Hemophilia A: genes and variants
Explore variant evidence for Hemophilia A across 5 analyzed proteins (F8, F9, ACVRL1, F10, F7). Linked ClinVar records include 280 pathogenic or likely pathogenic variants, 73 variants of uncertain significance and 27 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to Hemophilia A
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.
277 ClinVar pathogenic / likely pathogenic and 96 uncertain variants in F8 have source records linked to Hemophilia A. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 1 uncertain variants in F9 have source records linked to Hemophilia A. Association strength is not clinical gene validity.
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 ClinVar pathogenic / likely pathogenic and 2 uncertain variants in ACVRL1 have source records linked to Hemophilia A. Association strength is not clinical gene validity.
F10: Coagulation factor X
After activation to factor Xa, it converts prothrombin to thrombin within the prothrombinase complex and therefore occupies a central position in the coagulation cascade. Biallelic deficiency causes a rare bleeding disorder, while factor Xa is a major target of direct oral anticoagulants.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in F10 have source records linked to Hemophilia A. Association strength is not clinical gene validity.
F7: Coagulation factor VII
It binds tissue factor at sites of vascular injury and initiates coagulation by activating factors IX and X. Biallelic deficiency causes a rare bleeding disorder with highly variable severity, while recombinant activated factor VII is used therapeutically in selected bleeding conditions.
0 ClinVar pathogenic / likely pathogenic and 0 uncertain variants in F7 have source records linked to Hemophilia A. Association strength is not clinical gene validity.
Weakly linked (only a few uncertain records): VWF.
Where Hemophilia A variants cluster
- F8 F5/8 type A 1 (positions 20–348): 78 of 277 ClinVar pathogenic / likely pathogenic variants, 2.0× more than its size predicts.
- F8 F5/8 type A 2 (positions 399–730): 66 of 277 ClinVar pathogenic / likely pathogenic variants, 1.7× more than its size predicts.
- F8 F5/8 type C 1 (positions 2040–2188): 34 of 277 ClinVar pathogenic / likely pathogenic variants, 1.9× more than its size predicts.
- F8 F5/8 type C 2 (positions 2193–2345): 31 of 277 ClinVar pathogenic / likely pathogenic variants, 1.7× more than its size predicts.
- F8 Plastocyanin-like 5 (positions 1713–1877): 30 of 277 ClinVar pathogenic / likely pathogenic variants, 1.5× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to Hemophilia A
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| F8 R1768H | 1768 | Plastocyanin-like 5 | Pathogenic / likely pathogenic (★★★) |
| F8 R1800H | 1800 | Plastocyanin-like 5 | Pathogenic / likely pathogenic (★★★) |
| F8 Q2208E | 2208 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 L327P | 327 | Plastocyanin-like 2 | Pathogenic / likely pathogenic (★★★) |
| F8 L327V | 327 | Plastocyanin-like 2 | Pathogenic / likely pathogenic (★★★) |
| F8 G474E | 474 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 G474R | 474 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 T137A | 137 | Plastocyanin-like 1 | Pathogenic / likely pathogenic (★★★) |
| F8 E200G | 200 | F5/8 type A 1 | Pathogenic / likely pathogenic (★★★) |
| F8 Y256N | 256 | Plastocyanin-like 2 | Pathogenic / likely pathogenic (★★★) |
| F8 L327Q | 327 | Plastocyanin-like 2 | Pathogenic / likely pathogenic (★★★) |
| F8 F328L | 328 | Plastocyanin-like 2 | Pathogenic / likely pathogenic (★★★) |
| F8 R458C | 458 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 S554G | 554 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 Y605C | 605 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★★) |
| F8 N1941S | 1941 | Plastocyanin-like 6 | Pathogenic / likely pathogenic (★★★) |
| F8 R2016W | 2016 | Plastocyanin-like 6 | Pathogenic / likely pathogenic (★★★) |
| F8 Q2208R | 2208 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 K108T | 108 | Plastocyanin-like 1 | Pathogenic / likely pathogenic (★★★) |
| F8 A111T | 111 | Plastocyanin-like 1 | Pathogenic / likely pathogenic (★★★) |
| F8 I405S | 405 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 R550H | 550 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 M633I | 633 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★★) |
| F8 S308L | 308 | Plastocyanin-like 2 | Pathogenic / likely pathogenic (★★★) |
| F8 I405T | 405 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 T696I | 696 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★★) |
| F8 G2102D | 2102 | F5/8 type C 1 | Pathogenic / likely pathogenic (★★★) |
| F8 W2248C | 2248 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 R612C | 612 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★★) |
| F8 A2220P | 2220 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 Y365C | 365 | Pathogenic / likely pathogenic (★★★) | |
| F8 A415D | 415 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★★) |
| F8 G1729E | 1729 | Plastocyanin-like 5 | Pathogenic / likely pathogenic (★★★) |
| F8 V2251A | 2251 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 R2339W | 2339 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 E2341K | 2341 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 C2345R | 2345 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★★) |
