hemophilia A

Summary

hemophilia A (MONDO:0010602) is a disease (an umbrella term covering 5 Mondo subtypes) caused by F8 (GenCC Strong), with 8 cohort genes and 476 clinical trials. The dominant Reactome pathway is Amplification and propagation of coagulation cascade (3 cohort genes). Top therapeutic interventions include emicizumab, turoctocog alfa, and octocog alfa.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: F8 (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 801
• Phenotypes (HPO): 14
• Clinical trials: 476

Clinical features

Epidemiology

Prevalence records

110 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	8	Europe	Validated
Point prevalence	1-5 / 10 000	10.5	France	Validated
Point prevalence	1-9 / 100 000	7	United States	Validated
Point prevalence	1-9 / 100 000	1.58	Africa	Validated
Point prevalence	1-9 / 100 000	7.6	Albania	Validated
Point prevalence	1-9 / 100 000	2.8	Algeria	Validated
Point prevalence	1-9 / 100 000	4.5	Argentina	Validated
Point prevalence	1-9 / 100 000	5	Armenia	Validated
Point prevalence	1-9 / 100 000	6.8	Australia	Validated
Point prevalence	1-9 / 100 000	4.3	Austria	Validated
Point prevalence	1-9 / 100 000	8	Azerbaijan	Validated
Point prevalence	1-9 / 1 000 000	0.2	Bangladesh	Validated
Point prevalence	1-9 / 100 000	5.1	Belarus	Validated
Point prevalence	1-9 / 100 000	6	Belgium	Validated
Point prevalence	1-9 / 100 000	2.2	Belize	Validated
Point prevalence	1-9 / 1 000 000	0.1	Bolivia	Validated
Point prevalence	1-9 / 100 000	2.6	Bosnia and Herzegovina	Validated
Point prevalence	1-9 / 100 000	3.7	Brazil	Validated
Point prevalence	1-9 / 100 000	6.8	Bulgaria	Validated
Point prevalence	1-9 / 100 000	7.3	Canada	Validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003125	Reduced factor VIII activity	Very frequent (80-99%)
HP:0011889	Bleeding with minor or no trauma	Very frequent (80-99%)
HP:0001907	Thromboembolism	Frequent (30-79%)
HP:0007420	Spontaneous hematomas	Frequent (30-79%)
HP:0030140	Oral cavity bleeding	Frequent (30-79%)
HP:0005261	Joint hemorrhage	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0009811	Abnormality of the elbow	Occasional (5-29%)
HP:0012233	Intramuscular hematoma	Occasional (5-29%)
HP:0030746	Intraventricular hemorrhage	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Very rare (<1-4%)
HP:0012223	Splenic rupture	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hemophilia A
Mondo ID	MONDO:0010602
MeSH	D006467
OMIM	134500, 306700
Orphanet	98878
DOID	DOID:12134
ICD-10-CM	D66
ICD-11	337607970
NCIT	C27146
SNOMED CT	234440005
UMLS	C0019069
MedGen	5501
GARD	0006591
MedDRA	10016080
NORD	1221
Is cancer (heuristic)	no

Also known as: autosomal haemophilia a · classic haemophilia · classic hemophilia · classical haemophilia · classical hemophilia · congenital factor VIII disorder · factor 8 deficiency · factor VIII deficiency · Haemophilia A · haemophilia A, congenital · haemophilia a, X-linked recessive · haemophilia type A · haemophilia type a · hem A · HEMA · hemophilia A · hemophilia A, congenital · hemophilia a, X-linked recessive · hemophilia type A · hemophilia type a (+2 more)

Data availability: 801 ClinVar variants · 93 ClinGen variant curations · 2 GenCC gene-disease records · 22 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › hemophilia A

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Subtypes (5): hemophilia A with vascular abnormality, severe hemophilia A, moderately severe hemophilia A, mild hemophilia A, symptomatic form of hemophilia A in female carriers

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

600 retrieved; paginated sample, class counts are floors:

318 pathogenic, 129 likely pathogenic, 72 uncertain significance, 30 pathogenic/likely pathogenic, 22 conflicting classifications of pathogenicity, 17 benign, 9 likely benign, 2 benign/likely benign, 1 uncertain significance; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1728213	NM_000020.3(ACVRL1):c.1130C>T (p.Ala377Val)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
426040	NM_000020.3(ACVRL1):c.1468C>T (p.Gln490Ter)	ACVRL1	Pathogenic	reviewed by expert panel
10085	NM_000132.4(F8):c.6976C>T (p.Arg2326Ter)	F8	Pathogenic	reviewed by expert panel
10086	NM_000132.4(F8):c.6682C>T (p.Arg2228Ter)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
10087	NC_000023.11:g.(?154835791)(154837753_154860431)del	F8	Pathogenic	no assertion criteria provided
10088	NM_000132.4(F8):c.6403C>T (p.Arg2135Ter)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
10089	NC_000023.11:g.(154974508_154984686)_(154984804_154986431)del	F8	Pathogenic	no assertion criteria provided
10090	NC_000023.11:g.(154930804_?)_(?_154933516)del	F8	Pathogenic	no assertion criteria provided
10091	NG_011403.2:g.(164642_165857)_(167293_189971)del	F8	Pathogenic	no assertion criteria provided
10092	NG_011403.2:g.(131648_164496)_(167293_189971)del	F8	Pathogenic	no assertion criteria provided
10093	NG_011403.2:g.(127859_131491)_(131648_164496)del	F8	Pathogenic	no assertion criteria provided
10094	F8, EX26DEL	F8	Pathogenic	no assertion criteria provided
10095	NC_000023.11:g.(?155022409)(155022724_?)del	F8	Pathogenic	no assertion criteria provided
10096	NM_000132.4(F8):c.6496C>T (p.Arg2166Ter)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
10098	NM_000132.4(F8):c.6683G>A (p.Arg2228Gln)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
10099	NM_000132.4(F8):c.872A>G (p.Glu291Gly)	F8	Pathogenic	no assertion criteria provided
10100	NG_011403.2:g.(5315_28123)_(30752_30752)del	F8	Pathogenic	no assertion criteria provided
10101	NG_011403.2:g.(28246_30628)_(80027_96047)del	F8	Pathogenic	no assertion criteria provided
10102	NG_011403.2:g.(30752_34575)_(167293_189971)del	F8	Pathogenic	no assertion criteria provided
10103	NG_011403.2:g.(43038_58171)_(99154_121150)del	F8	Pathogenic	no assertion criteria provided
10105	F8, EX26DEL	F8	Pathogenic	no assertion criteria provided
10106	NM_000132.4:c.3065_3066insL13054_3065dup	F8	Pathogenic	no assertion criteria provided
10107	F8, EX15DEL	F8	Pathogenic	no assertion criteria provided
10109	NM_000132.4(F8):c.6977G>T (p.Arg2326Leu)	F8	Pathogenic	no assertion criteria provided
10110	NM_000132.4(F8):c.5879G>A (p.Arg1960Gln)	F8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10111	NM_000132.4(F8):c.1172G>A (p.Arg391His)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
10112	NM_000132.4(F8):c.5113C>T (p.Gln1705Ter)	F8	Pathogenic	no assertion criteria provided
10113	NG_011403.2:g.(80027_96047)_(99154_121150)del	F8	Pathogenic	no assertion criteria provided
10114	NM_000132.4(F8):c.5122C>T (p.Arg1708Cys)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts
10115	NM_000132.4(F8):c.5096A>T (p.Tyr1699Phe)	F8	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 28 · 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
F8	Strong	X-linked	hemophilia A	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
F8	Orphanet:169802	Severe hemophilia A
F8	Orphanet:169805	Moderate hemophilia A
F8	Orphanet:169808	Mild hemophilia A
F8	Orphanet:177926	Bleeding disorder in hemophilia A carriers
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
ACVRL1	Orphanet:275777	Heritable pulmonary arterial hypertension
ACVRL1	Orphanet:774	Hereditary hemorrhagic telangiectasia
F9	Orphanet:169793	Severe hemophilia B
F9	Orphanet:169796	Moderate hemophilia B
F9	Orphanet:169799	Mild hemophilia B
F9	Orphanet:177929	Bleeding disorder in hemophilia B carriers
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction
LMAN1	Orphanet:35909	Combined deficiency of factor V and factor VIII

