F8

Summary

F8 (coagulation factor VIII, HGNC:3546) is a protein-coding gene on chromosome Xq28, encoding Coagulation factor VIII (P00451). 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. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder.

Source: NCBI Gene 2157 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hemophilia A (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,577 total — 422 pathogenic, 246 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000132

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3546
Approved symbol	F8
Name	coagulation factor VIII
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	FVIII, DXS1253E, HEMA
Ensembl gene	ENSG00000185010
Ensembl biotype	protein_coding
OMIM	300841
Entrez	2157

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000330287, ENST00000360256, ENST00000423959, ENST00000453950, ENST00000483822, ENST00000644698, ENST00000647125

RefSeq mRNA: 2 — MANE Select: NM_000132 NM_000132, NM_019863

CCDS: CCDS35457, CCDS44026

Canonical transcript exons

ENST00000360256 — 26 exons

Exon	Start	End
ENSE00001096327	154904296	154904524
ENSE00001096342	154996973	154997095
ENSE00001096346	154903906	154904088
ENSE00001096349	154861718	154861866
ENSE00001096353	154906420	154906573
ENSE00001096366	154904811	154905023
ENSE00001096386	154860432	154860608
ENSE00001297698	154902051	154902167
ENSE00001308463	154863083	154863227
ENSE00001311652	154928571	154931676
ENSE00001403942	154896077	154896232
ENSE00001411839	154899866	154899951
ENSE00001413135	154901371	154901442
ENSE00001422135	154999479	154999600
ENSE00001591329	154947698	154947907
ENSE00001607410	154961075	154961168
ENSE00001633063	154987237	154987305
ENSE00001645223	155022410	155022723
ENSE00001653886	154969331	154969552
ENSE00001708410	154965970	154966141
ENSE00001748476	154956957	154957171
ENSE00001769821	154953892	154954042
ENSE00001776938	154966426	154966687
ENSE00001878069	154835792	154837752
ENSE00002220051	154992936	154993148
ENSE00002250458	154984687	154984803

Expression profiles

Bgee: expression breadth ubiquitous, 266 present calls, max score 94.87.

FANTOM5 (CAGE): breadth broad, TPM avg 1.8358 / max 136.4617, expressed in 385 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201072	1.3881	170
201075	0.4285	245
201073	0.0192	7

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	94.87	gold quality
heart right ventricle	UBERON:0002080	93.97	gold quality
myocardium	UBERON:0002349	93.61	gold quality
cardiac ventricle	UBERON:0002082	92.02	gold quality
heart left ventricle	UBERON:0002084	91.98	gold quality
right atrium auricular region	UBERON:0006631	91.54	gold quality
cardiac atrium	UBERON:0002081	91.52	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.50	gold quality
tibialis anterior	UBERON:0001385	90.89	gold quality
apex of heart	UBERON:0002098	90.84	gold quality
pericardium	UBERON:0002407	90.69	gold quality
heart	UBERON:0000948	90.23	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.87	gold quality
lower lobe of lung	UBERON:0008949	89.77	gold quality
omental fat pad	UBERON:0010414	89.74	gold quality
peritoneum	UBERON:0002358	89.67	gold quality
adipose tissue	UBERON:0001013	89.38	gold quality
connective tissue	UBERON:0002384	88.20	gold quality
choroid plexus epithelium	UBERON:0003911	88.00	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.43	gold quality
biceps brachii	UBERON:0001507	87.21	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.21	gold quality
gastrocnemius	UBERON:0001388	86.59	gold quality
muscle of leg	UBERON:0001383	86.57	gold quality
deltoid	UBERON:0001476	86.41	silver quality
adrenal tissue	UBERON:0018303	86.22	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.14	gold quality
muscle organ	UBERON:0001630	85.89	gold quality
left adrenal gland cortex	UBERON:0035825	84.58	gold quality
muscle tissue	UBERON:0002385	84.56	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	47.70
E-GEOD-134144	yes	40.74
E-GEOD-135922	yes	24.47
E-HCAD-9	yes	17.78
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APC, CEBPB, HLF, HNF1A, IRF6, NFKB1, RELA

miRNA regulators (miRDB)

80 targeting F8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3202	99.66	67.70	2737

