Pulmonary hypertension, primary, 1

Summary

Pulmonary hypertension, primary, 1 (MONDO:0024533) is a disease caused by BMPR2 (GenCC Definitive), with 9 cohort genes. The dominant Reactome pathway is Signaling by BMP (4 cohort genes).

At a glance

• Causal gene: BMPR2 (GenCC Definitive)
• Cohort genes: 9
• ClinVar variants: 789

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary hypertension, primary, 1
Mondo ID	MONDO:0024533
OMIM	178600
UMLS	C4552070
MedGen	1643124
GARD	0025415
Is cancer (heuristic)	no

Also known as: BMPR2 primary pulmonary hypertension · PHT · PPH1 · primary pulmonary hypertension caused by mutation in BMPR2 · pulmonary hypertension, familial primary, 1, with or without HHT · pulmonary hypertension, primary, 1 · pulmonary hypertension, primary, fenfluramine or dexfenfluramine-associated

Data availability: 789 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › heritable pulmonary arterial hypertension › pulmonary hypertension, primary, 1

Related subtypes (6): pulmonary hypertension, primary, 5, pulmonary hypertension, primary, 2, pulmonary hypertension, primary, 3, pulmonary hypertension, primary, 4, pulmonary hypertension, primary, 6, pulmonary hypertension, primary, 7

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

266 pathogenic, 160 uncertain significance, 39 likely pathogenic, 38 benign, 34 conflicting classifications of pathogenicity, 24 not provided, 20 likely benign, 11 pathogenic/likely pathogenic, 8 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
212804	NM_000020.3(ACVRL1):c.430C>T (p.Arg144Ter)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330302	NM_001204.7(BMPR2):c.1519_1520insAT (p.Ile507fs)	BMPR2	Pathogenic	criteria provided, single submitter
1706628	NM_001204.7(BMPR2):c.1169del (p.Gly390fs)	BMPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212811	NM_001204.7(BMPR2):c.1128+1G>A	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
212813	NM_001204.7(BMPR2):c.1426_1450del (p.Leu476fs)	BMPR2	Pathogenic	criteria provided, single submitter
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
238628	NM_001204.7(BMPR2):c.1125_1128+16del	BMPR2	Pathogenic	criteria provided, single submitter
264650	NM_001204.7(BMPR2):c.16C>T (p.Gln6Ter)	BMPR2	Pathogenic	no assertion criteria provided
264651	NM_001204.7(BMPR2):c.1277-10_1277-9insGGG	BMPR2	Pathogenic	no assertion criteria provided
264652	NM_001204.7(BMPR2):c.1443_1445del (p.Glu481del)	BMPR2	Pathogenic	no assertion criteria provided
264653	NM_001204.7(BMPR2):c.1469C>T (p.Ala490Val)	BMPR2	Pathogenic	criteria provided, single submitter
264655	NM_001204.7(BMPR2):c.174_175dup (p.Leu59fs)	BMPR2	Pathogenic	no assertion criteria provided
265619	NM_001204.7(BMPR2):c.1789C>T (p.Arg597Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
280019	NM_001204.7(BMPR2):c.637C>T (p.Arg213Ter)	BMPR2	Pathogenic	criteria provided, multiple submitters, no conflicts
3242570	NM_001204.7(BMPR2):c.663del (p.Leu222fs)	BMPR2	Pathogenic	criteria provided, single submitter
3256711	NC_000002.12:g.202467519del	BMPR2	Pathogenic	criteria provided, single submitter
3383090	NM_001204.7(BMPR2):c.845_852delinsTCTTCATAGA (p.Tyr282fs)	BMPR2	Pathogenic	criteria provided, single submitter
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
409829	NM_001204.7(BMPR2):c.968-5A>G	BMPR2	Pathogenic	reviewed by expert panel
417478	NM_001204.6(BMPR2):c.77-?_418+?del	BMPR2	Pathogenic	criteria provided, single submitter
425667	NC_000002.12:g.202249539_202474756del225218	BMPR2	Pathogenic	no assertion criteria provided
425668	NM_001204.7(BMPR2):c.-947_-946delinsAT	BMPR2	Pathogenic	no assertion criteria provided
425669	NM_001204.6(BMPR2):c.(?-540)(76+1_77-1)del	BMPR2	Pathogenic	no assertion criteria provided
425670	NM_001204.6(BMPR2):c.(?-540)(*1_?)del	BMPR2	Pathogenic	no assertion criteria provided
425671	NM_001204.6(BMPR2):c.(?-1)(76+1_77-1)del	BMPR2	Pathogenic	no assertion criteria provided
425672	NM_001204.6(BMPR2):c.(?-1)(418+1_419-1)del	BMPR2	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 24 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
BMPR2	Definitive	Autosomal dominant	pulmonary hypertension, primary, 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
ENG	Orphanet:231160	Familial cerebral saccular aneurysm
ENG	Orphanet:275777	Heritable pulmonary arterial hypertension
ENG	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
ENG	Orphanet:774	Hereditary hemorrhagic telangiectasia
KCNA5	Orphanet:334	Hereditary atrial fibrillation
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
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMPR2	HGNC:1078	ENSG00000204217	Q13873	Bone morphogenetic protein receptor type-2	gencc,clinvar
TBX4	HGNC:11603	ENSG00000121075	P57082	T-box transcription factor TBX4	clinvar
ACVRL1	HGNC:175	ENSG00000139567	P37023	Activin receptor type-1-like	clinvar
ENG	HGNC:3349	ENSG00000106991	P17813	Endoglin	clinvar
KCNA5	HGNC:6224	ENSG00000130037	P22460	Potassium voltage-gated channel subfamily A member 5	clinvar
KCNK3	HGNC:6278	ENSG00000171303	O14649	Potassium channel subfamily K member 3	clinvar
SMAD1	HGNC:6767	ENSG00000170365	Q15797	SMAD family member 1	clinvar
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	clinvar
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.
ENG	Endoglin	Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis.
KCNA5	Potassium voltage-gated channel subfamily A member 5	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.
KCNK3	Potassium channel subfamily K member 3	K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.
SMAD1	SMAD family member 1	Transcriptional modulator that plays a role in various cellular processes, including embryonic development, cell differentiation, and tissue homeostasis.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

