HABP2

Summary

HABP2 (hyaluronan binding protein 2, HGNC:4798) is a protein-coding gene on chromosome 10q25.3, encoding Factor VII-activating protease (Q14520). Cleaves the alpha-chain at multiple sites and the beta-chain between ‘Lys-53’ and ‘Lys-54’ but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly.

This gene encodes a member of the peptidase S1 family of serine proteases. The encoded preproprotein is secreted by hepatocytes and proteolytically processed to generate heavy and light chains that form the mature heterodimer. Further autoproteolysis leads to smaller, inactive peptides. This extracellular protease binds hyaluronic acid and may play a role in the coagulation and fibrinolysis systems. Mutations in this gene are associated with nonmedullary thyroid cancer and susceptibility to venous thromboembolism. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed.

Source: NCBI Gene 3026 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 290 total
• Phenotypes (HPO): 23
• Druggable target: yes
• MANE Select transcript: NM_004132

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4798
Approved symbol	HABP2
Name	hyaluronan binding protein 2
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	HABP, PHBP, HGFAL, FSAP
Ensembl gene	ENSG00000148702
Ensembl biotype	protein_coding
OMIM	603924
Entrez	3026

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000351270, ENST00000460714, ENST00000542051, ENST00000883707, ENST00000883708, ENST00000883709, ENST00000883710, ENST00000883711, ENST00000883712

RefSeq mRNA: 2 — MANE Select: NM_004132 NM_001177660, NM_004132

CCDS: CCDS53579, CCDS7577

Canonical transcript exons

ENST00000351270 — 13 exons

Exon	Start	End
ENSE00000986821	113553053	113553190
ENSE00000986827	113580595	113580692
ENSE00000986828	113581876	113582131
ENSE00000986829	113583216	113583358
ENSE00000986830	113584148	113584282
ENSE00000986831	113585793	113585938
ENSE00002210101	113588205	113589602
ENSE00003458901	113578627	113578798
ENSE00003489494	113578026	113578145
ENSE00003550371	113575897	113576004
ENSE00003558503	113567489	113567525
ENSE00003561520	113574289	113574405
ENSE00003659341	113577150	113577266

Expression profiles

Bgee: expression breadth ubiquitous, 115 present calls, max score 98.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6292 / max 699.7286, expressed in 75 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107121	1.0073	45
107120	0.3391	26
107123	0.2288	50
107122	0.0366	12
107124	0.0174	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.31	gold quality
pancreatic ductal cell	CL:0002079	98.14	gold quality
liver	UBERON:0002107	98.05	gold quality
gall bladder	UBERON:0002110	93.30	gold quality
oocyte	CL:0000023	88.85	gold quality
secondary oocyte	CL:0000655	87.23	gold quality
body of pancreas	UBERON:0001150	82.22	gold quality
epithelial cell of pancreas	CL:0000083	80.94	silver quality
pancreas	UBERON:0001264	80.62	gold quality
islet of Langerhans	UBERON:0000006	79.90	gold quality
adult mammalian kidney	UBERON:0000082	73.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.31	gold quality
metanephros cortex	UBERON:0010533	67.81	gold quality
tibialis anterior	UBERON:0001385	67.79	silver quality
kidney	UBERON:0002113	66.86	gold quality
diaphragm	UBERON:0001103	65.88	gold quality
cortex of kidney	UBERON:0001225	64.20	gold quality
kidney epithelium	UBERON:0004819	62.29	silver quality
hindlimb stylopod muscle	UBERON:0004252	62.22	gold quality
body of stomach	UBERON:0001161	62.18	gold quality
stomach	UBERON:0000945	61.81	gold quality
metanephros	UBERON:0000081	61.79	gold quality
renal glomerulus	UBERON:0000074	61.72	silver quality
nephron tubule	UBERON:0001231	61.61	silver quality
apex of heart	UBERON:0002098	61.19	gold quality
metanephric glomerulus	UBERON:0004736	61.08	silver quality
endometrium	UBERON:0001295	60.85	gold quality
ileal mucosa	UBERON:0000331	60.27	silver quality
decidua	UBERON:0002450	59.31	gold quality
duodenum	UBERON:0002114	57.12	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	337.54
E-ANND-3	no	3.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting HABP2, 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-4481	100.00	66.42	1669
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4744	99.01	69.91	1581
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-548S	98.50	67.17	1213
HSA-MIR-4252	98.45	66.37	987
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-3201	97.16	65.42	1044
HSA-MIR-939-5P	97.10	65.80	1579

