1, BMP10, ENG
cellular response to BMP stimulus	6	93.6×	8e-09	BMPR1A, BMPR1B, GDF2, SMAD4, BMPR2, ACVRL1
positive regulation of cartilage development	5	130.0×	5e-08	BMPR1B, GDF2, BMPR2, BMP10, SMAD1
positive regulation of BMP signaling pathway	5	63.3×	2e-06	GDF2, ACVRL1, ENG, KDR, NOTCH1
endocardial cushion morphogenesis	4	93.6×	9e-06	BMPR1A, ACVRL1, ENG, NOTCH1
transforming growth factor beta receptor signaling pathway	6	26.5×	9e-06	BMPR1A, SMAD4, ACVRL1, FLCN, ENG, SMAD1
endocardial cell differentiation	3	234.1×	1e-05	SOX17, SMAD4, NOTCH1
negative regulation of cell growth	6	24.0×	1e-05	SOX17, GDF2, SMAD4, BMPR2, ACVRL1, BMP10
positive regulation of transcription by RNA polymerase II	13	5.4×	2e-05	SOX17, BMPR1A, BMPR1B, GDF2, SMAD4, BMPR2, ACVRL1, TET2 (+5 more)
osteoblast differentiation	6	20.2×	3e-05	BMPR1A, BMPR1B, GDF2, SMAD4, BMPR2, SMAD1
dorsal aorta morphogenesis	3	175.5×	3e-05	BMPR1A, ACVRL1, ENG
negative regulation of muscle cell differentiation	3	140.4×	6e-05	BMPR1A, BMPR2, SMAD1
positive regulation of endothelial cell differentiation	3	127.7×	6e-05	GDF2, ACVRL1, NOTCH1
ventricular septum morphogenesis	4	48.0×	6e-05	BMPR1A, SMAD4, BMPR2, NOTCH1
angiogenesis	7	12.1×	6e-05	SOX17, BMPR1A, GDF2, BMPR2, TBX4, ACVRL1, KDR
epithelial to mesenchymal transition involved in endocardial cushion formation	3	117.0×	8e-05	SMAD4, ENG, NOTCH1
positive regulation of gene expression	8	8.6×	1e-04	SOX17, BMPR1A, BMPR1B, SMAD4, BMPR2, BMP10, SMAD1, NOTCH1
MAPK cascade	5	21.3×	1e-04	BMPR1A, BMPR1B, BMPR2, BRAP, SMAD1
negative regulation of cardiac muscle hypertrophy	3	93.6×	1e-04	SMAD4, BMP10, NOTCH1
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	2	468.1×	1e-04	BMPR2, NOTCH1
cardiac conduction system development	3	87.8×	1e-04	BMPR1A, SMAD4, SMAD1
ventricular trabecula myocardium morphogenesis	3	87.8×	1e-04	BMPR1A, ENG, NOTCH1
cellular response to growth factor stimulus	4	35.3×	1e-04	BMPR1A, BMPR1B, BMPR2, ACVRL1
epithelial cell proliferation	4	34.7×	1e-04	BMPR1A, FLCN, KDR, NOTCH1
outflow tract morphogenesis	4	34.0×	2e-04	SOX17, BMPR1A, BMPR2, NOTCH1
positive regulation of miRNA transcription	4	32.3×	2e-04	BMPR1A, SMAD4, SMAD1, NOTCH3
activin receptor signaling pathway	3	73.9×	2e-04	GDF2, SMAD4, BMP10
in utero embryonic development	6	12.0×	2e-04	BMPR1A, SMAD4, ACVRL1, FLCN, KLF2, NOTCH1
vasculogenesis	4	28.4×	3e-04	SOX17, GDF2, ENG, KDR

Therapeutics

Drugs indicated for this disease

10 approved, 12 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Ambrisentan	Approved (phase 4)
Bosentan	Approved (phase 4)
Iloprost	Approved (phase 4)
Macitentan	Approved (phase 4)
Nitric Oxide	Approved (phase 4)
Riociguat	Approved (phase 4)
Selexipag	Approved (phase 4)
Sotatercept	Approved (phase 4)
Tadalafil	Approved (phase 4)
Treprostinil	Approved (phase 4)
AV-101	Phase 3 (in late-stage trials)
Albuterol	Phase 3 (in late-stage trials)
Bardoxolone Methyl	Phase 3 (in late-stage trials)
Epoprostenol	Phase 3 (in late-stage trials)
Esuberaprost	Phase 3 (in late-stage trials)
Imatinib	Phase 3 (in late-stage trials)
Oxygen	Phase 3 (in late-stage trials)
Ralinepag	Phase 3 (in late-stage trials)
Seralutinib	Phase 3 (in late-stage trials)
Sildenafil	Phase 3 (in late-stage trials)
Sitaxentan	Phase 3 (in late-stage trials)
Udenafil	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetazolamide, Anastrozole, Apabetalone, Aspirin, Atorvastatin, Capsaicin, Carvedilol, Clopidogrel, Dapagliflozin, Fluoxetine, Fulvestrant, Iron Sucrose, Metformin, Nilotinib, Pioglitazone, Satralizumab, Selonsertib, Simvastatin, Sodium Chloride, Spironolactone, Tacrolimus Anhydrous, Tezosentan, Tocilizumab, Trimetazidine, Warfarin.