Protein-family classification

Druggable: 5 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.56

Family distribution

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

Family	Genes	Fold	FDR
Ion channel	2	24.8×	0.014
Kinase	2	6.2×	0.099
Enzyme (other)	1	1.3×	0.859
Transcription factor	1	0.9×	0.859
Other/Unknown	3	0.6×	0.955

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
ACVRL1	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ENG	Other/Unknown	no		TGFBR3/Endoglin-like_N
KCNA5	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
KCNK3	Ion channel	yes		2pore_dom_K_chnl_TASK, 2pore_dom_K_chnl, KCNK3
SMAD1	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra

Expression context

Cohort genes with no expression data: 0.

8 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	3
upper lobe of left lung	2
upper lobe of lung	2
cardiac atrium	2
lower lobe of lung	1
tendon of biceps brachii	1
visceral pleura	1
right atrium auricular region	1
blood vessel layer	1
cardiac muscle of right atrium	1
adrenal cortex	1
left adrenal gland	1
left adrenal gland cortex	1
corpus epididymis	1
nipple	1
secondary oocyte	1
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
gall bladder	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
ACVRL1	221	broad	marker	right lung, upper lobe of left lung, upper lobe of lung
ENG	265	ubiquitous	marker	right lung, right atrium auricular region, cardiac atrium
KCNA5	179	broad	marker	cardiac muscle of right atrium, blood vessel layer, cardiac atrium
KCNK3	203	broad	marker	left adrenal gland, adrenal cortex, left adrenal gland cortex
SMAD1	297	ubiquitous	marker	secondary oocyte, nipple, corpus epididymis
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
PAH	175	broad	marker	right lobe of liver, liver, gall bladder

Protein interactions among cohort

Intra-cohort edges: 12.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD4	7,320
ENG	3,236
BMPR2	3,152
KCNA5	2,288
ACVRL1	2,234
PAH	1,953
SMAD1	1,398
TBX4	1,054
KCNK3	934

Intra-cohort edges

A	B	Sources
ACVRL1	BMPR2	string_interaction
ACVRL1	ENG	intact, string_interaction
ACVRL1	KCNK3	string_interaction
ACVRL1	SMAD1	biogrid_interaction
ACVRL1	SMAD4	string_interaction
ACVRL1	TBX4	string_interaction
BMPR2	ENG	string_interaction
BMPR2	KCNK3	string_interaction
BMPR2	TBX4	string_interaction
KCNA5	KCNK3	string_interaction
KCNK3	TBX4	string_interaction
SMAD1	SMAD4	biogrid_interaction, intact, string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAH	P00439	20
SMAD4	Q13485	12
SMAD1	Q15797	10
BMPR2	Q13873	7
ACVRL1	P37023	7
KCNK3	O14649	4
ENG	P17813	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNA5	P22460	72.64
TBX4	P57082	60.96

