von Willebrand disease 3

Summary

von Willebrand disease 3 (MONDO:0010191) is a disease caused by VWF (GenCC Strong), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include emicizumab and eptacog alfa (activated).

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VWF (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 315
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

13 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1865	Worldwide	Validated
Point prevalence	<1 / 1 000 000	0.037	Austria	Validated
Point prevalence	<1 / 1 000 000	0.24	Finland	Validated
Point prevalence	<1 / 1 000 000	0.016	France	Validated
Point prevalence	<1 / 1 000 000	0.16	Israel	Validated
Point prevalence	<1 / 1 000 000	0.055	Italy	Validated
Point prevalence	<1 / 1 000 000	0.037	Netherlands	Validated
Point prevalence	1-9 / 1 000 000	0.25	Norway	Validated
Point prevalence	<1 / 1 000 000	0.022	Portugal	Validated
Point prevalence	<1 / 1 000 000	0.011	Spain	Validated
Point prevalence	1-9 / 1 000 000	0.312	Sweden	Validated
Point prevalence	<1 / 1 000 000	0.027	United Kingdom	Validated
Prevalence at birth	<1 / 1 000 000	0.044	Greece	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	von Willebrand disease 3
Mondo ID	MONDO:0010191
MeSH	D056729
OMIM	277480
Orphanet	166096
DOID	DOID:0111054
NCIT	C85213
SNOMED CT	128108002
UMLS	C1264041
MedGen	266075
GARD	0017025
Is cancer (heuristic)	no

Also known as: von Willebrand disease 3 · von Willebrand disease type 3 · VON WILLEBRAND disease, type 3 · von Willebrand’s disease 3 · von Willebrand’s disease type 3 · VWD3

Data availability: 315 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › hemorrhagic disease › hereditary von Willebrand disease › von Willebrand disease 3

Related subtypes (4): platelet-type von Willebrand disease, von Willebrand disease 1, Von Willebrand disease, X-linked form, von Willebrand disease 2

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

315 retrieved; paginated sample, class counts are floors:

100 pathogenic, 77 uncertain significance, 40 likely pathogenic, 34 benign/likely benign, 23 conflicting classifications of pathogenicity, 21 benign, 12 pathogenic/likely pathogenic, 7 likely benign, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
100171	NM_000552.5(VWF):c.100C>T (p.Arg34Ter)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100172	NM_000552.5(VWF):c.1093C>T (p.Arg365Ter)	VWF	Pathogenic	criteria provided, single submitter
100198	NM_000552.5(VWF):c.1930G>T (p.Glu644Ter)	VWF	Pathogenic	no assertion criteria provided
100202	NM_000552.5(VWF):c.2116C>T (p.Gln706Ter)	VWF	Pathogenic	no assertion criteria provided
100203	NM_000552.5(VWF):c.2124_2125del (p.Cys709fs)	VWF	Pathogenic	no assertion criteria provided
100207	NM_000552.5(VWF):c.2269_2270del (p.Leu757fs)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100222	NM_000552.5(VWF):c.2443-1G>C	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100225	NM_000552.5(VWF):c.2516del (p.Gly839fs)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100238	NM_000552.5(VWF):c.276del (p.Phe92fs)	VWF	Pathogenic	no assertion criteria provided
100257	NM_000552.5(VWF):c.3379+1G>A	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100264	NM_000552.5(VWF):c.3467C>T (p.Thr1156Met)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100269	NM_000552.5(VWF):c.3568T>C (p.Cys1190Arg)	VWF	Pathogenic	reviewed by expert panel
100307	NM_000552.5(VWF):c.3931C>T (p.Gln1311Ter)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100320	NM_000552.5(VWF):c.4036C>T (p.Gln1346Ter)	VWF	Pathogenic	no assertion criteria provided
100371	NM_000552.5(VWF):c.4570del (p.Glu1523_Val1524insTer)	VWF	Pathogenic	no assertion criteria provided
100375	NM_000552.5(VWF):c.4626C>G (p.Tyr1542Ter)	VWF	Pathogenic	no assertion criteria provided
100424	NM_000552.5(VWF):c.533-2A>G	VWF	Pathogenic	criteria provided, single submitter
100425	NM_000552.5(VWF):c.5335C>T (p.Arg1779Ter)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
100435	NM_000552.5(VWF):c.6182del (p.Phe2061fs)	VWF	Pathogenic	no assertion criteria provided
100441	NM_000552.5(VWF):c.652C>T (p.Gln218Ter)	VWF	Pathogenic	no assertion criteria provided
100446	NM_000552.5(VWF):c.666G>A (p.Trp222Ter)	VWF	Pathogenic	no assertion criteria provided
100451	NM_000552.5(VWF):c.6911G>A (p.Cys2304Tyr)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100464	NM_000552.5(VWF):c.7300C>T (p.Arg2434Ter)	VWF	Pathogenic	no assertion criteria provided
100467	NM_000552.5(VWF):c.7390C>T (p.Arg2464Cys)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100469	NM_000552.5(VWF):c.7408C>T (p.Gln2470Ter)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100479	NM_000552.5(VWF):c.7630C>T (p.Gln2544Ter)	VWF	Pathogenic	no assertion criteria provided
100481	NM_000552.5(VWF):c.7664_7665insAG (p.Cys2557fs)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100482	NM_000552.5(VWF):c.7674dup (p.Ser2559fs)	VWF	Pathogenic	no assertion criteria provided
100493	NM_000552.5(VWF):c.817C>T (p.Arg273Trp)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100512	NM_000552.5(VWF):c.970C>T (p.Arg324Ter)	VWF	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
VWF	Definitive	Autosomal dominant	von Willebrand disease 2	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VWF	Orphanet:166078	Von Willebrand disease type 1
VWF	Orphanet:166084	Von Willebrand disease type 2A
VWF	Orphanet:166087	Von Willebrand disease type 2B
VWF	Orphanet:166090	Von Willebrand disease type 2M
VWF	Orphanet:166093	Von Willebrand disease type 2N
VWF	Orphanet:166096	Von Willebrand disease type 3

