Pulmonary hypertension, primary, 3

Summary

Pulmonary hypertension, primary, 3 (MONDO:0014135) is a disease caused by CAV1 (GenCC Strong), with 2 cohort genes and 2 clinical trials. Top therapeutic interventions include spironolactone.

At a glance

• Causal gene: CAV1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 96
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary hypertension, primary, 3
Mondo ID	MONDO:0014135
OMIM	615343
UMLS	C3809192
MedGen	815522
GARD	0024973
Is cancer (heuristic)	no

Also known as: CAV1 primary pulmonary hypertension · PPH3 · primary pulmonary hypertension caused by mutation in CAV1 · pulmonary hypertension, primary, 3 · pulmonary hypertension, primary, type 3

Data availability: 96 ClinVar variants · 2 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, 3

Related subtypes (6): pulmonary hypertension, primary, 5, pulmonary hypertension, primary, 2, pulmonary hypertension, primary, 4, pulmonary hypertension, primary, 1, 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

96 retrieved; paginated sample, class counts are floors:

40 likely benign, 34 uncertain significance, 7 benign, 5 benign/likely benign, 5 conflicting classifications of pathogenicity, 4 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
128609	NM_001753.5(CAV1):c.401_402delinsA (p.Ile134fs)	CAV1	Pathogenic	criteria provided, single submitter
208669	NM_001753.5(CAV1):c.479_480del (p.Leu159_Phe160insTer)	CAV1	Pathogenic	criteria provided, single submitter
56967	NM_001753.5(CAV1):c.474del (p.Leu159fs)	CAV1	Pathogenic	no assertion criteria provided
56968	NM_001753.5(CAV1):c.473del (p.Pro158fs)	CAV1	Pathogenic	no assertion criteria provided
1493101	NM_001753.5(CAV1):c.446_447insT (p.Ile150fs)	CAV1	Likely pathogenic	criteria provided, single submitter
2894539	NM_001753.5(CAV1):c.358G>A (p.Ala120Thr)	CAV1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541324	NM_001753.5(CAV1):c.500T>C (p.Phe167Ser)	CAV1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
566670	NM_001753.5(CAV1):c.448A>G (p.Ile150Val)	CAV1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695522	NM_001753.5(CAV1):c.463G>A (p.Val155Ile)	CAV1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800276	NM_001753.5(CAV1):c.28G>T (p.Glu10Ter)	CAV1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
522761	NM_001203.3(BMPR1B):c.80C>G (p.Pro27Arg)	BMPR1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
1213801	NM_001753.5(CAV1):c.30G>C (p.Glu10Asp)	CAV1	Uncertain significance	criteria provided, single submitter
1301625	NM_001753.5(CAV1):c.407G>A (p.Ser136Asn)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1469176	NM_001753.5(CAV1):c.302G>A (p.Arg101His)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1677803	NM_001753.5(CAV1):c.394C>G (p.Pro132Ala)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1803889	NM_001753.5(CAV1):c.236A>G (p.His79Arg)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2198126	NM_001753.5(CAV1):c.211G>A (p.Val71Met)	CAV1	Uncertain significance	criteria provided, single submitter
2502255	NM_001753.5(CAV1):c.326T>A (p.Ile109Asn)	CAV1	Uncertain significance	criteria provided, single submitter
2584563	NM_001753.5(CAV1):c.257A>G (p.Lys86Arg)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2663785	NM_001753.5(CAV1):c.284C>T (p.Thr95Met)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2895477	NM_001753.5(CAV1):c.352T>C (p.Tyr118His)	CAV1	Uncertain significance	criteria provided, single submitter
2914806	NM_001753.5(CAV1):c.229G>A (p.Gly77Arg)	CAV1	Uncertain significance	criteria provided, single submitter
3245814	NC_000007.13:g.(?116165117)(116199341_?)del	CAV1	Uncertain significance	criteria provided, single submitter
3245815	NC_000007.13:g.(?116165117)(116199341_?)dup	CAV1	Uncertain significance	criteria provided, single submitter
3594247	NM_001753.5(CAV1):c.30+3A>G	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3594248	NM_001753.5(CAV1):c.31-5T>A	CAV1	Uncertain significance	criteria provided, single submitter
3594249	NM_001753.5(CAV1):c.87C>A (p.Asn29Lys)	CAV1	Uncertain significance	criteria provided, single submitter
3594250	NM_001753.5(CAV1):c.96G>A (p.Met32Ile)	CAV1	Uncertain significance	criteria provided, single submitter
3594252	NM_001753.5(CAV1):c.247G>A (p.Gly83Ser)	CAV1	Uncertain significance	criteria provided, single submitter
3594253	NM_001753.5(CAV1):c.301C>T (p.Arg101Cys)	CAV1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 9 · 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
CAV1	Strong	Autosomal dominant	pulmonary hypertension, primary, 3	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CAV1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
CAV1	Orphanet:220402	Limited cutaneous systemic sclerosis
CAV1	Orphanet:275777	Heritable pulmonary arterial hypertension
CAV1	Orphanet:696206	Congenital generalized lipodystrophy type 3
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CAV1	HGNC:1527	ENSG00000105974	Q03135	Caveolin-1	gencc,clinvar
BMPR1B	HGNC:1077	ENSG00000138696	O00238	Bone morphogenetic protein receptor type-1B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CAV1	Caveolin-1	May act as a scaffolding protein within caveolar membranes.
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CAV1	Other/Unknown	no		Caveolin, Caveolin_CS
BMPR1B	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower lobe of lung	1
parietal pleura	1
pleura	1
bronchial epithelial cell	1
calcaneal tendon	1
cauda epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CAV1	287	ubiquitous	marker	parietal pleura, lower lobe of lung, pleura
BMPR1B	239	broad	marker	calcaneal tendon, bronchial epithelial cell, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAV1	6,673
BMPR1B	116

