von Willebrand disease 1

Summary

von Willebrand disease 1 (MONDO:0008668) is a disease caused by VWF (GenCC Strong), with 2 cohort genes and 4 clinical trials.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Causal gene: VWF (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 311
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	von Willebrand disease 1
Mondo ID	MONDO:0008668
MeSH	D056725
OMIM	193400
Orphanet	166078
DOID	DOID:0060573
NCIT	C131685
SNOMED CT	128106003
UMLS	C1264039
MedGen	220393
GARD	0017019
Is cancer (heuristic)	no

Also known as: von Willebrand disease 1 · von Willebrand disease type 1 · VON WILLEBRAND disease, type 1 · von willebrand’s disease 1 · von Willebrand’s disease type 1 · VWD1

Data availability: 311 ClinVar variants · 3 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 1

Related subtypes (4): platelet-type von Willebrand disease, von Willebrand disease 3, 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

311 retrieved; paginated sample, class counts are floors:

117 uncertain significance, 50 pathogenic, 34 conflicting classifications of pathogenicity, 34 benign/likely benign, 30 likely pathogenic, 23 benign, 14 pathogenic/likely pathogenic, 8 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
100248	NM_000552.5(VWF):c.3179G>A (p.Cys1060Tyr)	VWF	Pathogenic	criteria provided, single submitter
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
100294	NM_000552.5(VWF):c.3863T>G (p.Leu1288Arg)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100310	NM_000552.5(VWF):c.3943C>T (p.Arg1315Cys)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100316	NM_000552.5(VWF):c.4021C>T (p.Arg1341Trp)	VWF	Pathogenic	reviewed by expert panel
100321	NM_000552.5(VWF):c.4075G>A (p.Glu1359Lys)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100330	NM_000552.5(VWF):c.4121G>A (p.Arg1374His)	VWF	Pathogenic	reviewed by expert panel
100338	NM_000552.5(VWF):c.421G>A (p.Asp141Asn)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100340	NM_000552.5(VWF):c.4213AAG[3] (p.Lys1408del)	VWF	Pathogenic	reviewed by expert panel
100347	NM_000552.5(VWF):c.4309G>A (p.Ala1437Thr)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100377	NM_000552.5(VWF):c.4636del (p.Met1545_Val1546insTer)	VWF	Pathogenic	criteria provided, single submitter
100427	NM_000552.5(VWF):c.5380A>G (p.Lys1794Glu)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100442	NM_000552.5(VWF):c.6536C>T (p.Ser2179Phe)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100451	NM_000552.5(VWF):c.6911G>A (p.Cys2304Tyr)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
100467	NM_000552.5(VWF):c.7390C>T (p.Arg2464Cys)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
1065275	NM_000552.5(VWF):c.2377C>T (p.Gln793Ter)	VWF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065306	NM_000552.5(VWF):c.7524_7525del (p.Asp2509fs)	VWF	Pathogenic	criteria provided, single submitter
1098431	NM_000552.5(VWF):c.3157dup (p.Gln1053fs)	VWF	Pathogenic	criteria provided, multiple submitters, no conflicts
1098436	NM_000552.5(VWF):c.1843dup (p.Cys615fs)	VWF	Pathogenic	criteria provided, single submitter
1098437	NM_000552.5(VWF):c.1730-1G>T	VWF	Pathogenic	criteria provided, single submitter
1098438	NM_000552.5(VWF):c.1110-1G>T	VWF	Pathogenic	criteria provided, single submitter
1098557	NM_000552.5(VWF):c.4413del (p.Asp1472fs)	VWF	Pathogenic	criteria provided, single submitter
1315522	NM_000552.5(VWF):c.221-2A>C	VWF	Pathogenic	no assertion criteria provided
1315524	NM_000552.5(VWF):c.322A>T (p.Arg108Ter)	VWF	Pathogenic	no assertion criteria provided
1315525	NM_000552.5(VWF):c.323+1G>T	VWF	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 7 · 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
CDH15	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

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
VWF	HGNC:12726	ENSG00000110799	P04275	von Willebrand factor	gencc,clinvar
CDH15	HGNC:1754	ENSG00000129910	P55291	Cadherin-15	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.
CDH15	Cadherin-15	Cadherins are calcium-dependent cell adhesion proteins.