Literature-anchored findings (GeneRIF, showing 40)

• The frequency of factor VII-activating protease Marburg I is significantly increased in patients with a history of venous thromboembolism (VTE) or idiopathic VTE compared to healthy controls. (PMID:15486068)
• An interactive effect upon risk was found between the 511E allele and elevated levels of cholesterol and triglyceride or fibrinogen. The findings support the proposal that the FSAP 511E allele exacerbates atherosclerosis or its clinical sequelae (PMID:15543324)
• extracellular RNA, present at sites of cell damage or vascular injury, can serve an important as yet unrecognized cofactor function in haemostasis by inducing (auto-)activation of FSAP through a novel surface-dependent mechanism (PMID:15654766)
• Marburg I polymorphism of factor VII-activating protease does not have a role in venous thrombosis [letter] (PMID:15933067)
• exhibits a significant growth factor-like activity on quiescent human lung and dermal fibroblasts (PMID:16153533)
• The identification of polyanion-binding sites will help to define the role of FSAP in the vasculature. (PMID:16332249)
• No association between polymorphism and risk of venous thromboembolism. (PMID:16461761)
• FSAP has a protective function in the vasculature, and analysis of G534E polymorphism (Marburg I) polymorphism is likely to be clinically relevant in restenosis. (PMID:17145954)
• The Marburg I polymorphism of factor VII-activating protease and the risk of venous thromboembolism. (PMID:17479202)
• factor VII activating protein (FSAP) was focally accumulated in hypocellular and lipid-rich areas within the necrotic core of atherosclerotic plaques in cornorary arteries (PMID:17482622)
• FSAP is a novel plasma-derived serine protease structurally homologous to tissue-type and urokinase-type plasminogen activators present in bronchoalveolar lavage fluids from patients with acute respiratory distress syndrome. (PMID:17540775)
• Failed to validate association of FSAP gene polymorphisms with venous thromboembolism amoung Californians of European ancestry. (PMID:18278202)
• The G534E variant of FSAP is a risk locus for HCV-induced liver fibrosis and cirrhosis by determining PDGF-BB-mediated hepatic stellate cell proliferation through a single amino acid substitution in FSAP. (PMID:19105210)
• The naturally occurring G534E-variant exhibited reduced proteolytic activity. The DeltaEGF-3 mutant showed diminished binding to and activation by heparin. (PMID:19446554)
• Report that polyamine induces the formation of pro-PHBP autoactivation complex, in which an intermolecular interaction between N-terminal region and the third EGF-like domain (E3) plays a role. (PMID:19817990)
• Hyaluronic acid binding protein 2 (HABP2) negatively regulates vascular integrity via activation of protease-activated receptor/RhoA/Rho kinase signaling. It represents a potential therapeutic target for syndromes of increased vascular permeability. (PMID:20042707)
• Marburg I polymorphism of FSAP might not be associated with cerebral infarction. (PMID:20045910)
• The protein products HABP2 and HYAL1 were associated with plasma PAI-1 concentration and play key roles in hyaluronan metabolism, providing genetic evidence to link these pathways. (PMID:20558613)
• FSAP inhibited platelet-derived growth factor-stimulated proliferation, migration, p42/p44 MAPK phosphorylation and collagen III synthesis of the human pulmonary fibroblasts. (PMID:20818495)
• identified laccaic acid as a potent inhibitor of the protease in terms of both autoactivation of the PHBP proenzyme (IC(50) = 0.35-0.55 microg/ml) and the catalytic activity of the active enzyme (IC(50) = 1.1 microg/ml). (PMID:21071862)
• These results indicate that polymorphisms in the regulatory region of HABP2 gene could influence gene expression levels in the receptive endometrium and be one reason for infertility complications in women with unexplained infertility. (PMID:21098215)