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CAV1	Q03135	1
BMPR1B	O00238	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 58. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of nitric oxide: NOS3 activation and regulation	1	1142.0×	0.022	CAV1
NOSTRIN mediated eNOS trafficking	1	1142.0×	0.022	CAV1
eNOS activation	1	439.2×	0.022	CAV1
SARS-CoV-2 targets host intracellular signalling and regulatory pathways	1	439.2×	0.022	CAV1
Thyroxine biosynthesis	1	407.9×	0.022	CAV1
Triglyceride metabolism	1	335.9×	0.022	CAV1
FOXO-mediated transcription of cell cycle genes	1	335.9×	0.022	CAV1
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	335.9×	0.022	CAV1
Triglyceride catabolism	1	237.9×	0.023	CAV1
Basigin interactions	1	219.6×	0.023	CAV1
VEGFR2 mediated vascular permeability	1	203.9×	0.023	CAV1
Signaling by BMP	1	178.4×	0.023	BMPR1B
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	178.4×	0.023	CAV1
FOXO-mediated transcription	1	167.9×	0.023	CAV1
RHOH GTPase cycle	1	154.3×	0.023	CAV1
RND1 GTPase cycle	1	132.8×	0.023	CAV1
RHOF GTPase cycle	1	129.8×	0.023	CAV1
RND3 GTPase cycle	1	129.8×	0.023	CAV1
RND2 GTPase cycle	1	129.8×	0.023	CAV1
Signaling by VEGF	1	109.8×	0.025	CAV1
RHOD GTPase cycle	1	102.0×	0.025	CAV1
RHOJ GTPase cycle	1	100.2×	0.025	CAV1
Signal Transduction	2	10.2×	0.025	CAV1, BMPR1B
RHOQ GTPase cycle	1	90.6×	0.026	CAV1
SARS-CoV-1-host interactions	1	87.8×	0.026	CAV1
Extra-nuclear estrogen signaling	1	85.2×	0.026	CAV1
RHOB GTPase cycle	1	77.2×	0.027	CAV1
RHOG GTPase cycle	1	74.2×	0.027	CAV1
RHOC GTPase cycle	1	73.2×	0.027	CAV1
SARS-CoV-1 Infection	1	71.4×	0.027	CAV1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of the force of heart contraction by chemical signal	1	4213.0×	0.005	CAV1
intracellular nitric oxide homeostasis	1	2808.7×	0.005	CAV1
insulin receptor internalization	1	2808.7×	0.005	CAV1
regulation of membrane repolarization during action potential	1	2808.7×	0.005	CAV1
protein localization to basolateral plasma membrane	1	2808.7×	0.005	CAV1
ovarian cumulus expansion	1	2106.5×	0.005	BMPR1B
protein localization to plasma membrane raft	1	2106.5×	0.005	CAV1
negative regulation of pinocytosis	1	2106.5×	0.005	CAV1
endochondral bone morphogenesis	1	2106.5×	0.005	BMPR1B
negative regulation of chondrocyte proliferation	1	2106.5×	0.005	BMPR1B
maintenance of protein location in cell	1	1685.2×	0.005	CAV1
cellular response to hyperoxia	1	1685.2×	0.005	CAV1
caveolin-mediated endocytosis	1	1685.2×	0.005	CAV1
regulation of entry of bacterium into host cell	1	1685.2×	0.005	CAV1
mammary gland involution	1	1404.3×	0.005	CAV1
ovulation cycle	1	1203.7×	0.005	BMPR1B
positive regulation of gap junction assembly	1	1203.7×	0.005	CAV1
glandular epithelial cell differentiation	1	1053.2×	0.005	CAV1
caveola assembly	1	1053.2×	0.005	CAV1
regulation of ruffle assembly	1	1053.2×	0.005	CAV1
negative regulation of cytokine-mediated signaling pathway	1	936.2×	0.005	CAV1
regulation of fatty acid metabolic process	1	936.2×	0.005	CAV1
regulation of blood coagulation	1	936.2×	0.005	CAV1
regulation of cardiac muscle cell action potential involved in regulation of contraction	1	936.2×	0.005	CAV1
regulation of cell communication by electrical coupling involved in cardiac conduction	1	936.2×	0.005	CAV1
MAPK cascade	2	153.2×	0.005	CAV1, BMPR1B
positive regulation of gene expression	2	38.7×	0.005	CAV1, BMPR1B
receptor-mediated endocytosis of virus by host cell	1	766.0×	0.005	CAV1
angiotensin-activated signaling pathway	1	766.0×	0.005	CAV1
nitric oxide metabolic process	1	702.2×	0.005	CAV1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
BMPR1B	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMPR1B	28	4
CAV1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1B
FEDRATINIB	4	BMPR1B
AXITINIB	4	BMPR1B
RUXOLITINIB	4	BMPR1B
VANDETANIB	4	BMPR1B
GILTERITINIB	4	BMPR1B
PAZOPANIB	4	BMPR1B
SUNITINIB	4	BMPR1B
DASATINIB	4	BMPR1B
QUIZARTINIB	4	BMPR1B
CRIZOTINIB	4	BMPR1B
SARACATINIB	3	BMPR1B
LINIFANIB	3	BMPR1B
CANERTINIB	3	BMPR1B
ALVOCIDIB	3	BMPR1B
LESTAURTINIB	3	BMPR1B
SU-014813	2	BMPR1B
R-406	2	BMPR1B
AT-9283	2	BMPR1B
ZILURGISERTIB	2	BMPR1B
TOZASERTIB	2	BMPR1B
KER-047	2	BMPR1B
TAK-285	1	BMPR1B
KW-2449	1	BMPR1B
MLN-8054	1	BMPR1B
XL-228	1	BMPR1B
ASP-3026	1	BMPR1B
AEW-541	1	BMPR1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BMPR1B	166	Binding:164, ADMET:2
CAV1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1B	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BMPR1B	166