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
F8	HGNC:3546	ENSG00000185010	P00451	Coagulation factor VIII	gencc,clinvar
VWF	HGNC:12726	ENSG00000110799	P04275	von Willebrand factor	clinvar
H2AB3	HGNC:14455	ENSG00000277745	P0C5Z0	Histone H2A-Bbd type 2/3	clinvar
ACVRL1	HGNC:175	ENSG00000139567	P37023	Activin receptor type-1-like	clinvar
CTAG1B	HGNC:2491	ENSG00000184033	P78358	Cancer/testis antigen 1	clinvar
F9	HGNC:3551	ENSG00000101981	P00740	Coagulation factor IX	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
LMAN1	HGNC:6631	ENSG00000074695	P49257	Protein ERGIC-53	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
F8	Coagulation factor VIII	Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.
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.
H2AB3	Histone H2A-Bbd type 2/3	Atypical histone H2A which can replace conventional H2A in some nucleosomes and is associated with active transcription and mRNA processing.
ACVRL1	Activin receptor type-1-like	Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development.
F9	Coagulation factor IX	Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
LMAN1	Protein ERGIC-53	Mannose-specific lectin.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.38

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
Protease	1	4.6×	0.340
Antibody/Immunoglobulin	1	3.6×	0.340
Kinase	1	3.5×	0.340
Other/Unknown	5	1.1×	0.496

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
F8	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf
VWF	Other/Unknown	no		VWF_dom, VWF_type-D, VWF_A
H2AB3	Other/Unknown	no		Histone_H2A, Histone-fold
ACVRL1	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
CTAG1B	Other/Unknown	no		CTAG/Pcc1
F9	Protease	yes	3.4.21.22	EGF-type_Asp/Asn_hydroxyl_site, GLA_domain, EGF
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
LMAN1	Other/Unknown	no		Lectin_leg, ConA-like_dom_sf, Intracellular_Lectin-GPT

Expression context

Cohort genes with no expression data: 0.

7 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
right coronary artery	2
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
apex of heart	1
tendon of biceps brachii	1
urethra	1
right testis	1
right lung	1
upper lobe of left lung	1
upper lobe of lung	1
male germ line stem cell (sensu Vertebrata) in testis	1
testis	1
liver	1
right lobe of liver	1
secondary oocyte	1
popliteal artery	1
tibial artery	1
germinal epithelium of ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
F8	266	broad	marker	left ventricle myocardium, heart right ventricle, myocardium
VWF	289	broad	marker	urethra, tendon of biceps brachii, apex of heart
H2AB3	104		yes	primordial germ cell in gonad, right coronary artery, right testis
ACVRL1	221	broad	marker	right lung, upper lobe of left lung, upper lobe of lung
CTAG1B	36	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, testis
F9	45	tissue_specific	marker	right lobe of liver, liver, secondary oocyte
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
LMAN1	280	ubiquitous	marker	germinal epithelium of ovary, jejunal mucosa, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNA	5,321
VWF	5,204
LMAN1	2,474
ACVRL1	2,234
F8	1,900
CTAG1B	1,470
F9	1,451
H2AB3	1,174