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. (PMID:11748850)
• Fourteen of the 21 females were confirmed to be carriers. (PMID:11769673)
• Cofactor activities of factor VIIIa and A2 subunit following cleavage of A1 subunit at Arg336 (PMID:11799130)
• 3-Dimensional structure of membrane-bound coagulation factor VIII from electron crystallography (PMID:11830468)
• No mutations at the APC interacting sites exons 8, 11, & 19) of factor VIII were found in Caucasians with recurrent deep venous thrombosis. (PMID:11848448)
• A founder factor VIII mutation, valine 2016 to alanine, was found in a Newfoundland population with an extraordinarily high prevalence of mild hemophilia A. (PMID:11848452)
• Forty-one novel causative factor VIII gene mutations have been identified and classified in hemophiliacs. (PMID:11857744)
• Heteroduplex screening identified 74 small mutations in the F8 genes of 72 families with hemophilia A. In 24 families, at least one affected member had an alloimmune response to F8: of these, 11 were associated with missense mutations. (PMID:11858487)
• Activation by thrombin dramatically increased fVIII affinity for LDL but not HDL, which may be related to differences in phospholipid composition of the LPs. (PMID:11864712)
• increased procoagulant activity due to formation of additional fVIII phosphatidylserine binding sites on the outer surface of oxLDL-treated cells and higher binding affinity between components of the Xase complex, activated factors VIII and IX. (PMID:12036878)
• Effect of deficiency on generation of thrombin (PMID:12058364)
• Mutations associated with hemophilia A in the 558-565 loop of the factor VIIIa A2 subunit alter the catalytic activity of the factor Xase complex. (PMID:12091341)
• Alu-repetitive elements are directly involved in the origin of a novel large FVIII gene deletion caused by unequal homologous Alu/Alu recombination in a severe hemophilia A patient (PMID:12154809)
• REVIEW: Molecular defects in coagulation Factor VIII and their impact on Factor VIII function. (PMID:12201837)
• Seven novel mutations causing severe, moderate and mild Hemophilia A. (PMID:12203998)
• Reported nine novel (6 deletions, two indels and one partial duplication) and five recurrent small rearrangements identified in 15 German patients with severe hemophilia A. (PMID:12204009)
• The activation of procofactor VIII to factor VIIIa increases the affinity of binding to platelets of both factor VIIIa and factor X. (PMID:12220193)
• Factor VIIIc may play a role in the development of venous thromboembolism in factor V Leiden carriers (PMID:12368162)
• The intron 1 factor VIII gene inversion was found in 1 of 20 in a population of Italian hemophilia A patients. (PMID:12412575)
• Mutagenecity studies suggests that the entire tightly packed hydrophobic core within the predicted pseudo-threefold axis contributes to stabilization of FVIIIa. (PMID:12428094)
• coagulation factor VIII has a specific domain (A3) for binding low density lipoprotein receptor-related protein and factor IXa (PMID:12522143)
• mutation, or lack of mutation in this protein in hemophilia A (PMID:12567191)
• The role of factor VIII in tissue factor-initiated spatial clot growth was studied on fibroblast monolayers in recalcified plasma from severe haemophilia A. Functioning of the intrinsic tenase complex is critical for normal spatial clot growth. (PMID:12574801)
• review of the response of T- and B-cells to transfused Factor VIII, epitope mapping, and the mechanism of inhibition of F8 by alloantibodies (PMID:12617176)
• inactivating mutations in MCFD2 cause combined deficiency of factor V and factor VIII with a phenotype indistinguishable from that caused by mutations in LMAN1 (PMID:12717434)
• The binding activity of the C-C2 domain to PS-containing phospholipid vesicles was measured, showing that the C2 domain alone does not have full membrane binding activity, and that the other light chain domains, A3 and/or C1, are also involved. (PMID:12719774)
• Competitive ELISAs suggested that F2200 plays a more important role in both phospholipid-binding and vWF-binding than N2198 and M2199. (PMID:12719775)
• Large gene rearrangements of introns of the factor VIII gene in severe hemophilia A. (PMID:12857556)
• Molecular modeling suggested mechanisms by which substitutions at residues 382 and 569, located outside the proposed FIXa-binding region, may influence FVIII/FIXa interaction. His2155 was predicted to participate in FVIII/VFW binding. (PMID:12871415)
• antibodies against FVIII acidic regions can inhibit FVIII function by a variety of mechanisms, in particular by interfering with the binding of FVIII to phospholipids & VWF. (PMID:12958606)
• A deletion of Ala2201 (Del2201) was identified in the FVIII C2 domain of 2 unrelated patients with mild hemophilia A. This mutation prevents FVIII binding to a human monoclonal antibody recognizing the C2 domain. (PMID:12969981)
• studied a group of healthy non-bleeding women to evaluate normal ranges OF F8 and VWF and their relationship to blood group and parity in normal pregnancy, and the return to non-pregnant factor levels in puerperium (PMID:14517489)
• high levels of coagulation FXI, FIX and FVIII are related to risk of inherited thrombophilia syndrome (PMID:14521595)
• FIXa/FVIIIa binding studies of coordinate binding of FVIIIa and FX to equivalent numbers of binding sites on activated platelets provide strong evidence that FVIIIa comprises the receptor that presents FX to FIXa for catalysis on the platelet membrane. (PMID:14629468)
• an interaction between LMAN1 and FVIII in vivo was mediated via high mannose-containing asparagine-linked oligosaccharides that are densely situated within the B domain of FVIII, as well as protein-protein interactions (PMID:14629470)
• occurrence of high levels associated with stroke in a 5-year old girl (PMID:14644079)
• elevated factor (F)VIII:C plasma levels are a risk factor for early recurrent miscarriages (PMID:14675089)
• review of role of factor VIIIa to markedly increase the catalytic efficiency of factor IXa in the activation of factor X (PMID:14684146)
• The factor VIII gene intron 1 inversion mutation: prevalence in severe hemophilia A patients in the UK. (PMID:14717992)
• factor VIII has a Ca2+ binding site required for cofactor activity in the A1 domain (PMID:14722121)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	F8	ENSMUSG00000031196
rattus_norvegicus	F8	ENSRNOG00000031197