| F8 N713I | 713 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★★) |
| F8 E739K | 739 | Pathogenic / likely pathogenic (★★★) | |
| F8 Y1699F | 1699 | Pathogenic / likely pathogenic (★★) | |
| F8 R1708C | 1708 | Pathogenic / likely pathogenic (★★) | |
| F8 R2178C | 2178 | F5/8 type C 1 | Pathogenic / likely pathogenic (★★) |
| F8 R2326Q | 2326 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★) |
| F8 R391C | 391 | Pathogenic / likely pathogenic (★★) | |
| F8 R2178H | 2178 | F5/8 type C 1 | Pathogenic / likely pathogenic (★★) |
| F8 R2182C | 2182 | F5/8 type C 1 | Pathogenic / likely pathogenic (★★) |
| F8 R2323C | 2323 | F5/8 type C 2 | Pathogenic / likely pathogenic (★★) |
| F8 P165S | 165 | Plastocyanin-like 1 | Pathogenic / likely pathogenic (★★) |
| F8 I192T | 192 | Plastocyanin-like 1 | Pathogenic / likely pathogenic (★★) |
| F8 R391H | 391 | Pathogenic / likely pathogenic (★★) | |
| F8 G439V | 439 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★) |
| F8 G498R | 498 | Plastocyanin-like 3 | Pathogenic / likely pathogenic (★★) |
| F8 N637S | 637 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★) |
| F8 R717W | 717 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★) |
| F8 A723T | 723 | Plastocyanin-like 4 | Pathogenic / likely pathogenic (★★) |
| F8 Y1699S | 1699 | Pathogenic / likely pathogenic (★★) | |
| F8 Y1699C | 1699 | Pathogenic / likely pathogenic (★★) | |
| F8 R1768C | 1768 | Plastocyanin-like 5 | Pathogenic / likely pathogenic (★★) |
| F8 H1938R | 1938 | Plastocyanin-like 6 | Pathogenic / likely pathogenic (★★) |
| F8 R1960Q | 1960 | Plastocyanin-like 6 | Pathogenic / likely pathogenic (★★) |
Showing 60 of 280.
Uncertain variants prioritized for review in Hemophilia A
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| F8 R717L | 717 | Plastocyanin-like 4 | Conflicting reports (★) | +7: 2 other pathogenic changes within 3 positions; R717W at the same position is pathogenic; seen in 1.8e-06 of gnomAD DNA copies; REVEL 0.874 |
| F8 S2125T | 2125 | F5/8 type C 1 | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; S2125R at the same position is pathogenic; REVEL 0.941 |
| F8 T314P | 314 | Plastocyanin-like 2 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; T314A at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.57 |
Which prediction tools work for Hemophilia A
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- CATVariant: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 97 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: 92 out of 100
- SIFT: 87 out of 100
- phyloP: 85 out of 100
Same protein, different disease
- Hemophilia B also has ClinVar records linked to F8 variants; they fall in the same places as the Hemophilia A variants (35 pathogenic / likely pathogenic).
- Thrombophilia, X-linked, due to factor 8 defect also has ClinVar records linked to F8 variants; they fall mostly in different places as the Hemophilia A variants (15 pathogenic / likely pathogenic).
- Hemophilia B also has ClinVar records linked to F9 variants; they fall mostly in different places as the Hemophilia A variants (157 pathogenic / likely pathogenic).
- Thrombophilia, X-linked, due to factor 9 defect also has ClinVar records linked to F9 variants; they fall mostly in different places as the Hemophilia A variants (62 pathogenic / likely pathogenic).
- Warfarin sensitivity, X-linked also has ClinVar records linked to F9 variants; they fall mostly in different places as the Hemophilia A variants (6 pathogenic / likely pathogenic).
- Telangiectasia, hereditary hemorrhagic, type 2 also has ClinVar records linked to ACVRL1 variants; they fall mostly in different places as the Hemophilia A variants (178 pathogenic / likely pathogenic).
- Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia also has ClinVar records linked to ACVRL1 variants; they fall mostly in different places as the Hemophilia A variants (6 pathogenic / likely pathogenic).
- Hereditary hemorrhagic telangiectasia also has ClinVar records linked to ACVRL1 variants; they fall mostly in different places as the Hemophilia A variants (4 pathogenic / likely pathogenic).
- Pulmonary hypertension, primary, 1 also has ClinVar records linked to ACVRL1 variants; they fall mostly in different places as the Hemophilia A variants (3 pathogenic / likely pathogenic).
Diseases related to Hemophilia A
- Hemophilia B, also linked to F7, 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
- Hereditary factor X deficiency disease, also linked to F10
- Thrombophilia, X-linked, due to factor 8 defect, also linked to F8
- Factor X deficiency, also linked to F10
- Factor VII deficiency, also linked to F7
- Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia, also linked to ACVRL1
- Warfarin sensitivity, X-linked, also linked to F9
- Myocardial infarction, also linked to F7
Frequently asked questions
Which genes have records linked to Hemophilia A?
This view contains 5 analyzed proteins: F8, F9, ACVRL1, F10, F7. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 280 pathogenic or likely pathogenic variants, 73 variants of uncertain significance and 27 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 3 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 496 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses 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.
Download every variant as CSV · Browse all diseases · Methods · About the Center