Intra-cohort edges

A	B	Sources
F8	F9	intact, string_interaction
F8	LMAN1	string_interaction
F8	VWF	biogrid_interaction, intact, string_interaction
F9	VWF	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F9	P00740	56
VWF	P04275	48
FLNA	P21333	26
F8	P00451	25
CTAG1B	P78358	23
LMAN1	P49257	18
ACVRL1	P37023	7
H2AB3	P0C5Z0	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 65. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amplification and propagation of coagulation cascade	3	317.2×	4e-06	F8, VWF, F9
Defective F8 binding to von Willebrand factor	2	1903.3×	5e-06	F8, VWF
Initiation of coagulation cascade	3	237.9×	5e-06	F8, VWF, F9
Defective factor IX causes thrombophilia	2	1268.9×	6e-06	F8, F9
Defective F8 cleavage by thrombin	2	1268.9×	6e-06	F8, VWF
Defective cofactor function of FVIIIa variant	2	1268.9×	6e-06	F8, F9
Defective F9 variant does not activate FX	2	1268.9×	6e-06	F8, F9
Regulation of clotting cascade	3	116.5×	1e-05	F8, VWF, F9
GP1b-IX-V activation signalling	2	317.2×	1e-04	VWF, FLNA
Platelet degranulation	3	43.9×	2e-04	F8, VWF, FLNA
Cargo concentration in the ER	2	112.0×	8e-04	F8, LMAN1
Defective F8 accelerates dissociation of the A2 domain	1	1903.3×	0.002	F8
Defective F8 binding to the cell membrane	1	1903.3×	0.002	F8
Defective F8 secretion	1	1903.3×	0.002	F8
Defective F9 secretion	1	1903.3×	0.002	F9
COPII-mediated vesicle transport	2	54.4×	0.002	F8, LMAN1
Defective gamma-carboxylation of F9	1	951.7×	0.004	F9
Defective F8 sulfation at Y1699	1	634.4×	0.005	F8
Defective VWF binding to collagen type I	1	634.4×	0.005	VWF
Enhanced cleavage of VWF variant by ADAMTS13	1	475.8×	0.007	VWF
Defective VWF cleavage by ADAMTS13 variant	1	475.8×	0.007	VWF
Defective F9 activation	1	317.2×	0.009	F9
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	271.9×	0.010	VWF
Defective binding of VWF variant to GPIb:IX:V	1	271.9×	0.010	VWF
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	211.5×	0.012	F9
OAS antiviral response	1	211.5×	0.012	FLNA
Gamma-carboxylation of protein precursors	1	190.3×	0.012	F9
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	190.3×	0.012	F9
FXIIa, PKa-dependent activation of coagulation pathway	1	190.3×	0.012	F9
p130Cas linkage to MAPK signaling for integrins	1	126.9×	0.017	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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
blood coagulation	4	86.9×	8e-06	F8, VWF, F9, LMAN1
blood coagulation, intrinsic pathway	2	526.6×	3e-04	F8, FLNA
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	2106.5×	0.013	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	2106.5×	0.013	FLNA
positive regulation of organelle organization	1	702.2×	0.018	LMAN1
tubulin deacetylation	1	702.2×	0.018	FLNA
regulation of endothelial cell proliferation	1	526.6×	0.018	ACVRL1
formation of radial glial scaffolds	1	526.6×	0.018	FLNA
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	421.3×	0.018	FLNA
negative regulation of endothelial cell differentiation	1	421.3×	0.018	ACVRL1
venous blood vessel development	1	421.3×	0.018	ACVRL1
establishment of Sertoli cell barrier	1	421.3×	0.018	FLNA
regulation of blood vessel endothelial cell migration	1	351.1×	0.018	ACVRL1
tRNA threonylcarbamoyladenosine metabolic process	1	351.1×	0.018	CTAG1B
protein localization to bicellular tight junction	1	351.1×	0.018	FLNA
obsolete negative regulation of protein targeting to mitochondrion	1	351.1×	0.018	LMAN1
blood vessel maturation	1	300.9×	0.018	ACVRL1
blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	300.9×	0.018	ACVRL1
negative regulation of transcription by RNA polymerase I	1	300.9×	0.018	FLNA
lymphatic endothelial cell differentiation	1	300.9×	0.018	ACVRL1
dorsal aorta morphogenesis	1	263.3×	0.020	ACVRL1
positive regulation of epithelial cell differentiation	1	234.1×	0.020	ACVRL1
endothelial tube morphogenesis	1	234.1×	0.020	ACVRL1
hemostasis	1	210.7×	0.020	VWF
retina vasculature development in camera-type eye	1	210.7×	0.020	ACVRL1
positive regulation of bicellular tight junction assembly	1	210.7×	0.020	ACVRL1
positive regulation of endothelial cell differentiation	1	191.5×	0.020	ACVRL1
in utero embryonic development	2	18.0×	0.020	ACVRL1, LMAN1
artery development	1	175.5×	0.021	ACVRL1
positive regulation of platelet activation	1	162.0×	0.021	FLNA

