Pulmonary venoocclusive disease 2

Summary

Pulmonary venoocclusive disease 2 (MONDO:0009329) is a disease caused by EIF2AK4 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: EIF2AK4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 108
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0005954	Pulmonary capillary hemangiomatosis	Very frequent (80-99%)
HP:0025104	Capillary malformation	Very frequent (80-99%)
HP:0025179	Ground-glass opacification on pulmonary HRCT	Very frequent (80-99%)
HP:0030879	Interlobular septal thickening on pulmonary HRCT	Very frequent (80-99%)
HP:0045051	Decreased DLCO	Very frequent (80-99%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001708	Right ventricular failure	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002105	Hemoptysis	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0004890	Elevated pulmonary artery pressure	Frequent (30-79%)
HP:0010741	Pedal edema	Frequent (30-79%)
HP:0012151	Hemothorax	Frequent (30-79%)
HP:0012418	Hypoxemia	Frequent (30-79%)
HP:0025180	Centrilobular ground-glass opacification on pulmonary HRCT	Frequent (30-79%)
HP:0025420	Diffuse alveolar hemorrhage	Frequent (30-79%)
HP:0030968	Abnormal pulmonary vein morphology	Frequent (30-79%)
HP:0100721	Mediastinal lymphadenopathy	Frequent (30-79%)
HP:0100759	Clubbing of fingers	Frequent (30-79%)
HP:0002202	Pleural effusion	Occasional (5-29%)
HP:0100598	Pulmonary edema	Occasional (5-29%)
HP:0003493	Antinuclear antibody positivity	Excluded (0%)
HP:0032230	Cytoplasmic antineutrophil antibody positivity	Excluded (0%)
HP:0001698	Pericardial effusion	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pulmonary venoocclusive disease 2
Mondo ID	MONDO:0009329
MeSH	C535861
OMIM	234810
Orphanet	199241
DOID	DOID:0081269
SNOMED CT	233949008
UMLS	C0340848
MedGen	90956
GARD	0015027
Is cancer (heuristic)	no

Also known as: familial pulmonary capillary hemangiomatosis · pulmonary capillary hemangiomatosis · pulmonary venoocclusive disease 2, autosomal recessive · PVOD2

Data availability: 108 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 › pulmonary venoocclusive disease › pulmonary venoocclusive disease 2

Related subtypes (1): pulmonary venoocclusive disease 1

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

108 retrieved; paginated sample, class counts are floors:

31 pathogenic, 20 benign, 17 likely pathogenic, 12 uncertain significance, 11 benign/likely benign, 10 likely benign, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101527	NM_001013703.4(EIF2AK4):c.1153dup (p.Val385fs)	EIF2AK4	Pathogenic	criteria provided, single submitter
101528	NM_001013703.4(EIF2AK4):c.3766C>T (p.Arg1256Ter)	EIF2AK4	Pathogenic	criteria provided, multiple submitters, no conflicts
101529	NM_001013703.4(EIF2AK4):c.3448C>T (p.Arg1150Ter)	EIF2AK4	Pathogenic	no assertion criteria provided
101530	NM_001013703.4(EIF2AK4):c.860-1G>A	EIF2AK4	Pathogenic	no assertion criteria provided
1322819	NM_001013703.4(EIF2AK4):c.4065+1G>T	EIF2AK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1937703	NM_001013703.4(EIF2AK4):c.4009C>T (p.Arg1337Ter)	EIF2AK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280131	NM_001013703.4(EIF2AK4):c.560_564del (p.Lys187fs)	EIF2AK4	Pathogenic	criteria provided, multiple submitters, no conflicts
426050	NM_001013703.4(EIF2AK4):c.354_355del (p.Cys118fs)	EIF2AK4	Pathogenic	no assertion criteria provided
426051	NM_001013703.4(EIF2AK4):c.745C>T (p.Arg249Ter)	EIF2AK4	Pathogenic	criteria provided, single submitter
426052	NM_001013703.4(EIF2AK4):c.1554-4C>A	EIF2AK4	Pathogenic	no assertion criteria provided
426053	NM_001013703.4(EIF2AK4):c.1928T>G (p.Leu643Arg)	EIF2AK4	Pathogenic	no assertion criteria provided
426054	NM_001013703.4(EIF2AK4):c.2136_2139dup (p.Ser714fs)	EIF2AK4	Pathogenic	no assertion criteria provided
426055	NM_001013703.4(EIF2AK4):c.2319+1G>A	EIF2AK4	Pathogenic	no assertion criteria provided
426056	NM_001013703.4(EIF2AK4):c.2458C>T (p.Arg820Ter)	EIF2AK4	Pathogenic	no assertion criteria provided
426057	NM_001013703.4(EIF2AK4):c.2857C>T (p.Gln953Ter)	EIF2AK4	Pathogenic	no assertion criteria provided
426058	NM_001013703.4(EIF2AK4):c.3159G>A (p.Lys1053=)	EIF2AK4	Pathogenic	no assertion criteria provided
426059	NM_001013703.4(EIF2AK4):c.3244C>T (p.Gln1082Ter)	EIF2AK4	Pathogenic	no assertion criteria provided
426060	NM_001013703.4(EIF2AK4):c.3344C>T (p.Pro1115Leu)	EIF2AK4	Pathogenic	no assertion criteria provided
426061	NM_001013703.4(EIF2AK4):c.3576+1G>T	EIF2AK4	Pathogenic	no assertion criteria provided
426062	NM_001013703.4(EIF2AK4):c.4065+1G>C	EIF2AK4	Pathogenic	no assertion criteria provided
426063	NM_001013703.4(EIF2AK4):c.4205dup (p.Ser1403fs)	EIF2AK4	Pathogenic	criteria provided, multiple submitters, no conflicts
426064	NM_001013703.4(EIF2AK4):c.4728+1_4728+13delinsTTCT	EIF2AK4	Pathogenic	no assertion criteria provided
4277825	NM_001013703.4(EIF2AK4):c.4659+1G>A	EIF2AK4	Pathogenic	criteria provided, single submitter
812856	NM_001013703.4(EIF2AK4):c.145-2A>G	EIF2AK4	Pathogenic	no assertion criteria provided
812858	NM_001013703.4(EIF2AK4):c.281dup (p.Asn94fs)	EIF2AK4	Pathogenic	no assertion criteria provided
812866	NM_001013703.4(EIF2AK4):c.3097C>T (p.Gln1033Ter)	EIF2AK4	Pathogenic	no assertion criteria provided
812870	NM_001013703.4(EIF2AK4):c.4392dup (p.Lys1465Ter)	EIF2AK4	Pathogenic	criteria provided, single submitter
812871	NM_001013703.4(EIF2AK4):c.4400dup (p.Glu1468fs)	EIF2AK4	Pathogenic	criteria provided, single submitter
812872	NM_001013703.4(EIF2AK4):c.4418_4421del (p.Thr1473fs)	EIF2AK4	Pathogenic	no assertion criteria provided
97064	NM_001013703.4(EIF2AK4):c.1392del (p.Arg465fs)	EIF2AK4	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 6 · 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
EIF2AK4	Strong	Autosomal recessive	pulmonary venoocclusive disease 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2AK4	Orphanet:199241	Pulmonary capillary hemangiomatosis
EIF2AK4	Orphanet:275777	Heritable pulmonary arterial hypertension
EIF2AK4	Orphanet:31837	Pulmonary venoocclusive disease
BMPR2	Orphanet:275777	Heritable pulmonary arterial hypertension
BMPR2	Orphanet:275786	Drug- or toxin-induced pulmonary arterial hypertension
BMPR2	Orphanet:31837	Pulmonary venoocclusive disease

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
EIF2AK4	HGNC:19687	ENSG00000128829	Q9P2K8	eIF-2-alpha kinase GCN2	gencc,clinvar
BMPR2	HGNC:1078	ENSG00000204217	Q13873	Bone morphogenetic protein receptor type-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	2	27.7×	0.001

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EIF2AK4	Kinase	yes		Prot_kinase_dom, RWD_dom, Ser/Thr_kinase_AS
BMPR2	Kinase	yes		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
adenohypophysis	1
bone marrow cell	1
pituitary gland	1
lower lobe of lung	1
tendon of biceps brachii	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2AK4	258	ubiquitous	marker	adenohypophysis, pituitary gland, bone marrow cell
BMPR2	271	ubiquitous	marker	visceral pleura, lower lobe of lung, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2AK4	3,193
BMPR2	3,152

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2AK4	Q9P2K8	8
BMPR2	Q13873	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Signaling by BMP	1	178.4×	0.022	BMPR2
Signaling by TGFB family members	1	57.7×	0.024	BMPR2
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	55.4×	0.024	EIF2AK4
Signal Transduction	1	5.1×	0.187	BMPR2