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 9 evidence-associated genes (7 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 7 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	4	203.9×	1e-07	BMPR2, ACVRL1, SMAD1, SMAD4
Signaling by TGFB family members	4	65.9×	5e-06	BMPR2, ACVRL1, SMAD1, SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation	2	326.3×	3e-04	SMAD1, SMAD4
RUNX2 regulates bone development	2	233.1×	4e-04	SMAD1, SMAD4
Cardiogenesis	2	120.8×	0.001	SMAD1, SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	2	108.8×	0.001	SMAD1, SMAD4
Transcriptional regulation by RUNX2	2	72.5×	0.003	SMAD1, SMAD4
Phenylketonuria	1	1631.4×	0.005	PAH
Adipogenesis	2	44.7×	0.006	SMAD1, SMAD4
TWIK-releated acid-sensitive K+ channel (TASK)	1	815.7×	0.007	KCNK3
Potassium Channels	2	38.4×	0.007	KCNA5, KCNK3
Deubiquitination	2	35.5×	0.007	SMAD1, SMAD4
Loss of Function of SMAD4 in Cancer	1	543.8×	0.007	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	543.8×	0.007	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	543.8×	0.007	SMAD4
Cardiac conduction	2	31.1×	0.007	KCNA5, KCNK3
Signal Transduction	4	5.8×	0.009	BMPR2, ACVRL1, SMAD1, SMAD4
RUNX3 regulates BCL2L11 (BIM) transcription	1	326.3×	0.010	SMAD4
Loss of Function of SMAD2/3 in Cancer	1	271.9×	0.010	SMAD4
Signaling by TGF-beta Receptor Complex in Cancer	1	271.9×	0.010	SMAD4
Phenylalanine metabolism	1	271.9×	0.010	PAH
Muscle contraction	2	22.1×	0.010	KCNA5, KCNK3
RUNX3 regulates CDKN1A transcription	1	233.1×	0.011	SMAD4
Phase 3 - rapid repolarisation	1	163.1×	0.015	KCNA5
Ub-specific processing proteases	2	15.2×	0.017	SMAD1, SMAD4
Tandem pore domain potassium channels	1	135.9×	0.017	KCNK3
Signaling by Activin	1	108.8×	0.019	SMAD4
Formation of definitive endoderm	1	102.0×	0.019	SMAD4
FOXO-mediated transcription of cell cycle genes	1	96.0×	0.019	SMAD4
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	96.0×	0.019	SMAD4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 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	5	111.5×	8e-08	BMPR2, ACVRL1, ENG, SMAD1, SMAD4
positive regulation of SMAD protein signal transduction	4	170.2×	6e-07	BMPR2, ACVRL1, ENG, SMAD4
transforming growth factor beta receptor signaling pathway	4	70.7×	1e-05	ACVRL1, ENG, SMAD1, SMAD4
cellular response to BMP stimulus	3	187.2×	3e-05	BMPR2, ACVRL1, SMAD4
venous blood vessel development	2	749.0×	1e-04	BMPR2, ACVRL1
lymphatic endothelial cell differentiation	2	535.0×	2e-04	BMPR2, ACVRL1
dorsal aorta morphogenesis	2	468.1×	2e-04	ACVRL1, ENG
negative regulation of muscle cell differentiation	2	374.5×	3e-04	BMPR2, SMAD1
retina vasculature development in camera-type eye	2	374.5×	3e-04	BMPR2, ACVRL1
epithelial to mesenchymal transition involved in endocardial cushion formation	2	312.1×	4e-04	ENG, SMAD4
artery development	2	312.1×	4e-04	BMPR2, ACVRL1
negative regulation of cytosolic calcium ion concentration	2	288.1×	4e-04	KCNA5, KCNK3
lymphangiogenesis	2	267.5×	4e-04	BMPR2, ACVRL1
negative regulation of cell growth	3	48.0×	5e-04	BMPR2, ACVRL1, SMAD4
cardiac conduction system development	2	234.1×	5e-04	SMAD1, SMAD4
positive regulation of cartilage development	2	208.1×	6e-04	BMPR2, SMAD1
osteoblast differentiation	3	40.4×	6e-04	BMPR2, SMAD1, SMAD4
endocardial cushion morphogenesis	2	187.2×	7e-04	ACVRL1, ENG
SMAD protein signal transduction	2	162.8×	8e-04	SMAD1, SMAD4
outflow tract septum morphogenesis	2	144.0×	0.001	ENG, SMAD4
response to hypoxia	3	31.9×	0.001	ENG, KCNA5, SMAD4
negative regulation of endothelial cell proliferation	2	120.8×	0.001	ACVRL1, ENG
cell fate specification	2	117.0×	0.001	BMPR2, TBX4
positive regulation of transcription by RNA polymerase II	5	8.3×	0.001	BMPR2, ACVRL1, ENG, SMAD1, SMAD4
cell differentiation	4	12.9×	0.001	BMPR2, ACVRL1, SMAD1, SMAD4
positive regulation of BMP signaling pathway	2	101.2×	0.002	ACVRL1, ENG
ventricular septum morphogenesis	2	96.0×	0.002	BMPR2, SMAD4
blood vessel remodeling	2	85.1×	0.002	BMPR2, ACVRL1
angiogenesis	3	20.8×	0.003	BMPR2, TBX4, ACVRL1
cellular response to growth factor stimulus	2	70.7×	0.003	BMPR2, ACVRL1