Therapeutics

Drugs indicated for this disease

19 approved, 6 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
ANTIHEMOPHILIC FACTOR, PEGYLATED (MW 20000) HUMAN SEQUENCE RECOMBINANT	Approved (phase 4)
Damoctocog Alfa Pegol	Approved (phase 4)
Efanesoctocog Alfa	Approved (phase 4)
Efmoroctocog Alfa	Approved (phase 4)
Emicizumab	Approved (phase 4)
Eptacog Alfa (Activated)	Approved (phase 4)
Eptacog Beta (Activated)	Approved (phase 4)
Human Coagulation Factor Viii	Approved (phase 4)
Lonoctocog Alfa	Approved (phase 4)
Marstacimab	Approved (phase 4)
Moroctocog Alfa	Approved (phase 4)
Octocog Alfa	Approved (phase 4)
Simoctocog Alfa	Approved (phase 4)
Susoctocog Alfa	Approved (phase 4)
Tranexamic Acid	Approved (phase 4)
Turoctocog Alfa	Approved (phase 4)
Turoctocog Alfa Pegol	Approved (phase 4)
Valoctocogene Roxaparvovec	Approved (phase 4)
Von Willebrand Factor Human	Approved (phase 4)
Anti-Inhibitor Coagulant Complex	Phase 3 (in late-stage trials)
Antithrombin Iii Human	Phase 3 (in late-stage trials)
Concizumab	Phase 3 (in late-stage trials)
Fitusiran	Phase 3 (in late-stage trials)
Giroctocogene Fitelparvovec	Phase 3 (in late-stage trials)
Omfiloctocog Alfa	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ataluren, Oprelvekin, Prednisone, Rituximab, Thrombin, Vatreptacog Alfa (Activated).

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 7 of 8 evidence-associated genes (88%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ACVRL1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACVRL1	11	4
F9	2	2
FLNA	1	2
F8	0	0
VWF	0	0
H2AB3	0	0
CTAG1B	0	0
LMAN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	ACVRL1
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
NINTEDANIB	4	ACVRL1
DASATINIB	4	ACVRL1
ALVOCIDIB	3	ACVRL1
LESTAURTINIB	3	ACVRL1
AT-9283	2	ACVRL1
ZILURGISERTIB	2	ACVRL1
TOZASERTIB	2	ACVRL1
LETAXABAN	2	F9
RAZAXABAN	2	F9
MOLIBRESIB	2	FLNA
PF-06952229	1	ACVRL1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACVRL1	213	Binding:207, Functional:3, Toxicity:2, ADMET:1
F9	108	Binding:107, ADMET:1
VWF	17	Binding:17
F8	8	Binding:8
FLNA	7	Binding:7
LMAN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACVRL1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
F9	3.4.21.22	coagulation factor IXa

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ACVRL1	213
F9	108

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

14 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	ACVRL1
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
NINTEDANIB	4	ACVRL1
DASATINIB	4	ACVRL1
ALVOCIDIB	3	ACVRL1
LESTAURTINIB	3	ACVRL1
AT-9283	2	ACVRL1
ZILURGISERTIB	2	ACVRL1
TOZASERTIB	2	ACVRL1
LETAXABAN	2	F9
RAZAXABAN	2	F9
MOLIBRESIB	2	FLNA
PF-06952229	1	ACVRL1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACVRL1
B	Phased (≥1) drug, not yet approved	2	F9, FLNA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	F8, VWF, H2AB3, CTAG1B, LMAN1

