Hereditary factor VIII deficiency disease: genes and variants

Genes linked to Hereditary factor VIII deficiency disease

• F8: Coagulation factor VIII

  After activation, it acts as a cofactor for factor IXa and greatly accelerates factor X activation during coagulation. Loss-of-function variants cause X-linked hemophilia A, with bleeding severity determined largely by residual factor VIII activity.

  273 disease-causing and 95 uncertain variants in F8 are linked to Hereditary factor VIII deficiency disease.

• F9: Coagulation factor IX

  Its activated form combines with factor VIIIa to efficiently activate factor X during coagulation. Pathogenic loss-of-function variants cause X-linked hemophilia B, with bleeding severity determined largely by residual factor IX activity.

  2 disease-causing and 1 uncertain variants in F9 are linked to Hereditary factor VIII deficiency disease.

• ACVRL1: Activin receptor type-1-like

  It mediates BMP9 and BMP10 signaling in vascular endothelial cells and helps maintain normal vessel maturation and quiescence. Heterozygous loss-of-function variants cause hereditary hemorrhagic telangiectasia type 2, with telangiectasias and arteriovenous malformations.

  1 disease-causing and 2 uncertain variants in ACVRL1 are linked to Hereditary factor VIII deficiency disease.

Weakly linked (only a few uncertain records): VWF.

Where Hereditary factor VIII deficiency disease variants cluster

• F8 F5/8 type A 1 (positions 20–348): 77 of 273 disease-causing changes, 2.0× more than its size predicts.
• F8 F5/8 type A 2 (positions 399–730): 65 of 273 disease-causing changes, 1.7× more than its size predicts.
• F8 F5/8 type C 1 (positions 2040–2188): 34 of 273 disease-causing changes, 2.0× more than its size predicts.
• F8 F5/8 type C 2 (positions 2193–2345): 31 of 273 disease-causing changes, 1.7× more than its size predicts.
• F8 Plastocyanin-like 5 (positions 1713–1877): 30 of 273 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Hereditary factor VIII deficiency disease

Showing 60 of 276.

Uncertain variants in Hereditary factor VIII deficiency disease that look disease-causing

Which prediction tools work for Hereditary factor VIII deficiency disease

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

• CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 91 out of 100
• SIFT: 87 out of 100
• phyloP: 84 out of 100

Same protein, different disease

• Hereditary factor IX deficiency disease is also caused by F8 variants; they fall in the same places as the Hereditary factor VIII deficiency disease variants (35 disease-causing).
• Thrombophilia, X-linked, due to factor 8 defect is also caused by F8 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (15 disease-causing).
• Factor VIII deficiency is also caused by F8 variants; they fall partly in the same places as the Hereditary factor VIII deficiency disease variants (5 disease-causing).
• Hereditary factor IX deficiency disease is also caused by F9 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (157 disease-causing).
• Thrombophilia, X-linked, due to factor 9 defect is also caused by F9 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (62 disease-causing).
• Warfarin sensitivity, X-linked is also caused by F9 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (6 disease-causing).
• Telangiectasia, hereditary hemorrhagic, type 2 is also caused by ACVRL1 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (178 disease-causing).
• Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia is also caused by ACVRL1 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (6 disease-causing).
• Hereditary hemorrhagic telangiectasia is also caused by ACVRL1 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (4 disease-causing).
• Pulmonary hypertension, primary, 1 is also caused by ACVRL1 variants; they fall mostly in different places as the Hereditary factor VIII deficiency disease variants (3 disease-causing).

Diseases related to Hereditary factor VIII deficiency disease

• Hereditary factor IX deficiency disease, also linked to F8 and F9
• Telangiectasia, hereditary hemorrhagic, type 2, also linked to ACVRL1
• Thrombophilia, X-linked, due to factor 9 defect, also linked to F9
• Pulmonary hypertension, primary, 1, also linked to ACVRL1
• Pulmonary arterial hypertension, also linked to ACVRL1
• Thrombophilia, X-linked, due to factor 8 defect, also linked to F8
• Warfarin sensitivity, X-linked, also linked to F9
• Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia, also linked to ACVRL1
• Factor VIII deficiency, also linked to F8
• Hereditary hemorrhagic telangiectasia, also linked to ACVRL1

Frequently asked questions

Which genes are linked to Hereditary factor VIII deficiency disease?

In CATVariant, Hereditary factor VIII deficiency disease is linked to 3 analyzed proteins: F8 (Coagulation factor VIII), F9 (Coagulation factor IX) and ACVRL1 (Activin receptor type-1-like).

How many genetic variants are linked to Hereditary factor VIII deficiency disease?

398 variants: 276 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 99 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary factor VIII deficiency disease look disease-causing?

3 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example F8 R717L, F8 S2125T and F8 T314P. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Hereditary factor VIII deficiency disease?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 75 disease-causing and 106 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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