Therapeutics

Drug target analysis

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

Druggability breadth: 7 of 9 evidence-associated genes (78%) 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
BMPR2	FEDRATINIB
ACVRL1	FEDRATINIB
KCNA5	DRONEDARONE HYDROCHLORIDE
KCNK3	ROPIVACAINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMPR2	19	4
ACVRL1	11	4
KCNA5	8	4
KCNK3	6	4
TBX4	0	0
ENG	0	0
SMAD1	0	0
SMAD4	0	0
PAH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	ACVRL1, BMPR2
RUXOLITINIB	4	BMPR2
BOSUTINIB	4	BMPR2
DEUCRAVACITINIB	4	BMPR2
NINTEDANIB	4	ACVRL1, BMPR2
SUNITINIB	4	BMPR2
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
DASATINIB	4	ACVRL1
DRONEDARONE HYDROCHLORIDE	4	KCNA5
SERTINDOLE	4	KCNA5
QUINIDINE	4	KCNA5
NIFEDIPINE	4	KCNA5
VERNAKALANT HYDROCHLORIDE	4	KCNA5
FLECAINIDE	4	KCNA5
ROPIVACAINE	4	KCNK3
BUPIVACAINE	4	KCNK3
ETIDOCAINE	4	KCNK3
MEXILETINE	4	KCNK3
PROPAFENONE	4	KCNK3
LINIFANIB	3	BMPR2
ORANTINIB	3	BMPR2
DOVITINIB	3	BMPR2
LESTAURTINIB	3	ACVRL1, BMPR2
ALVOCIDIB	3	ACVRL1
SILMITASERTIB	2	BMPR2
SU-014813	2	BMPR2
OSI-027	2	BMPR2
AT-9283	2	ACVRL1, BMPR2
TOZASERTIB	2	ACVRL1, BMPR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ACVRL1	213	Binding:207, Functional:3, Toxicity:2, ADMET:1
BMPR2	166	Binding:165, ADMET:1
KCNA5	152	Binding:130, Functional:14, ADMET:5, Toxicity:3
KCNK3	39	Binding:38, Functional:1
SMAD4	6	Binding:6
PAH	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACVRL1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
PAH	1.14.16.1	phenylalanine 4-monooxygenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BMPR2	166
ACVRL1	213
KCNA5	152

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; 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)
FEDRATINIB	4	ACVRL1, BMPR2
RUXOLITINIB	4	BMPR2
BOSUTINIB	4	BMPR2
DEUCRAVACITINIB	4	BMPR2
NINTEDANIB	4	ACVRL1, BMPR2
SUNITINIB	4	BMPR2
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
DASATINIB	4	ACVRL1
DRONEDARONE HYDROCHLORIDE	4	KCNA5
SERTINDOLE	4	KCNA5
QUINIDINE	4	KCNA5
NIFEDIPINE	4	KCNA5
VERNAKALANT HYDROCHLORIDE	4	KCNA5
FLECAINIDE	4	KCNA5
ROPIVACAINE	4	KCNK3
BUPIVACAINE	4	KCNK3
ETIDOCAINE	4	KCNK3
MEXILETINE	4	KCNK3
PROPAFENONE	4	KCNK3
LINIFANIB	3	BMPR2
ORANTINIB	3	BMPR2
DOVITINIB	3	BMPR2
LESTAURTINIB	3	ACVRL1, BMPR2
ALVOCIDIB	3	ACVRL1
SILMITASERTIB	2	BMPR2
SU-014813	2	BMPR2
OSI-027	2	BMPR2
AT-9283	2	ACVRL1, BMPR2
TOZASERTIB	2	ACVRL1, BMPR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	BMPR2, ACVRL1, KCNA5, KCNK3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TBX4, ENG, SMAD1, SMAD4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ENG	0	ACVRL1
TBX4	0	—
SMAD1	0	—
SMAD4	6	—
PAH	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.