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 translational initiation by eIF2 alpha phosphorylation	1	8426.0×	0.002	EIF2AK4
viral translation	1	8426.0×	0.002	EIF2AK4
positive regulation of translational initiation in response to starvation	1	8426.0×	0.002	EIF2AK4
semi-lunar valve development	1	8426.0×	0.002	BMPR2
obsolete negative regulation of cell proliferation involved in heart valve morphogenesis	1	4213.0×	0.003	BMPR2
regulation of lung blood pressure	1	4213.0×	0.003	BMPR2
pulmonary valve development	1	2106.5×	0.003	BMPR2
obsolete negative regulation of CREB transcription factor activity	1	2106.5×	0.003	EIF2AK4
endochondral bone morphogenesis	1	2106.5×	0.003	BMPR2
GCN2-mediated signaling	1	2106.5×	0.003	EIF2AK4
negative regulation of chondrocyte proliferation	1	2106.5×	0.003	BMPR2
response to amino acid starvation	1	2106.5×	0.003	EIF2AK4
aortic valve development	1	1685.2×	0.003	BMPR2
tricuspid valve morphogenesis	1	1685.2×	0.003	BMPR2
negative regulation of translational initiation in response to stress	1	1685.2×	0.003	EIF2AK4
venous blood vessel development	1	1685.2×	0.003	BMPR2
positive regulation of axon extension involved in axon guidance	1	1203.7×	0.004	BMPR2
lymphatic endothelial cell differentiation	1	1203.7×	0.004	BMPR2
positive regulation of adaptive immune response	1	1053.2×	0.004	EIF2AK4
regulation of feeding behavior	1	936.2×	0.004	EIF2AK4
mitral valve morphogenesis	1	842.6×	0.004	BMPR2
negative regulation of vasoconstriction	1	842.6×	0.004	BMPR2
negative regulation of muscle cell differentiation	1	842.6×	0.004	BMPR2
retina vasculature development in camera-type eye	1	842.6×	0.004	BMPR2
maternal placenta development	1	766.0×	0.004	BMPR2
host-mediated suppression of viral genome replication	1	766.0×	0.004	EIF2AK4
lung vasculature development	1	766.0×	0.004	BMPR2
endocardial cushion development	1	702.2×	0.004	BMPR2
artery development	1	702.2×	0.004	BMPR2
atrial septum morphogenesis	1	648.1×	0.004	BMPR2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

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
EIF2AK4	FEDRATINIB
BMPR2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2AK4	19	4
BMPR2	19	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	BMPR2, EIF2AK4
NERATINIB	4	EIF2AK4
BOSUTINIB	4	BMPR2, EIF2AK4
NINTEDANIB	4	BMPR2, EIF2AK4
SUNITINIB	4	BMPR2, EIF2AK4
DASATINIB	4	EIF2AK4
ERLOTINIB	4	EIF2AK4
MIDOSTAURIN	4	EIF2AK4
RUXOLITINIB	4	BMPR2
DEUCRAVACITINIB	4	BMPR2
DOVITINIB	3	BMPR2, EIF2AK4
MOTESANIB	3	EIF2AK4
LESTAURTINIB	3	BMPR2, EIF2AK4
LINIFANIB	3	BMPR2
ORANTINIB	3	BMPR2
SU-014813	2	BMPR2, EIF2AK4
R-406	2	EIF2AK4
RAF-265	2	EIF2AK4
TOZASERTIB	2	BMPR2, EIF2AK4
PELITINIB	2	EIF2AK4
SILMITASERTIB	2	BMPR2
OSI-027	2	BMPR2
AT-9283	2	BMPR2
GSK-461364	1	EIF2AK4
KW-2449	1	BMPR2, EIF2AK4
LY-3009120	1	EIF2AK4
RGB-286638	1	BMPR2
PF-03814735	1	BMPR2
CYC-116	1	BMPR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EIF2AK4	170	Binding:170
BMPR2	166	Binding:165, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EIF2AK4	170
BMPR2	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

29 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	BMPR2, EIF2AK4
NERATINIB	4	EIF2AK4
BOSUTINIB	4	BMPR2, EIF2AK4
NINTEDANIB	4	BMPR2, EIF2AK4
SUNITINIB	4	BMPR2, EIF2AK4
DASATINIB	4	EIF2AK4
ERLOTINIB	4	EIF2AK4
MIDOSTAURIN	4	EIF2AK4
RUXOLITINIB	4	BMPR2
DEUCRAVACITINIB	4	BMPR2
DOVITINIB	3	BMPR2, EIF2AK4
MOTESANIB	3	EIF2AK4
LESTAURTINIB	3	BMPR2, EIF2AK4
LINIFANIB	3	BMPR2
ORANTINIB	3	BMPR2
SU-014813	2	BMPR2, EIF2AK4
R-406	2	EIF2AK4
RAF-265	2	EIF2AK4
TOZASERTIB	2	BMPR2, EIF2AK4
PELITINIB	2	EIF2AK4
SILMITASERTIB	2	BMPR2
OSI-027	2	BMPR2
AT-9283	2	BMPR2
GSK-461364	1	EIF2AK4
KW-2449	1	BMPR2, EIF2AK4
LY-3009120	1	EIF2AK4
RGB-286638	1	BMPR2
PF-03814735	1	BMPR2
CYC-116	1	BMPR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	EIF2AK4, BMPR2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.