Pulmonary hypertension, primary, 2

Summary

Pulmonary hypertension, primary, 2 (MONDO:0014134) is a disease caused by SMAD9 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include spironolactone.

At a glance

• Causal gene: SMAD9 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 216
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary hypertension, primary, 2
Mondo ID	MONDO:0014134
OMIM	615342
UMLS	C3888002
MedGen	854709
GARD	0018394
Is cancer (heuristic)	no

Also known as: PPH2 · primary pulmonary hypertension caused by mutation in SMAD9 · pulmonary hypertension, primary, 2 · pulmonary hypertension, primary, type 2 · SMAD9 primary pulmonary hypertension

Data availability: 216 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, 2

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

216 retrieved; paginated sample, class counts are floors:

87 likely benign, 82 uncertain significance, 15 pathogenic, 10 likely pathogenic, 9 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179087	NM_001127217.3(SMAD9):c.386dup (p.Tyr129Ter)	SMAD9	Pathogenic	criteria provided, multiple submitters, no conflicts
2195334	NM_001127217.3(SMAD9):c.71G>A (p.Trp24Ter)	SMAD9	Pathogenic	criteria provided, single submitter
2423749	NC_000013.10:g.(?37446775)(37453826_?)del	SMAD9	Pathogenic	criteria provided, single submitter
2792531	NM_001127217.3(SMAD9):c.686del (p.Leu229fs)	SMAD9	Pathogenic	criteria provided, single submitter
2892767	NM_001127217.3(SMAD9):c.850C>T (p.Arg284Ter)	SMAD9	Pathogenic	criteria provided, single submitter
2905695	NM_001127217.3(SMAD9):c.137_140del (p.Lys46fs)	SMAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3613689	NM_001127217.3(SMAD9):c.811C>T (p.Gln271Ter)	SMAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3649577	NM_001127217.3(SMAD9):c.98G>A (p.Trp33Ter)	SMAD9	Pathogenic	criteria provided, single submitter
3649700	NM_001127217.3(SMAD9):c.199_232del (p.Lys67fs)	SMAD9	Pathogenic	criteria provided, single submitter
3678444	NM_001127217.3(SMAD9):c.203dup (p.Cys68fs)	SMAD9	Pathogenic	criteria provided, single submitter
3690588	NM_001127217.3(SMAD9):c.812del (p.Gln271fs)	SMAD9	Pathogenic	criteria provided, single submitter
3707978	NM_001127217.3(SMAD9):c.668C>G (p.Ser223Ter)	SMAD9	Pathogenic	criteria provided, single submitter
3716791	NM_001127217.3(SMAD9):c.767del (p.Leu255_Ser256insTer)	SMAD9	Pathogenic	criteria provided, single submitter
4727900	NM_001127217.3(SMAD9):c.282_283del (p.Trp96fs)	SMAD9	Pathogenic	criteria provided, single submitter
4755191	NM_001127217.3(SMAD9):c.696dup (p.Ala233fs)	SMAD9	Pathogenic	criteria provided, single submitter
56970	NM_001127217.3(SMAD9):c.880C>T (p.Arg294Ter)	SMAD9	Pathogenic	criteria provided, multiple submitters, no conflicts
6515	NM_001127217.3(SMAD9):c.606C>A (p.Cys202Ter)	SMAD9	Pathogenic	no assertion criteria provided
1325103	NM_001127217.3(SMAD9):c.564_567dup (p.Pro190fs)	SMAD9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330824	NM_001127217.3(SMAD9):c.810_811dup (p.Gln271fs)	SMAD9	Likely pathogenic	criteria provided, single submitter
3575894	NM_001127217.3(SMAD9):c.1035_1036del (p.Tyr346fs)	SMAD9	Likely pathogenic	criteria provided, single submitter
3575895	NM_001127217.3(SMAD9):c.1004-2A>G	SMAD9	Likely pathogenic	criteria provided, single submitter
3575906	NM_001127217.3(SMAD9):c.868C>T (p.Gln290Ter)	SMAD9	Likely pathogenic	criteria provided, single submitter
3575916	NM_001127217.3(SMAD9):c.671-1G>A	SMAD9	Likely pathogenic	criteria provided, single submitter
3575925	NM_001127217.3(SMAD9):c.318_322dup (p.Lys108delinsSerTer)	SMAD9	Likely pathogenic	criteria provided, single submitter
3575928	NM_001127217.3(SMAD9):c.270_276dup (p.Cys93fs)	SMAD9	Likely pathogenic	criteria provided, single submitter
3575933	NM_001127217.3(SMAD9):c.137dup (p.Lys47fs)	SMAD9	Likely pathogenic	criteria provided, single submitter
4077556	NM_001127217.3(SMAD9):c.801C>A (p.Tyr267Ter)	SMAD9	Likely pathogenic	criteria provided, single submitter
1063362	NM_001127217.3(SMAD9):c.449A>G (p.Tyr150Cys)	SMAD9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2069523	NM_001127217.3(SMAD9):c.920A>G (p.Asn307Ser)	SMAD9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213811	NM_001127217.3(SMAD9):c.65T>C (p.Leu22Pro)	SMAD9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
SMAD9	Strong	Autosomal dominant	pulmonary hypertension, primary, 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD9	Orphanet:275777	Heritable pulmonary arterial hypertension

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMAD9	HGNC:6774	ENSG00000120693	O15198	SMAD family member 9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD9	SMAD family member 9	Transcriptional modulator activated by BMP (bone morphogenetic proteins) type 1 receptor kinase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD9	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD9	253	ubiquitous	marker	corpus epididymis, caput epididymis, urethra

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD9	2,030

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD9	O15198	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	356.9×	0.008	SMAD9
Signaling by TGFB family members	1	115.3×	0.013	SMAD9
Signal Transduction	1	10.2×	0.098	SMAD9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
SMAD protein signal transduction	1	732.7×	0.009	SMAD9
cellular response to BMP stimulus	1	561.7×	0.009	SMAD9
intracellular iron ion homeostasis	1	244.2×	0.012	SMAD9
BMP signaling pathway	1	200.6×	0.012	SMAD9
transforming growth factor beta receptor signaling pathway	1	159.0×	0.012	SMAD9
anatomical structure morphogenesis	1	139.3×	0.012	SMAD9
osteoblast differentiation	1	121.2×	0.012	SMAD9
cell differentiation	1	29.1×	0.043	SMAD9
positive regulation of transcription by RNA polymerase II	1	14.9×	0.075	SMAD9
regulation of transcription by RNA polymerase II	1	11.7×	0.086	SMAD9

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMAD9	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	SMAD9

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)
SMAD9	0	—

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