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), TLL2 (ENSG00000095587), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Coagulation factor VIII — P00451 (reviewed: P00451)

Alternative names: Antihemophilic factor, Procoagulant component

All UniProt accessions (5): P00451, A0A2R8Y707, A0A2R8Y7J7, B1B0G8, B1B0G9

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Interacts with VWF/vWF. vWF binding is essential for the stabilization of F8 in circulation.

Subcellular location. Secreted. Extracellular space.

Post-translational modifications. Sulfation on Tyr-1699 is essential for binding vWF. Proteolytically cleaved by cathepsin CTSG to produce a partially activated form.

Disease relevance. Hemophilia A (HEMA) [MIM:306700] A disorder of blood coagulation characterized by a permanent tendency to hemorrhage. About 50% of patients have severe hemophilia resulting in frequent spontaneous bleeding into joints, muscles and internal organs. Less severe forms are characterized by bleeding after trauma or surgery. The disease is caused by variants affecting the gene represented in this entry. Of particular interest for the understanding of the function of F8 is the category of CRM (cross-reacting material) positive patients (approximately 5%) that have considerable amount of F8 in their plasma (at least 30% of normal), but the protein is non-functional; i.e. the F8 activity is much less than the plasma protein level. CRM-reduced is another category of patients in which the F8C antigen and activity are reduced to approximately the same level. Most mutations are CRM negative, and probably affect the folding and stability of the protein. Thrombophilia 13, X-linked, due to factor VIII defect (THPH13) [MIM:301071] An X-linked dominant, hemostatic disorder associated with markedly elevated F8 levels, and characterized by severe thrombophilia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Domain F5/8 type C 2 is responsible for phospholipid-binding and essential for factor VIII activity.

Similarity. Belongs to the multicopper oxidase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P00451-1	1	yes
P00451-2	2, F8B

RefSeq proteins (2): NP_000123, NP_063916 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000421	FA58C	Domain
IPR008972	Cupredoxin	Homologous_superfamily
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR011706	Cu-oxidase_C	Domain
IPR011707	Cu-oxidase-like_N	Domain
IPR024715	Factor_5/8-like	Family
IPR033138	Cu_oxidase_CS	Conserved_site
IPR050633	Neuropilin_MCO_CoagFactor	Family

Pfam: PF00754, PF07731, PF07732

UniProt features (669 total): sequence variant 485, strand 87, glycosylation site 22, helix 21, domain 11, turn 11, disulfide bond 8, modified residue 6, chain 5, site 5, region of interest 3, sequence conflict 2, splice variant 2, signal peptide 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
3HNY	X-RAY DIFFRACTION	1.07
3HNB	X-RAY DIFFRACTION	1.15
1D7P	X-RAY DIFFRACTION	1.5
9D5D	X-RAY DIFFRACTION	1.83
1IQD	X-RAY DIFFRACTION	2
3HOB	X-RAY DIFFRACTION	2.07
4PT6	X-RAY DIFFRACTION	2.1
4KI5	X-RAY DIFFRACTION	2.47
4XZU	X-RAY DIFFRACTION	2.61
7KWO	ELECTRON MICROSCOPY	2.9
9JBV	ELECTRON MICROSCOPY	3.17
6MF0	X-RAY DIFFRACTION	3.2
8TY1	ELECTRON MICROSCOPY	3.46
6MF2	X-RAY DIFFRACTION	3.61
2R7E	X-RAY DIFFRACTION	3.7
7K66	X-RAY DIFFRACTION	3.92
3CDZ	X-RAY DIFFRACTION	3.98
4BDV	X-RAY DIFFRACTION	3.98
7KBT	X-RAY DIFFRACTION	4.15
5K8D	X-RAY DIFFRACTION	4.19
8G6I	ELECTRON MICROSCOPY	4.23
3J2Q	ELECTRON CRYSTALLOGRAPHY	15
3J2S	ELECTRON MICROSCOPY	15
1CFG	SOLUTION NMR
1FAC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00451-F1	61.20	0.32

Antibody-complex structures (SAbDab): 7 — 1IQD, 4KI5, 4XZU, 7K66, 7KBT, 8G6I, 8TY1

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 391–392 (cleavage; by thrombin); 759–760 (cleavage; by thrombin); 1332–1333 (cleavage (activation)); 1667–1668 (cleavage (activation)); 1708–1709 (cleavage; by thrombin)

Post-translational modifications (6): 365, 737, 738, 742, 1683, 1699

Disulfide bonds (8): 172–198, 267–348, 547–573, 649–730, 1851–1877, 1918–1922, 2040–2188, 2193–2345