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
F8	8	F9
VWF	17	—
H2AB3	0	—
CTAG1B	0	—
LMAN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 476.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	221
PHASE3	102
PHASE1	56
PHASE4	52
PHASE2	17
PHASE1/PHASE2	15
PHASE2/PHASE3	10
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05181618	PHASE4	ACTIVE_NOT_RECRUITING	A Study to Evaluate Overall Health, Physical Activity, and Joint Outcomes in Participants With Severe or Moderate Hemophilia A Without Factor VIII Inhibitors on Emicizumab Prophylaxis
NCT05936580	PHASE4	RECRUITING	Nuwiq Dosing and Outcomes In the ManagEment of Women/Girls With Haemophilia A Needing FVIII Treatment for Surgery
NCT06145373	PHASE4	RECRUITING	A Study to Test a Medicine (Fitusiran) for Preventing Bleeds in People With Severe Hemophilia Who Previously Received Preventive Treatment With Emicizumab
NCT06752850	PHASE4	ACTIVE_NOT_RECRUITING	A Study to Investigate the Course of Synovial Hypertrophy in Patients With Haemophilia A on Efanesoctocog Alfa Prophylaxis
NCT06940830	PHASE4	RECRUITING	Long-term Study Evaluating Joint Health in People With Haemophilia A Receiving Real-world Prophylactic Treatment With Efanesoctocog Alfa
NCT06941870	PHASE4	RECRUITING	Efanesoctocog Alfa Prophylaxis in Patients With Hemophilia A With Synovial Hypertrophy
NCT00002386	PHASE4	COMPLETED	Effect of Indinavir Plus Two Other Anti-HIV Drugs on Blood Clotting in HIV-Positive Males With Hemophilia
NCT00092976	PHASE4	COMPLETED	Study Evaluating ReFacto® in Hemophilia A Undergoing Major Surgery
NCT00151385	PHASE4	WITHDRAWN	Study Evaluating Inhibitor Specificity in Hemophilia A
NCT00168051	PHASE4	WITHDRAWN	Study Comparing Blood Levels of ReFacto and Advante in Hemophilia A
NCT00243386	PHASE4	COMPLETED	Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
NCT00284193	PHASE4	COMPLETED	Combination Therapy of Low Doses of rFVIIa and FEIBA for Severe Hemophilia A Patients With an Inhibitor to Factor VIII
NCT00289536	PHASE4	COMPLETED	Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
NCT00357656	PHASE4	COMPLETED	Phase 3/4 Study of a Recombinant Protein-Free Factor VIII (rAHF-PFM): Comparison of Continuous Infusion Versus Intermittent Bolus Infusion in Hemophilia A Subjects Undergoing Major Orthopedic Surgery
NCT00586521	PHASE4	COMPLETED	BAY14-2222 Prophylaxis and Joint Function Improvement (Adults)
NCT00621673	PHASE4	TERMINATED	Assessment of the Risk of Inhibitor Formation in Previously Treated Patients With Severe Hemophilia A
NCT00632814	PHASE4	COMPLETED	Russian Kogenate Pediatric Study
NCT00638001	PHASE4	COMPLETED	Impact of Conservative Treatment by Custom-made Orthoses in Patients With Haemophilic Ankle Arthropathy
NCT00666406	PHASE4	COMPLETED	Pharmacokinetic Comparison of Advate rAHF-PFM With Recombinate rAHF in Patients With Severe Hemophilia A
NCT00765726	PHASE4	TERMINATED	Study Evaluating The Safety Of Xyntha In Usual Care Settings
NCT00884390	PHASE4	TERMINATED	Study Evaluating Safety Of Patients Switching To ReFacto AF In Usual Care Settings
NCT00914459	PHASE4	COMPLETED	Study Evaluating Safety And Efficacy Of Moroctocog Alfa (AF-CC) In Previously Treated Hemophilia A Patients
NCT00916032	PHASE4	COMPLETED	Pharmacokinetic Study of ADVATE 3000 IU in Previously Treated Patients With Severe Hemophilia A
NCT00927667	PHASE4	COMPLETED	Joint Status in Subjects With Severe Hemophilia A in Relation to Different Treatment Regimens
NCT00950170	PHASE4	COMPLETED	Study of Safety And Efficacy Of ReFacto AF In Previously Untreated Hemophilia A Patients In The Usual Care Setting
NCT01064284	PHASE4	COMPLETED	Survey of Inhibitors in Plasma-Product Exposed Toddlers
NCT01748201	PHASE4	COMPLETED	Viscosupplementation in Patients With Hemophilic Arthropathy
NCT01810666	PHASE4	COMPLETED	Prophylaxis Versus on Demand Treatment for Children With Hemophilia A
NCT01811875	PHASE4	TERMINATED	Post-Marketing Safety Study Following Long-Term Prophylactic OptivateTreatment in Subjects With Severe Haemophilia A
NCT02170402	PHASE4	COMPLETED	China ADVATE PTP Study
NCT02314325	PHASE4	UNKNOWN	Subclinical Joint Bleeding in Irish Adults With Severe Haemophilia A on Personalised Prophylaxis Regimens
NCT02479087	PHASE4	UNKNOWN	Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients
NCT02492984	PHASE4	COMPLETED	PF-05208756, Moroctocog Alfa (AF-CC), Xyntha For Hemophilia A
NCT02697370	PHASE4	COMPLETED	Efficacy and Cost Effectiveness of Pharmacokinetic Dosing in Haemophilia A
NCT02727647	PHASE4	COMPLETED	Comparison of Different Prophylaxis Regimens for Moderate to Severe Hemophilia A Pediatric Patients
NCT03103542	PHASE4	COMPLETED	Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies
NCT03204539	PHASE4	TERMINATED	INdividualized ITI Based on Fviii(ATE) Protection by VWF
NCT03361137	PHASE4	TERMINATED	Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures
NCT03379974	PHASE4	COMPLETED	Exercise Versus DDAVP in Patients With Mild Hemophilia A
NCT03449342	PHASE4	COMPLETED	Research Study to Look at Side Effects During Regular Injection With Factor VIII Medicine Named Turoctocog Alfa for a 8 Weeks Period