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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	BMPR1B
FEDRATINIB	4	BMPR1B
AXITINIB	4	BMPR1B
RUXOLITINIB	4	BMPR1B
VANDETANIB	4	BMPR1B
GILTERITINIB	4	BMPR1B
PAZOPANIB	4	BMPR1B
SUNITINIB	4	BMPR1B
DASATINIB	4	BMPR1B
QUIZARTINIB	4	BMPR1B
CRIZOTINIB	4	BMPR1B
SARACATINIB	3	BMPR1B
LINIFANIB	3	BMPR1B
CANERTINIB	3	BMPR1B
ALVOCIDIB	3	BMPR1B
LESTAURTINIB	3	BMPR1B
SU-014813	2	BMPR1B
R-406	2	BMPR1B
AT-9283	2	BMPR1B
ZILURGISERTIB	2	BMPR1B
TOZASERTIB	2	BMPR1B
KER-047	2	BMPR1B
TAK-285	1	BMPR1B
KW-2449	1	BMPR1B
MLN-8054	1	BMPR1B
XL-228	1	BMPR1B
ASP-3026	1	BMPR1B
AEW-541	1	BMPR1B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BMPR1B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CAV1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CAV1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE4	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial
NCT04808596	Not specified	RECRUITING	Pulmonary Hypertension Biorepository and Registry

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SPIRONOLACTONE	4	1
CHEMBL1562223	0	1
CHEMBL30458	0	1