Telangiectasia, hereditary hemorrhagic, type 2

Summary

Telangiectasia, hereditary hemorrhagic, type 2 (MONDO:0010880) is a disease caused by ACVRL1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ACVRL1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 978

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	telangiectasia, hereditary hemorrhagic, type 2
Mondo ID	MONDO:0010880
OMIM	600376
UMLS	C1838163
MedGen	324960
GARD	0009901
Is cancer (heuristic)	no

Also known as: ACVRL1 hereditary hemorrhagic telangiectasia · hereditary hemorrhagic telangiectasia caused by mutation in ACVRL1 · hereditary hemorrhagic telangiectasia type 2 · HHT2 · ORW2 · Osler Weber Rendu syndrome type 2 · telangiectasia hereditary hemorrhagic type 2 · telangiectasia, hereditary hemorrhagic, type 2

Data availability: 978 ClinVar variants · 24 ClinGen variant curations · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › hereditary hemorrhagic telangiectasia › telangiectasia, hereditary hemorrhagic, type 2

Related subtypes (4): telangiectasia, hereditary hemorrhagic, type 1, hereditary hemorrhagic telangiectasia type 3, hereditary hemorrhagic telangiectasia type 4, telangiectasia, hereditary hemorrhagic, type 5

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:

169 pathogenic, 137 uncertain significance, 111 likely benign, 54 likely pathogenic, 46 conflicting classifications of pathogenicity, 40 benign, 33 pathogenic/likely pathogenic, 9 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1015010	NM_000020.3(ACVRL1):c.1411T>G (p.Cys471Gly)	ACVRL1	Pathogenic	criteria provided, single submitter
1066979	NM_000020.3(ACVRL1):c.106T>C (p.Cys36Arg)	ACVRL1	Pathogenic	criteria provided, single submitter
1066980	NM_000020.3(ACVRL1):c.1325T>C (p.Val442Ala)	ACVRL1	Pathogenic	criteria provided, single submitter
1069624	NM_000020.3(ACVRL1):c.362_374del (p.Leu121fs)	ACVRL1	Pathogenic	criteria provided, single submitter
1070651	NM_000020.3(ACVRL1):c.121T>G (p.Cys41Gly)	ACVRL1	Pathogenic	criteria provided, single submitter
1070764	NM_000020.3(ACVRL1):c.1297C>T (p.Pro433Ser)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072475	NM_000020.3(ACVRL1):c.78_81del (p.Ser27fs)	ACVRL1	Pathogenic	criteria provided, single submitter
1072776	NM_000020.3(ACVRL1):c.115_116del (p.Pro39fs)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073041	NM_000020.3(ACVRL1):c.329C>A (p.Ser110Ter)	ACVRL1	Pathogenic	criteria provided, single submitter
1073109	NC_000012.11:g.52308281_52308282insAlu	ACVRL1	Pathogenic	criteria provided, single submitter
1073797	NM_000020.3(ACVRL1):c.412_413del (p.Leu138fs)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074142	NM_000020.3(ACVRL1):c.131_132insCACA (p.Cys46fs)	ACVRL1	Pathogenic	criteria provided, single submitter
1074702	NM_000020.3(ACVRL1):c.1010del (p.Leu337fs)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1074703	NM_000020.3(ACVRL1):c.1069C>T (p.Gln357Ter)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1075285	NM_000020.3(ACVRL1):c.871A>T (p.Arg291Ter)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076534	NM_000020.3(ACVRL1):c.525+1G>T	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1163055	NM_000020.3(ACVRL1):c.199C>G (p.Arg67Gly)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1163056	NM_000020.3(ACVRL1):c.525+2T>C	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1163057	NM_000020.3(ACVRL1):c.1048+1G>A	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319603	NM_000020.3(ACVRL1):c.983A>C (p.His328Pro)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322795	NM_000020.3(ACVRL1):c.510del (p.Asp171fs)	ACVRL1	Pathogenic	criteria provided, single submitter
1322799	NM_000020.3(ACVRL1):c.505C>T (p.Gln169Ter)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330267	NM_000020.3(ACVRL1):c.68del (p.Pro23fs)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330268	NM_000020.3(ACVRL1):c.205T>C (p.Cys69Arg)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1330270	NM_000020.3(ACVRL1):c.868C>T (p.Gln290Ter)	ACVRL1	Pathogenic	criteria provided, single submitter
1330572	NM_000020.3(ACVRL1):c.961C>T (p.Gln321Ter)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1343364	NM_000020.3(ACVRL1):c.546C>A (p.Cys182Ter)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359265	NM_000020.3(ACVRL1):c.130_143del (p.Pro44fs)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1363480	NM_000020.3(ACVRL1):c.375del (p.Val126fs)	ACVRL1	Pathogenic	criteria provided, multiple submitters, no conflicts
1369732	NM_000020.3(ACVRL1):c.1199C>A (p.Ala400Asp)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
ACVRL1	Definitive	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACVRL1	Orphanet:275777	Heritable pulmonary arterial hypertension
ACVRL1	Orphanet:774	Hereditary hemorrhagic telangiectasia

