Telangiectasia, hereditary hemorrhagic, type 5

Summary

Telangiectasia, hereditary hemorrhagic, type 5 (MONDO:0014217) is a disease caused by GDF2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: GDF2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 250

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	telangiectasia, hereditary hemorrhagic, type 5
Mondo ID	MONDO:0014217
OMIM	615506
UMLS	C3809710
MedGen	816040
GARD	0015978
Is cancer (heuristic)	no

Also known as: GDF2 hereditary hemorrhagic telangiectasia · GDF2 related HHT-like syndrome · hereditary hemorrhagic telangiectasia caused by mutation in GDF2 · HHT5 · telangiectasia, hereditary hemorrhagic, type 5

Data availability: 250 ClinVar variants · 5 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 5

Related subtypes (4): telangiectasia, hereditary hemorrhagic, type 1, telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia type 3, hereditary hemorrhagic telangiectasia type 4

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

250 retrieved; paginated sample, class counts are floors:

123 likely benign, 72 uncertain significance, 26 conflicting classifications of pathogenicity, 12 pathogenic, 9 benign/likely benign, 4 benign, 3 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703569	GRCh37/hg19 10q11.22-11.23(chr10:46576515-51680164)	AGAP10	Pathogenic	no assertion criteria provided
2426281	NC_000010.10:g.(?48413578)(48416693_?)del	GDF2	Pathogenic	criteria provided, single submitter
2778406	NM_016204.4(GDF2):c.1185_1191delinsTG (p.Thr396fs)	GDF2	Pathogenic	criteria provided, single submitter
2969924	NM_016204.4(GDF2):c.857dup (p.Leu287fs)	GDF2	Pathogenic	criteria provided, single submitter
3003292	NM_016204.4(GDF2):c.641G>A (p.Trp214Ter)	GDF2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3603321	NM_016204.4(GDF2):c.751del (p.Leu251fs)	GDF2	Pathogenic	criteria provided, single submitter
3606806	NM_016204.4(GDF2):c.1240_1249del (p.Leu414fs)	GDF2	Pathogenic	criteria provided, single submitter
3714037	NM_016204.4(GDF2):c.61C>T (p.Gln21Ter)	GDF2	Pathogenic	criteria provided, single submitter
3719687	NM_016204.4(GDF2):c.1063G>T (p.Glu355Ter)	GDF2	Pathogenic	criteria provided, single submitter
3729767	NM_016204.4(GDF2):c.178G>T (p.Glu60Ter)	GDF2	Pathogenic	criteria provided, single submitter
4714707	NM_016204.4(GDF2):c.217_220del (p.Ser73fs)	GDF2	Pathogenic	criteria provided, single submitter
541539	NM_016204.4(GDF2):c.1267G>A (p.Val423Met)	GDF2	Pathogenic	criteria provided, single submitter
541541	NM_016204.4(GDF2):c.76C>T (p.Gln26Ter)	GDF2	Pathogenic	criteria provided, multiple submitters, no conflicts
1478658	NM_016204.4(GDF2):c.329G>A (p.Arg110Gln)	GDF2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3381190	NM_016204.4(GDF2):c.1282T>C (p.Cys428Arg)	GDF2	Likely pathogenic	criteria provided, single submitter
88651	NM_016204.4(GDF2):c.203G>T (p.Arg68Leu)	GDF2	Likely pathogenic	criteria provided, single submitter
1033807	NM_016204.4(GDF2):c.252G>A (p.Glu84=)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1312603	NM_016204.4(GDF2):c.712G>A (p.Asp238Asn)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342888	NM_016204.4(GDF2):c.484C>A (p.Pro162Thr)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1362792	NM_016204.4(GDF2):c.825del (p.Met275fs)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1401328	NM_016204.4(GDF2):c.1243A>T (p.Lys415Ter)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1408617	NM_016204.4(GDF2):c.1135del (p.Leu379fs)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2173715	NM_016204.4(GDF2):c.1084T>C (p.Phe362Leu)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2609335	NM_016204.4(GDF2):c.451C>T (p.Arg151Ter)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3350727	NM_016204.4(GDF2):c.358A>G (p.Ile120Val)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3665805	NM_016204.4(GDF2):c.88C>T (p.Arg30Ter)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3677674	NM_016204.4(GDF2):c.338G>A (p.Ser113Asn)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374605	NM_016204.4(GDF2):c.1290G>A (p.Ter430=)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
390215	NM_016204.4(GDF2):c.871G>A (p.Gly291Ser)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424503	NM_016204.4(GDF2):c.1139T>C (p.Val380Ala)	GDF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
GDF2	Strong	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GDF2	Orphanet:275777	Heritable pulmonary arterial hypertension
GDF2	Orphanet:774	Hereditary hemorrhagic telangiectasia