Glycosylation sites (22): 60, 258, 601, 776, 803, 847, 919, 962, 982, 1020, 1024, 1074, 1085, 1204, 1274, 1278, 1301, 1319, 1431, 1461 …

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-5694530	Cargo concentration in the ER
R-HSA-9672383	Defective factor IX causes thrombophilia
R-HSA-9672387	Defective F8 accelerates dissociation of the A2 domain
R-HSA-9672391	Defective F8 cleavage by thrombin
R-HSA-9672393	Defective F8 binding to von Willebrand factor
R-HSA-9672395	Defective F8 binding to the cell membrane
R-HSA-9672396	Defective cofactor function of FVIIIa variant
R-HSA-9672397	Defective F8 secretion
R-HSA-9673202	Defective F9 variant does not activate FX
R-HSA-9674519	Defective F8 sulfation at Y1699
R-HSA-9769735	Initiation of coagulation cascade
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9769743	Amplification and propagation of coagulation cascade
R-HSA-140837
R-HSA-140875

MSigDB gene sets: 277 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_PROTEIN_ACTIVATION_CASCADE, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, REACTOME_MEMBRANE_TRAFFICKING, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, GOBP_WOUND_HEALING, MAHAJAN_RESPONSE_TO_IL1A_DN, MODULE_75, GOBP_PROTEIN_MATURATION, GOCC_COATED_VESICLE, GOBP_BLOOD_COAGULATION_INTRINSIC_PATHWAY, REACTOME_INTRINSIC_PATHWAY_OF_FIBRIN_CLOT_FORMATION, GOBP_HEMOSTASIS

GO Biological Process (4): acute-phase response (GO:0006953), blood coagulation (GO:0007596), blood coagulation, intrinsic pathway (GO:0007597), hemostasis (GO:0007599)

GO Molecular Function (4): copper ion binding (GO:0005507), oxidoreductase activity (GO:0016491), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), Golgi lumen (GO:0005796), plasma membrane (GO:0005886), COPII-coated ER to Golgi transport vesicle (GO:0030134), platelet alpha granule lumen (GO:0031093), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Defective factor VIII causes hemophilia A	7
Coagulation pathway	3
ER to Golgi Anterograde Transport	2
Response to elevated platelet cytosolic Ca2+	1
Post-translational protein modification	1
Defects of Coagulation cascade	1
Defective factor IX causes hemophilia B	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular organelle lumen	2
acute inflammatory response	1
hemostasis	1
wound healing	1
coagulation	1
protein activation cascade	1
blood coagulation, fibrin clot formation	1
regulation of body fluid levels	1
transition metal ion binding	1
catalytic activity	1
binding	1
cation binding	1
cellular anatomical structure	1
endoplasmic reticulum	1
Golgi apparatus	1
membrane	1
cell periphery	1
coated vesicle	1
platelet alpha granule	1
secretory granule lumen	1
endoplasmic reticulum-Golgi intermediate compartment	1
bounding membrane of organelle	1

Protein interactions and networks

STRING

1850 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
F8	VWF	P04275	999
F8	F9	P00740	990
F8	F10	P00742	987
F8	FN1	P02751	975
F8	MCFD2	Q8NI22	943
F8	F7	P08709	935
F8	F11	P03951	925
F8	F2	P00734	923
F8	ADAMTS13	Q76LX8	920
F8	F3	P13726	881
F8	ST14	Q9Y5Y6	869
F8	LMAN1	P49257	842
F8	SERPINC1	P01008	809
F8	GP1BA	P07359	783
F8	THBD	P07204	726

IntAct

18 interactions, top by confidence:

A	B	Type	Score
F8	VWF	psi-mi:“MI:0407”(direct interaction)	0.620
F8	F8	psi-mi:“MI:0407”(direct interaction)	0.440
F2	F8	psi-mi:“MI:0407”(direct interaction)	0.440
F8	ADAMTS13	psi-mi:“MI:0407”(direct interaction)	0.440
IGKV3-20	F8	psi-mi:“MI:0407”(direct interaction)	0.440
F8	RPL18A	psi-mi:“MI:0915”(physical association)	0.400
F8	HNRNPC	psi-mi:“MI:0915”(physical association)	0.400
GGA1	F8	psi-mi:“MI:0915”(physical association)	0.370
F8	UBQLN1	psi-mi:“MI:0915”(physical association)	0.370
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350
RYBP	FAM186A	psi-mi:“MI:0914”(association)	0.350
MAP1LC3A		psi-mi:“MI:0914”(association)	0.350
INSR	RIMOC1	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
F8	CALR	psi-mi:“MI:2364”(proximity)	0.270
EIF1B	F8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (32): F8 (Co-localization), PHYH (Two-hybrid), F8 (Two-hybrid), F8 (Affinity Capture-MS), F8 (Affinity Capture-Western), F8 (Affinity Capture-MS), HNRNPC (Proximity Label-MS), RPL18A (Proximity Label-MS), F8 (Reconstituted Complex), F8 (Reconstituted Complex), F8 (Reconstituted Complex), CANX (Affinity Capture-Western), PROS1 (Reconstituted Complex), PHYH (Reconstituted Complex), PHYH (Affinity Capture-Western)