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
ACVRL1	HGNC:175	ENSG00000139567	P37023	Activin receptor type-1-like	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 1 · 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	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACVRL1	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

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
right lung	1
upper lobe of left lung	1
upper lobe of lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACVRL1	221	broad	marker	right lung, upper lobe of left lung, upper lobe of lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACVRL1	2,234

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACVRL1	P37023	7

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	ACVRL1
Signaling by TGFB family members	1	115.3×	0.013	ACVRL1
Signal Transduction	1	10.2×	0.098	ACVRL1

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
regulation of endothelial cell proliferation	1	4213.0×	0.002	ACVRL1
negative regulation of endothelial cell differentiation	1	3370.4×	0.002	ACVRL1
venous blood vessel development	1	3370.4×	0.002	ACVRL1
regulation of blood vessel endothelial cell migration	1	2808.7×	0.002	ACVRL1
blood vessel maturation	1	2407.4×	0.002	ACVRL1
blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	2407.4×	0.002	ACVRL1
lymphatic endothelial cell differentiation	1	2407.4×	0.002	ACVRL1
dorsal aorta morphogenesis	1	2106.5×	0.002	ACVRL1
positive regulation of epithelial cell differentiation	1	1872.4×	0.002	ACVRL1
endothelial tube morphogenesis	1	1872.4×	0.002	ACVRL1
retina vasculature development in camera-type eye	1	1685.2×	0.002	ACVRL1
positive regulation of bicellular tight junction assembly	1	1685.2×	0.002	ACVRL1
positive regulation of endothelial cell differentiation	1	1532.0×	0.003	ACVRL1
artery development	1	1404.3×	0.003	ACVRL1
lymphangiogenesis	1	1203.7×	0.003	ACVRL1
wound healing, spreading of epidermal cells	1	1053.2×	0.003	ACVRL1
endocardial cushion morphogenesis	1	842.6×	0.003	ACVRL1
positive regulation of chondrocyte differentiation	1	802.5×	0.003	ACVRL1
negative regulation of endothelial cell migration	1	766.0×	0.003	ACVRL1
negative regulation of focal adhesion assembly	1	766.0×	0.003	ACVRL1
negative regulation of blood vessel endothelial cell migration	1	732.7×	0.003	ACVRL1
cellular response to BMP stimulus	1	561.7×	0.004	ACVRL1
negative regulation of endothelial cell proliferation	1	543.6×	0.004	ACVRL1
blood circulation	1	510.7×	0.004	ACVRL1
positive regulation of BMP signaling pathway	1	455.5×	0.004	ACVRL1
dorsal/ventral pattern formation	1	421.3×	0.005	ACVRL1
blood vessel remodeling	1	383.0×	0.005	ACVRL1
negative regulation of cell adhesion	1	383.0×	0.005	ACVRL1
positive regulation of SMAD protein signal transduction	1	383.0×	0.005	ACVRL1
regulation of DNA replication	1	366.4×	0.005	ACVRL1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
ACVRL1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACVRL1	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	ACVRL1
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
NINTEDANIB	4	ACVRL1
DASATINIB	4	ACVRL1
ALVOCIDIB	3	ACVRL1
LESTAURTINIB	3	ACVRL1
AT-9283	2	ACVRL1
ZILURGISERTIB	2	ACVRL1
TOZASERTIB	2	ACVRL1
PF-06952229	1	ACVRL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ACVRL1	213	Binding:207, Functional:3, Toxicity:2, ADMET:1

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ACVRL1	213

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

11 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
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
NINTEDANIB	4	ACVRL1
DASATINIB	4	ACVRL1
ALVOCIDIB	3	ACVRL1
LESTAURTINIB	3	ACVRL1
AT-9283	2	ACVRL1
ZILURGISERTIB	2	ACVRL1
TOZASERTIB	2	ACVRL1
PF-06952229	1	ACVRL1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACVRL1
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.