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 12 · Phased (≥1): 15 · Undrugged: 22

Druggability breadth: 25 of 37 evidence-associated genes (68%) 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
BMPR1A	MOMELOTINIB
BMPR1B	MOMELOTINIB
ABCC8	REPAGLINIDE
KCNK3	ROPIVACAINE
TET2	VADADUSTAT
KDR	VANDETANIB
BMPR2	FEDRATINIB
ACVRL1	FEDRATINIB
EIF2AK4	FEDRATINIB
KCNA5	DRONEDARONE HYDROCHLORIDE
PDE1A	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDR	172	4
BMPR1B	28	4
BMPR2	19	4
EIF2AK4	19	4
PDE1A	17	4
BMPR1A	11	4
ACVRL1	11	4
KCNA5	8	4
ABCC8	6	4
KCNK3	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1A, BMPR1B
GILTERITINIB	4	BMPR1A, BMPR1B
DASATINIB	4	ACVRL1, BMPR1A, BMPR1B, EIF2AK4, KDR
FEDRATINIB	4	ACVRL1, BMPR1B, BMPR2, EIF2AK4, KDR
AXITINIB	4	BMPR1B, KDR
RUXOLITINIB	4	BMPR1B, BMPR2
VANDETANIB	4	ACVRL1, BMPR1B, KDR
PAZOPANIB	4	BMPR1B, KDR
SUNITINIB	4	BMPR1B, BMPR2, EIF2AK4, KDR
QUIZARTINIB	4	BMPR1B, KDR
CRIZOTINIB	4	BMPR1B, KDR
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
ROPIVACAINE	4	KCNK3
BUPIVACAINE	4	KCNK3
ETIDOCAINE	4	KCNK3
MEXILETINE	4	KCNK3
PROPAFENONE	4	KCNK3
VADADUSTAT	4	TET2
PANOBINOSTAT	4	TET2
DEFEROXAMINE	4	TET2
ERLOTINIB	4	EIF2AK4, KDR
INDIGOTINDISULFONATE	4	KDR
PONATINIB	4	KDR
SORAFENIB TOSYLATE	4	KDR
PHENYL AMINOSALICYLATE	4	KDR
VEMURAFENIB	4	KDR
TIVOZANIB	4	KDR
LENVATINIB	4	KDR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
KDR	2,687	Binding:2594, Functional:64, ADMET:27, Toxicity:2
PDE1A	215	Binding:203, ADMET:7, Functional:5
ACVRL1	213	Binding:207, Functional:3, Toxicity:2, ADMET:1
EIF2AK4	170	Binding:170
BMPR1A	169	Binding:166, ADMET:3
BMPR1B	166	Binding:164, ADMET:2
BMPR2	166	Binding:165, ADMET:1
KCNA5	152	Binding:130, Functional:14, ADMET:5, Toxicity:3
KLK1	111	Binding:108, ADMET:3
ABCC8	84	Functional:52, Binding:32
KCNK3	39	Binding:38, Functional:1
TET2	24	Binding:24
NOTCH1	23	Binding:19, ADMET:4
HNMT	9	Binding:7, ADMET:2
AQP1	8	Binding:8
DNAJC10	7	Binding:7
SMAD4	6	Binding:6
GDF2	4	Binding:4
PHF6	4	Binding:4
TOPBP1	3	Binding:3
NOTCH3	3	Binding:3
BRAP	2	Binding:2
SOX17	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1A	2.7.10.2	non-specific protein-tyrosine kinase
BMPR1B	2.7.10.2	non-specific protein-tyrosine kinase
KDR	2.7.10.1	receptor protein-tyrosine kinase
KLK1	3.4.21.35	tissue kallikrein
ACVRL1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
HNMT	2.1.1.8	histamine N-methyltransferase
PDE1A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BMPR1A	169
BMPR1B	166
KDR	2,687
KLK1	111
BMPR2	166
ACVRL1	213
EIF2AK4	170
KCNA5	152
PDE1A	215