ESM2 similar proteins: A0A1D5NSM8, A6NHS7, A8E7N9, B8UU59, E9Q612, F8W3R9, I1FQB6, O18806, O76411, O88393, O88422, O88783, O97827, P00451, P09534, P10379, P10731, P12259, P12263, P19021, P20239, P26342, P27825, P30432, P34822, P35054, P36888, Q00342, Q03167, Q06194, Q14CH0, Q25197, Q25410, Q28107, Q58DX5, Q58L90, Q58L91, Q593B6, Q5MD89, Q6P995

Diamond homologs: A2RUV9, A5A6K7, O14786, O17754, O18806, O35276, O35375, O35474, O43854, O54858, O54991, O60462, O75976, O88783, O89001, P00451, P02886, P02887, P02888, P04836, P12259, P12263, P14384, P15087, P15169, P16870, P21956, P28824, P29068, P37892, P39041, P42787, P70490, P78357, P79385, P79795, P83852, P97333, P97846, P98092

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
VWF	“up-regulates activity”	F8	binding
VWF	“up-regulates quantity by stabilization”	F8
F8	“form complex”	“Factor VIIIa-IXa”	binding
F2	“up-regulates activity”	F8	cleavage
“Factor FVIIa:TF”	“down-regulates activity”	F8	cleavage
CSNK2A3	“down-regulates activity”	F8	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1577 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	422
Likely pathogenic	246
Uncertain significance	393
Likely benign	76
Benign	41

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10085	NM_000132.4(F8):c.6976C>T (p.Arg2326Ter)	Pathogenic
10086	NM_000132.4(F8):c.6682C>T (p.Arg2228Ter)	Pathogenic
10087	NC_000023.11:g.(?154835791)(154837753_154860431)del	Pathogenic
10088	NM_000132.4(F8):c.6403C>T (p.Arg2135Ter)	Pathogenic
10089	NC_000023.11:g.(154974508_154984686)_(154984804_154986431)del	Pathogenic
10090	NC_000023.11:g.(154930804_?)_(?_154933516)del	Pathogenic
10091	NG_011403.2:g.(164642_165857)_(167293_189971)del	Pathogenic
10092	NG_011403.2:g.(131648_164496)_(167293_189971)del	Pathogenic
10093	NG_011403.2:g.(127859_131491)_(131648_164496)del	Pathogenic
10094	F8, EX26DEL	Pathogenic
10095	NC_000023.11:g.(?155022409)(155022724_?)del	Pathogenic
10096	NM_000132.4(F8):c.6496C>T (p.Arg2166Ter)	Pathogenic
10098	NM_000132.4(F8):c.6683G>A (p.Arg2228Gln)	Pathogenic
10099	NM_000132.4(F8):c.872A>G (p.Glu291Gly)	Pathogenic
10100	NG_011403.2:g.(5315_28123)_(30752_30752)del	Pathogenic
10101	NG_011403.2:g.(28246_30628)_(80027_96047)del	Pathogenic
10102	NG_011403.2:g.(30752_34575)_(167293_189971)del	Pathogenic
10103	NG_011403.2:g.(43038_58171)_(99154_121150)del	Pathogenic
10105	F8, EX26DEL	Pathogenic
10106	NM_000132.4:c.3065_3066insL13054_3065dup	Pathogenic
10107	F8, EX15DEL	Pathogenic
10109	NM_000132.4(F8):c.6977G>T (p.Arg2326Leu)	Pathogenic
10111	NM_000132.4(F8):c.1172G>A (p.Arg391His)	Pathogenic
10112	NM_000132.4(F8):c.5113C>T (p.Gln1705Ter)	Pathogenic
10113	NG_011403.2:g.(80027_96047)_(99154_121150)del	Pathogenic
10114	NM_000132.4(F8):c.5122C>T (p.Arg1708Cys)	Pathogenic
10115	NM_000132.4(F8):c.5096A>T (p.Tyr1699Phe)	Pathogenic
10116	NM_000132.4(F8):c.5183A>G (p.Tyr1728Cys)	Pathogenic
10117	F8, EX11-18DEL	Pathogenic
10118	NM_000132.4(F8):c.5878C>T (p.Arg1960Ter)	Pathogenic

SpliceAI

4161 predictions. Top by Δscore:

Variant	Effect	Δscore
X:154860427:CTTA:C	donor_loss	1.0000
X:154860428:TTA:T	donor_loss	1.0000
X:154860429:TACCT:T	donor_loss	1.0000
X:154860430:A:C	donor_loss	1.0000
X:154861712:TCTTA:T	donor_loss	1.0000
X:154861713:CTTA:C	donor_loss	1.0000
X:154861714:TTA:T	donor_loss	1.0000
X:154861715:TAC:T	donor_loss	1.0000
X:154861716:A:AC	donor_gain	1.0000
X:154861716:ACC:A	donor_loss	1.0000
X:154861717:C:CA	donor_loss	1.0000
X:154861717:C:CC	donor_gain	1.0000
X:154861867:C:T	acceptor_gain	1.0000
X:154861869:C:CT	acceptor_gain	1.0000
X:154861870:A:T	acceptor_gain	1.0000
X:154863076:CACT:C	donor_loss	1.0000
X:154863077:ACTT:A	donor_loss	1.0000
X:154863079:TTA:T	donor_loss	1.0000
X:154863081:A:AC	donor_gain	1.0000
X:154863081:ACTA:A	donor_loss	1.0000
X:154863082:C:CT	donor_gain	1.0000
X:154863082:CT:C	donor_gain	1.0000
X:154863082:CTA:C	donor_gain	1.0000
X:154863082:CTAT:C	donor_gain	1.0000
X:154896073:ATAC:A	donor_loss	1.0000
X:154896074:TAC:T	donor_loss	1.0000
X:154896075:ACCAT:A	donor_loss	1.0000
X:154896076:C:CA	donor_loss	1.0000
X:154903900:TCATA:T	donor_loss	1.0000
X:154903901:CATA:C	donor_loss	1.0000

AlphaMissense

15622 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:154957115:A:G	W532R	0.999
X:154957115:A:T	W532R	0.999
X:154956990:G:C	C573W	0.998
X:154956992:A:G	C573R	0.998
X:154861729:A:G	W2238R	0.997
X:154861729:A:T	W2238R	0.997
X:154947845:A:G	W656R	0.997
X:154947845:A:T	W656R	0.997
X:154957070:A:G	C547R	0.997
X:154837676:C:G	R2326P	0.996
X:154931671:A:G	W707R	0.996
X:154931671:A:T	W707R	0.996
X:154956991:C:T	C573Y	0.996
X:154861727:C:A	W2238C	0.995
X:154861727:C:G	W2238C	0.995
X:154957000:A:G	L570P	0.995
X:154957068:G:C	C547W	0.995
X:154957069:C:G	C547S	0.995
X:154957070:A:T	C547S	0.995
X:154863112:C:G	R2182P	0.994
X:154928632:C:G	A1720P	0.994
X:154931616:A:G	L725P	0.994
X:154957113:C:A	W532C	0.994
X:154957113:C:G	W532C	0.994
X:154860586:A:G	L2249P	0.993
X:154899898:A:G	W2081R	0.993
X:154899898:A:T	W2081R	0.993
X:154905016:A:G	F1794S	0.993
X:154956991:C:G	C573S	0.993
X:154956992:A:T	C573S	0.993

dbSNP variants (sampled 300 via entrez): RS1000007967 (X:154936355 A>G), RS1000075153 (X:154838494 G>T), RS1000089108 (X:154972913 A>G), RS1000216438 (X:155002678 T>C), RS1000248634 (X:154855367 T>C), RS1000256712 (X:154972225 G>A,T), RS1000290380 (X:154931309 G>A), RS1000322716 (X:154854929 C>T), RS1000375586 (X:154911297 C>G,T), RS1000401122 (X:154921444 G>C), RS1000450707 (X:154844052 T>C), RS1000457282 (X:154990845 G>A), RS1000464962 (X:154880595 G>T), RS1000482350 (X:154874407 A>T), RS1000522451 (X:155024197 C>T)

Disease associations

OMIM: gene MIM:300841 | disease phenotypes: MIM:134500, MIM:306700, MIM:306900, MIM:301071, MIM:615981, MIM:610921, MIM:188050

GenCC curated gene-disease

Disease	Classification	Inheritance
hemophilia A	Strong	X-linked
severe hemophilia A	Supportive	X-linked
moderately severe hemophilia A	Supportive	X-linked
mild hemophilia A	Supportive	X-linked
symptomatic form of hemophilia A in female carriers	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hemophilia A	Definitive	XL

Mondo (13): hemophilia A (MONDO:0010602), hemophilia B (MONDO:0010604), thrombophilia, X-linked, due to factor 8 defect (MONDO:0859082), severe hemophilia A (MONDO:0015719), mild hemophilia A (MONDO:0015721), cerebral palsy (MONDO:0006497), Bardet-Biedl syndrome 2 (MONDO:0014432), interstitial lung disease due to ABCA3 deficiency (MONDO:0012582), inherited thrombophilia (MONDO:0100240), microcephaly (MONDO:0001149), thrombocytopenia (MONDO:0002049), moderately severe hemophilia A (MONDO:0015720), symptomatic form of hemophilia A in female carriers (MONDO:0015787)

