Hereditary von Willebrand disease: genes and variants

Genes linked to Hereditary von Willebrand disease

• VWF: von Willebrand factor

  It tethers platelets to damaged vessel walls and carries factor VIII in the circulation, linking primary hemostasis with coagulation. Quantitative or qualitative pathogenic variants cause von Willebrand disease, the most common inherited bleeding disorder.

  26 disease-causing and 50 uncertain variants in VWF are linked to Hereditary von Willebrand disease.

Where Hereditary von Willebrand disease variants cluster

• VWF VWFA 1 (positions 1277–1453): 6 of 26 disease-causing changes, 3.7× more than its size predicts.
• VWF VWFA 2 (positions 1498–1665): 3 of 26 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Hereditary von Willebrand disease

Which prediction tools work for Hereditary von Willebrand disease

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 91 out of 100
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• phyloP: 79 out of 100

Same protein, different disease

• Von Willebrand disease is also caused by VWF variants; they fall mostly in different places as the Hereditary von Willebrand disease variants (112 disease-causing).
• Von Willebrand disorder is also caused by VWF variants; they fall mostly in different places as the Hereditary von Willebrand disease variants (12 disease-causing).

Diseases related to Hereditary von Willebrand disease

• Hypertrophic cardiomyopathy, also linked to VWF
• Noonan syndrome, also linked to VWF
• Von Willebrand disease, also linked to VWF
• Von Willebrand disorder, also linked to VWF
• Thrombotic thrombocytopenic purpura, also linked to VWF

Frequently asked questions

Which genes are linked to Hereditary von Willebrand disease?

In CATVariant, Hereditary von Willebrand disease is linked to 1 analyzed protein: VWF (von Willebrand factor).

How many genetic variants are linked to Hereditary von Willebrand disease?

120 variants: 26 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 50 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary von Willebrand disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Hereditary von Willebrand disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 26 disease-causing and 37 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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