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
VWF	HGNC:12726	ENSG00000110799	P04275	von Willebrand factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VWF	von Willebrand factor	Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V.

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)
VWF	Other/Unknown	no		VWF_dom, VWF_type-D, VWF_A

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
apex of heart	1
tendon of biceps brachii	1
urethra	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VWF	289	broad	marker	urethra, tendon of biceps brachii, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VWF	5,204

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VWF	P04275	48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. 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
Defective F8 binding to von Willebrand factor	1	5710.0×	0.002	VWF
Defective F8 cleavage by thrombin	1	3806.7×	0.002	VWF
Defective VWF binding to collagen type I	1	3806.7×	0.002	VWF
Enhanced cleavage of VWF variant by ADAMTS13	1	2855.0×	0.002	VWF
Defective VWF cleavage by ADAMTS13 variant	1	2855.0×	0.002	VWF
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	1631.4×	0.002	VWF
Defective binding of VWF variant to GPIb:IX:V	1	1631.4×	0.002	VWF
GP1b-IX-V activation signalling	1	951.7×	0.003	VWF
p130Cas linkage to MAPK signaling for integrins	1	761.3×	0.003	VWF
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	713.8×	0.003	VWF
Platelet Adhesion to exposed collagen	1	671.8×	0.003	VWF
Amplification and propagation of coagulation cascade	1	634.4×	0.003	VWF
Initiation of coagulation cascade	1	475.8×	0.004	VWF
Platelet Aggregation (Plug Formation)	1	439.2×	0.004	VWF
Integrin signaling	1	423.0×	0.004	VWF
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	VWF
MAP2K and MAPK activation	1	285.5×	0.005	VWF
Signaling by RAF1 mutants	1	278.5×	0.005	VWF
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	VWF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	VWF
Signaling downstream of RAS mutants	1	253.8×	0.005	VWF
Regulation of clotting cascade	1	233.1×	0.005	VWF
Signaling by BRAF and RAF1 fusions	1	170.4×	0.006	VWF
Integrin cell surface interactions	1	134.3×	0.008	VWF
Platelet degranulation	1	87.8×	0.011	VWF

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
hemostasis	1	1685.2×	0.004	VWF
cell-substrate adhesion	1	766.0×	0.004	VWF
positive regulation of intracellular signal transduction	1	648.1×	0.004	VWF
platelet activation	1	267.5×	0.006	VWF
response to wounding	1	221.7×	0.006	VWF
blood coagulation	1	173.7×	0.007	VWF
cell adhesion	1	37.5×	0.027	VWF

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VWF	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
VWF	17	Binding:17

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	VWF

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)
VWF	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06998524	PHASE3	RECRUITING	A Study to Assess the Efficacy and Safety of Emicizumab in Participants With Type 3 Von Willebrand Disease
NCT05500807	PHASE1	RECRUITING	Emicizumab for Severe Von Willebrand Disease (VWD) and VWD/Hemophilia A
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06610201	Not specified	RECRUITING	A Study of Bleeding and Treatment in Participants With Von Willebrand Disease
NCT06883240	Not specified	RECRUITING	An Observational Study of Participants With Type 3 Von Willebrand Disease on Prophylactic Standard-of-Care Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMICIZUMAB	4	2
EPTACOG ALFA (ACTIVATED)	4	1