Orphanet (7): Hemophilia A (Orphanet:98878), Hemophilia B (Orphanet:98879), Severe hemophilia A (Orphanet:169802), Mild hemophilia A (Orphanet:169808), Bardet-Biedl syndrome (Orphanet:110), Interstitial lung disease due to ABCA3 deficiency (Orphanet:440402), Rare hereditary thrombophilia (Orphanet:217454)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000132	Menorrhagia
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001058	Poor wound healing
HP:0001250	Seizure
HP:0001297	Stroke
HP:0001376	Limitation of joint mobility
HP:0001386	Joint swelling
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001417	X-linked inheritance
HP:0001419	X-linked recessive inheritance
HP:0001744	Splenomegaly
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001933	Subcutaneous hemorrhage
HP:0001934	Persistent bleeding after trauma
HP:0002170	Intracranial hemorrhage
HP:0002204	Pulmonary embolism
HP:0002239	Gastrointestinal hemorrhage
HP:0002248	Hematemesis
HP:0002249	Melena
HP:0002315	Headache
HP:0002625	Deep venous thrombosis
HP:0002758	Osteoarthritis
HP:0002829	Arthralgia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001613_11	Antineutrophil cytoplasmic antibody-associated vasculitis	4.000000e-07
GCST001873_11	Red blood cell traits	4.000000e-19
GCST001873_9	Red blood cell traits	4.000000e-14
GCST003390_5	Thrombosis	7.000000e-13
GCST007445_43	Factor VIII levels	3.000000e-09
GCST009030_33	Venous thromboembolism	3.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0003907	deep vein thrombosis
EFO:0004630	factor VIII measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D006467	Hemophilia A	C15.378.100.100.500; C15.378.100.141.500; C15.378.463.500; C16.320.099.500
D002836	Hemophilia B	C15.378.100.100.510; C15.378.100.141.510; C15.378.463.510; C16.320.099.510; C16.320.322.235
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
C537910	Bardet-Biedl syndrome 2 (supp.)
C567046	Surfactant Metabolism Dysfunction, Pulmonary, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3143 (SINGLE PROTEIN), CHEMBL4296076 (PROTEIN COMPLEX)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Blood coagulation components

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.85	IC50	14	nM	CHEMBL4782167
7.76	IC50	17.2	nM	CHEMBL4786745
5.11	IC50	7800	nM	CHEMBL1614804
5.05	IC50	8900	nM	CHEMBL261865

PubChem BioAssay actives

26 with measured affinity, of 64 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
docosasodium;(2R,3R,4S)-2-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4S,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4S,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4S,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4S,5R,6R)-3-acetamido-2-[(1S,2R,3R,4S)-1-carboxylato-1,4,5-trihydroxy-3-[(2S,3S,4R,5S,6S)-4-hydroxy-6-methyl-5-sulfonatooxy-3-sulfooxyoxan-2-yl]oxypentan-2-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4R,5S,6S)-4-hydroxy-6-methyl-5-sulfonatooxy-3-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4R,5S,6S)-4-hydroxy-6-methyl-5-sulfonatooxy-3-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4R,5S,6S)-4-hydroxy-6-methyl-5-sulfonatooxy-3-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4R,5S,6S)-4-hydroxy-6-methyl-5-sulfonatooxy-3-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-3-hydroxy-4-[(2S,3S,4R,5S,6S)-4-hydroxy-6-methyl-5-sulfonatooxy-3-sulfooxyoxan-2-yl]oxy-3,4-dihydro-2H-pyran-6-carboxylate	1743224: Inhibition of human citrated plasma iXase (factor 8a-factor 9a complex) preincubated for 2 mins followed by factor 10 addition and measured after 1 min by FXa chromogenic substrate SXa-11 based assay	ic50	0.0140	uM
docosasodium;(2R,3R,4S)-2-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(1S,2R,3R,4S)-1-carboxylato-1,4,5-trihydroxy-3-[(2S,3S,4S,5R,6S)-3-hydroxy-6-methyl-5-sulfonatooxy-4-sulfooxyoxan-2-yl]oxypentan-2-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4S,5R,6S)-3-hydroxy-6-methyl-5-sulfonatooxy-4-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4S,5R,6S)-3-hydroxy-6-methyl-5-sulfonatooxy-4-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4S,5R,6S)-3-hydroxy-6-methyl-5-sulfonatooxy-4-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-2-carboxylato-5-hydroxy-4-[(2S,3S,4S,5R,6S)-3-hydroxy-6-methyl-5-sulfonatooxy-4-sulfooxyoxan-2-yl]oxyoxan-3-yl]oxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-4-yl]oxy-3-hydroxy-4-[(2S,3S,4S,5R,6S)-3-hydroxy-6-methyl-5-sulfonatooxy-4-sulfooxyoxan-2-yl]oxy-3,4-dihydro-2H-pyran-6-carboxylate	1743224: Inhibition of human citrated plasma iXase (factor 8a-factor 9a complex) preincubated for 2 mins followed by factor 10 addition and measured after 1 min by FXa chromogenic substrate SXa-11 based assay	ic50	0.0172	uM
(5Z)-5-[[5-(2,4-dichlorophenyl)furan-2-yl]methylidene]-2-sulfanylidene-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-4-one	1799494: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	2.1000	uM
5-[[5-(2,5-dichloro-4-nitrophenyl)furan-2-yl]methylidene]-2-sulfanylidene-1,3-diazinane-4,6-dione	1799493: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	2.1100	uM
2-chloro-5-[5-[(4,6-dioxo-2-sulfanylidene-1,3-diazinan-5-ylidene)methyl]furan-2-yl]benzoate	1799493: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	3.8900	uM
(5Z)-5-[(5-bromofuran-2-yl)methylidene]-3-(4-nitrophenyl)-2-sulfanylidene-1,3-thiazolidin-4-one	1799492: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	4.6300	uM
(5E)-5-[[5-(4-chlorophenyl)sulfanylfuran-2-yl]methylidene]-3-(4-nitrophenyl)-2-sulfanylidene-1,3-thiazolidin-4-one	1799493: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	4.8100	uM
(5Z)-5-[(5-iodofuran-2-yl)methylidene]-2-sulfanylidene-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-4-one	1799494: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	5.0000	uM
2-chloro-3-[5-[(4,6-dioxo-2-sulfanylidene-1,3-diazinan-5-ylidene)methyl]furan-2-yl]benzoate	1799492: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	6.2900	uM
(5Z)-5-[(5-bromofuran-2-yl)methylidene]-2-sulfanylidene-3-[3-(trifluoromethyl)phenyl]-1,3-thiazolidin-4-one	1799492: Inhibition Assay from Article 10.1016/j.chembiol.2004.08.006: “Disruption of protein-membrane binding and identification of small-molecule inhibitors of coagulation factor VIII.”	ic50	6.6600	uM
(2R)-1-(2,4-dichlorophenoxy)-3-[2-imino-3-(2-piperidin-1-ylethyl)benzimidazol-1-yl]propan-2-ol	328633: Inhibition of human factor 8 binding to immobilized phospholipid by surface plasmon resonance assay	ic50	7.8000	uM
(5Z)-5-[[5-chloro-2-[(4-nitrophenyl)methoxy]phenyl]methylidene]-1-(2-fluorophenyl)-1,3-diazinane-2,4,6-trione	328633: Inhibition of human factor 8 binding to immobilized phospholipid by surface plasmon resonance assay	ic50	8.9000	uM