Pharmacogenomics

Cohort genes with a PharmGKB record: 37; 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)
MOMELOTINIB	4	BMPR1A, BMPR1B
GILTERITINIB	4	BMPR1A, BMPR1B
DASATINIB	4	ACVRL1, BMPR1A, BMPR1B, EIF2AK4, KDR
FEDRATINIB	4	ACVRL1, BMPR1B, BMPR2, EIF2AK4, KDR
AXITINIB	4	BMPR1B, KDR
RUXOLITINIB	4	BMPR1B, BMPR2
VANDETANIB	4	ACVRL1, BMPR1B, KDR
PAZOPANIB	4	BMPR1B, KDR
SUNITINIB	4	BMPR1B, BMPR2, EIF2AK4, KDR
QUIZARTINIB	4	BMPR1B, KDR
CRIZOTINIB	4	BMPR1B, KDR
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
ROPIVACAINE	4	KCNK3
BUPIVACAINE	4	KCNK3
ETIDOCAINE	4	KCNK3
MEXILETINE	4	KCNK3
PROPAFENONE	4	KCNK3
VADADUSTAT	4	TET2
PANOBINOSTAT	4	TET2
DEFEROXAMINE	4	TET2
ERLOTINIB	4	EIF2AK4, KDR
INDIGOTINDISULFONATE	4	KDR
PONATINIB	4	KDR
SORAFENIB TOSYLATE	4	KDR
PHENYL AMINOSALICYLATE	4	KDR
VEMURAFENIB	4	KDR
TIVOZANIB	4	KDR
LENVATINIB	4	KDR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	BMPR1A, BMPR1B, ABCC8, KCNK3, TET2, KDR, BMPR2, ACVRL1, EIF2AK4, KCNA5 (+1 more)
B	Phased (≥1) drug, not yet approved	4	KLK1, DNAJC10, NOTCH1, NOTCH3
C	Druggable family + PDB, no drug	3	HLA-DPA1, HLA-DPB1, HNMT
D	Druggable family + AlphaFold only, no drug	2	FBLN2, DIPK1A
E	Difficult family or no structure, no drug	17	SOX17, ATP13A3, GDF2, SMAD4, BRAP, BMP10, PDGFD, AQP1, KLF2, SMAD1 (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP13A3	0	KCNK3
GDF2	4	ACVRL1, BMPR2
BMP10	0	ACVRL1, BMPR2
CBLN2	0	KCNK3
ENG	0	ACVRL1
SOX17	1	—
FBLN2	0	—
SMAD4	6	—
BRAP	2	—
PDGFD	0	—
AQP1	8	—
KLF2	0	—
SMAD1	0	—
TBX4	0	—
TOPBP1	3	—
PHF6	4	—
ABI2	0	—
FLCN	0	—
DIPK1A	0	—
HLA-DPA1	0	—
HLA-DPB1	0	—
HNMT	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 577.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	252
PHASE2	100
PHASE3	82
PHASE1	66
PHASE4	54
PHASE1/PHASE2	10
PHASE2/PHASE3	8
EARLY_PHASE1	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05203510	PHASE4	ACTIVE_NOT_RECRUITING	A Study of a Mean Pulmonary Artery Pressure-Targeted Approach With Early and Rapid Treprostinil Therapy to Reverse Right Ventricular Remodeling in Participants With Pulmonary Arterial Hypertension
NCT05825417	PHASE4	RECRUITING	Pulmonary Hypertension: Intensification and Personalisation of Combination Rx
NCT06025916	PHASE4	RECRUITING	Postpartum Hemorrhage Reduction With Oral Tranexamic Acid: a Clinical Trial
NCT06317805	PHASE4	RECRUITING	Initial Triple Therapy Including Parenteral Treprostinil vs Initial Double Oral Therapy in PAH Group I Patients
NCT06658522	PHASE4	RECRUITING	Right Ventricular Compensation With Sotatercept: A Prospective Single Arm Open Label Phase 4 Study to Evaluate the Effects of Sotatercept on Right Ventricular Function in Pulmonary Arterial Hypertension (RECOMPENSE)
NCT06671990	PHASE4	NOT_YET_RECRUITING	The CardioMEMS Vericiguat Heart Failure Trial
NCT07600723	PHASE4	NOT_YET_RECRUITING	A Study of Sotatercept (MK-7962) in People With Pulmonary Arterial Hypertension (PAH) in India (MK-7962-037)
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TREPROSTINIL	4	52
SILDENAFIL	4	45
MACITENTAN	4	19
BOSENTAN	4	17
SOTATERCEPT	4	15
AMBRISENTAN	4	14
IMATINIB	4	13
SITAXENTAN	4	11
SELEXIPAG	4	10
ILOPROST	4	8
TADALAFIL	4	8
FLUOXETINE	4	4
CARVEDILOL	4	3
EPOPROSTENOL	4	3
RIOCIGUAT	4	3
VARDENAFIL	4	3
NITRIC OXIDE	4	2
RANOLAZINE	4	2
ANAKINRA	4	1
ARTESUNATE	4	1
CAPSAICIN	4	1
DILTIAZEM HYDROCHLORIDE	4	1
DOBUTAMINE	4	1
EPINEPHRINE	4	1
FAMOTIDINE	4	1
FERRIC CARBOXYMALTOSE	4	1
LEVOCARNITINE	4	1
LIDOCAINE	4	1
MORPHINE SULFATE	4	1
NILOTINIB	4	1