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)
VWF	Other/Unknown	no		VWF_dom, VWF_type-D, VWF_A
CDH15	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf

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
apex of heart	1
tendon of biceps brachii	1
urethra	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	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
CDH15	139	broad	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VWF	5,204
CDH15	1,775

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VWF	P04275	48

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDH15	P55291	78.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. 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
Defective F8 binding to von Willebrand factor	1	2855.0×	0.004	VWF
Defective F8 cleavage by thrombin	1	1903.3×	0.004	VWF
Defective VWF binding to collagen type I	1	1903.3×	0.004	VWF
Enhanced cleavage of VWF variant by ADAMTS13	1	1427.5×	0.004	VWF
Defective VWF cleavage by ADAMTS13 variant	1	1427.5×	0.004	VWF
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	815.7×	0.005	VWF
Defective binding of VWF variant to GPIb:IX:V	1	815.7×	0.005	VWF
GP1b-IX-V activation signalling	1	475.8×	0.008	VWF
p130Cas linkage to MAPK signaling for integrins	1	380.7×	0.008	VWF
GRB2:SOS provides linkage to MAPK signaling for Integrins	1	356.9×	0.008	VWF
Platelet Adhesion to exposed collagen	1	335.9×	0.008	VWF
Amplification and propagation of coagulation cascade	1	317.2×	0.008	VWF
Initiation of coagulation cascade	1	237.9×	0.010	VWF
Platelet Aggregation (Plug Formation)	1	219.6×	0.010	VWF
Integrin signaling	1	211.5×	0.010	VWF
Myogenesis	1	190.3×	0.010	CDH15
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.010	VWF
MAP2K and MAPK activation	1	142.8×	0.010	VWF
Signaling by RAF1 mutants	1	139.3×	0.010	VWF
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.010	VWF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.010	VWF
Signaling downstream of RAS mutants	1	126.9×	0.010	VWF
Adherens junctions interactions	1	124.1×	0.010	CDH15
Cell-cell junction organization	1	124.1×	0.010	CDH15
Regulation of clotting cascade	1	116.5×	0.011	VWF
Cell junction organization	1	93.6×	0.013	CDH15
Signaling by BRAF and RAF1 fusions	1	85.2×	0.013	VWF
Cell-Cell communication	1	68.8×	0.016	CDH15
Integrin cell surface interactions	1	67.2×	0.016	VWF
Platelet degranulation	1	43.9×	0.023	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 2 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	842.6×	0.008	VWF
cell adhesion	2	37.5×	0.008	VWF, CDH15
cell-substrate adhesion	1	383.0×	0.009	VWF
positive regulation of intracellular signal transduction	1	324.1×	0.009	VWF
adherens junction organization	1	255.3×	0.009	CDH15
calcium-dependent cell-cell adhesion	1	240.7×	0.009	CDH15
cell-cell junction assembly	1	221.7×	0.009	CDH15
cell-cell adhesion mediated by cadherin	1	205.5×	0.009	CDH15
platelet activation	1	133.8×	0.012	VWF
response to wounding	1	110.9×	0.013	VWF
blood coagulation	1	86.9×	0.015	VWF
cell morphogenesis	1	78.8×	0.015	CDH15
homophilic cell-cell adhesion	1	70.2×	0.015	CDH15
cell migration	1	30.8×	0.032	CDH15

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
VWF	0	0
CDH15	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: 2; 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	VWF, CDH15

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)
VWF	17	—
CDH15	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06754852	PHASE1/PHASE2	RECRUITING	A Study Assessing HMB-002 in Participants With Von Willebrand Disease
NCT06610201	Not specified	RECRUITING	A Study of Bleeding and Treatment in Participants With Von Willebrand Disease
NCT03915873	Not specified	UNKNOWN	Evaluation of Bleeding Score in Egyptian Patients With vWD Type I and Correlate it With Laboratory Parameters
NCT06064851	Not specified	COMPLETED	Delivering Transcutaneous Auricular Neurostimulation to Reduce Heavy Menstrual Bleeding in Patients With and Without Von Willebrand Disease