CTD chemical–gene interactions

54 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, decreases methylation, increases expression	5
Benzo(a)pyrene	affects methylation, increases mutagenesis	3
Gestodene	affects activity, affects cotreatment, increases expression	2
Ethinyl Estradiol	affects cotreatment, increases expression, affects activity	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation	2
Raloxifene Hydrochloride	increases activity, increases expression	2
bisphenol F	affects cotreatment, decreases methylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	decreases expression	1
norgestimate	increases expression, affects cotreatment	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
ethinyl estradiol-desogestrel combination	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
Irinotecan	affects cotreatment, increases response to substance	1
Arsenic Trioxide	decreases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Aluminum	affects folding, affects binding, decreases activity, increases reaction	1
Betaine	affects localization, increases secretion	1
Cadmium	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1038115	Binding	Inhibition of human Coagulation factor 8a	Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577. — Bioorg Med Chem Lett

Cellosaurus cell lines

11 cell lines: 6 induced pluripotent stem cell, 3 spontaneously immortalized cell line, 1 transformed cell line, 1 hybrid cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5A31	CHO-DXB11 F435	Transformed cell line	Female
CVCL_6347	20B8	Hybrid cell line
CVCL_6349	2254-62.2	Spontaneously immortalized cell line	Male
CVCL_A0TS	CHO-S/H9C2	Spontaneously immortalized cell line	Female
CVCL_A4EK	GZLSL-i001-A	Induced pluripotent stem cell	Male
CVCL_A9YX	YCMi001-B	Induced pluripotent stem cell	Male
CVCL_A9YY	YCMi001-B-1	Induced pluripotent stem cell	Male
CVCL_B0P8	BCHSCTi001-A	Induced pluripotent stem cell	Male
CVCL_C0F5	SXMUi002-A	Induced pluripotent stem cell	Male
CVCL_XY23	BHK HL-1	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
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
NCT03915080	PHASE4	COMPLETED	Optimizing the Use of Prophylaxis in Patients With Severe Haemophilia A
NCT03947567	PHASE4	UNKNOWN	Safety and Efficacy of Long-term Treatment With SCT800 in Previously Treated Hemophilia A Patients.
NCT04085458	PHASE4	COMPLETED	Study to Gain More Information on How Safe and Effective Jivi Works in Patients With Severe Hemophilia A (Post-marketing Investigation)
NCT04396639	PHASE4	COMPLETED	Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Hemophilia A Patients
NCT04565236	PHASE4	COMPLETED	A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A
NCT04621916	PHASE4	UNKNOWN	Preventing Inhibitor Recurrence Indefinitely