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GDF2	HGNC:4217	ENSG00000263761	Q9UK05	Growth/differentiation factor 2	gencc,clinvar
AGAP10P	HGNC:23659	ENSG00000230869		ArfGAP with GTPase domain, ankyrin repeat and PH domain 10, pseudogene	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GDF2	Growth/differentiation factor 2	Potent circulating inhibitor of angiogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GDF2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
AGAP10P	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cervix squamous epithelium	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GDF2	17	tissue_specific	yes	cervix squamous epithelium, diaphragm, skeletal muscle tissue of biceps brachii
AGAP10P	128		yes	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GDF2	1,277
AGAP10P	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDF2	Q9UK05	20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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×	0.003	GDF2

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
positive regulation of epithelial cell differentiation	1	1872.4×	0.005	GDF2
positive regulation of bicellular tight junction assembly	1	1685.2×	0.005	GDF2
positive regulation of endothelial cell differentiation	1	1532.0×	0.005	GDF2
positive regulation of cartilage development	1	936.2×	0.005	GDF2
negative regulation of DNA replication	1	887.0×	0.005	GDF2
activin receptor signaling pathway	1	887.0×	0.005	GDF2
blood vessel morphogenesis	1	802.5×	0.005	GDF2
negative regulation of endothelial cell migration	1	766.0×	0.005	GDF2
negative regulation of blood vessel endothelial cell migration	1	732.7×	0.005	GDF2
cellular response to BMP stimulus	1	561.7×	0.005	GDF2
negative regulation of endothelial cell proliferation	1	543.6×	0.005	GDF2
branching involved in blood vessel morphogenesis	1	526.6×	0.005	GDF2
positive regulation of BMP signaling pathway	1	455.5×	0.005	GDF2
positive regulation of SMAD protein signal transduction	1	383.0×	0.006	GDF2
positive regulation of Notch signaling pathway	1	351.1×	0.006	GDF2
vasculogenesis	1	255.3×	0.006	GDF2
cartilage development	1	251.5×	0.006	GDF2
intracellular iron ion homeostasis	1	244.2×	0.006	GDF2
positive regulation of interleukin-8 production	1	244.2×	0.006	GDF2
positive regulation of endothelial cell proliferation	1	230.8×	0.006	GDF2
ossification	1	227.7×	0.006	GDF2
BMP signaling pathway	1	200.6×	0.007	GDF2
negative regulation of angiogenesis	1	168.5×	0.008	GDF2
negative regulation of cell growth	1	144.0×	0.009	GDF2
osteoblast differentiation	1	121.2×	0.010	GDF2
positive regulation of angiogenesis	1	115.4×	0.010	GDF2
transcription by RNA polymerase II	1	70.5×	0.016	GDF2
angiogenesis	1	62.4×	0.017	GDF2
positive regulation of DNA-templated transcription	1	27.9×	0.037	GDF2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	GDF2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GDF2	0	0
AGAP10P	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GDF2	4	Binding:4

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	2	GDF2, AGAP10P

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GDF2	4	—
AGAP10P	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.