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMICIZUMAB	4	22
TUROCTOCOG ALFA	4	18
OCTOCOG ALFA	4	17
ANTIHEMOPHILIC FACTOR, PEGYLATED (MW 20000) HUMAN SEQUENCE RECOMBINANT	4	14
MOROCTOCOG ALFA	4	13
TUROCTOCOG ALFA PEGOL	4	13
EFANESOCTOCOG ALFA	4	12
EPTACOG ALFA (ACTIVATED)	4	10
HUMAN COAGULATION FACTOR VIII	4	7
CONCIZUMAB	4	6
MARSTACIMAB	4	6
VALOCTOCOGENE ROXAPARVOVEC	4	6
EFMOROCTOCOG ALFA	4	5
LONOCTOCOG ALFA	4	3
ZIDOVUDINE	4	3
DESMOPRESSIN	4	2
EFTRENONACOG ALFA	4	2
SIMOCTOCOG ALFA	4	2
ATALUREN	4	1
DIDANOSINE	4	1
INDINAVIR SULFATE	4	1
LAMIVUDINE	4	1
STAVUDINE	4	1
ZALCITABINE	4	1
FITUSIRAN	3	5
ANTI-INHIBITOR COAGULANT COMPLEX	3	2
OMFILOCTOCOG ALFA	3	2
GIROCTOCOGENE FITELPARVOVEC	3	1
VATREPTACOG ALFA (ACTIVATED)	3	1
DENECIMIG	2	4