• these results suggest pathophysiological relevance of histone-dependent pro-PHBP activation in hyperinflammatory process. (PMID:21600885)
• SNP analyses indicate an important role for FSAP in the regulation of the haemostasis system as well as fibroproliferative inflammatory processes. [review] (PMID:21655671)
• The increase in FSAP is comparable in the seven OC-groups studied but is more significant in women carrying the 1601GG genotype than in women with the 1601GA genotype and results in increased activation of FVII (PMID:21737124)
• Factor VII-activating protease promotes the proteolysis and inhibition of tissue factor pathway inhibitor. (PMID:22116096)
• FSAP activates single-chain urokinase-type plasminogen activator, but FVII appears remarkably resistant to activation. (PMID:22235940)
• A high correlation between FSAP activity and C5a was found in multiple trauma patients (PMID:22308306)
• Data suggest that plasma FSAP activity levels were higher in women with recurrent pregnancy loss than in fertile women. (PMID:22383781)
• Increased plasma FSAP antigen levels and activity were associated with ischemic stroke and all main etiologic subtypes. (PMID:22409238)
• We conclude that FSAP Marburg-I genotyping may be used to determine the risk for thromboembolic disorders in patients with suspected thrombophilia and known DVT or PE. (PMID:22421107)
• Report tissue factor pathway inhibitor as an efficient inhibitor of factor VII-activating protease. (PMID:22449009)
• High levels of FSAP activity were predictive of adverse events during follow-up, suggesting its potential role in risk stratification and clinical management of CAD patients. (PMID:22850287)
• The study demonstrated that a single nucleotide polymorphism (Marburg I) in the FSAP gene (HABP-2)results in a weak proteolytic activity against all substrates including FVII. (PMID:22906531)
• Lower FSAP expression is associated with enhanced liver fibrosis and inflammation in patients with chronic hepatic disorders and murine experimental liver injury. (PMID:22989567)
• Data indicate that FSAP mediates proteolytic cleavage and activation of bone morphogenetic protein-2 (BMP-2). (PMID:23341458)
• The possible effects of omega-3 FA on clinical AF potential could be linked with modulation of circulating FSAP levels. (PMID:23575879)
• FSAP activates the NF-kappaB pathway and the associated downstream pro-inflammatory factors in monocytic cells (PMID:24075769)
• FSAP functions in initiation and progression of hepatic fibrosis (PMID:24497464)
• Patients with Gram-negative sepsis caused by B. pseudomallei have abundant FSAP activation, which significantly correlates with stage of disease. (PMID:25370187)
• CD44 expression in squamous cell carcinoma of the penis cannot predict the need of performing inguinal lymphadenectomy. (PMID:25847894)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Habp2	ENSMUSG00000025075
rattus_norvegicus	Habp2	ENSRNOG00000016659
drosophila_melanogaster	CG14780	FBGN0025383
drosophila_melanogaster	CG14227	FBGN0031058
drosophila_melanogaster	CG11664	FBGN0040341
drosophila_melanogaster	CG30287	FBGN0050287
drosophila_melanogaster	CG30288	FBGN0050288
drosophila_melanogaster	CG30289	FBGN0050289
drosophila_melanogaster	CG30414	FBGN0050414
drosophila_melanogaster	CG31205	FBGN0051205
drosophila_melanogaster	CG33225	FBGN0053225
drosophila_melanogaster	CG33226	FBGN0069056
drosophila_melanogaster	CG30283	FBGN0260477

Paralogs (5): HGF (ENSG00000019991), PIK3IP1 (ENSG00000100100), GZMK (ENSG00000113088), GZMA (ENSG00000145649), MST1 (ENSG00000173531)

Protein

Protein identifiers

Factor VII-activating protease — Q14520 (reviewed: Q14520)

Alternative names: FVII activator, Hepatocyte growth factor activator-like protein, Hyaluronan-binding protein 2, Plasma hyaluronan-binding protein, Plasma hyaluronan-binding serine protease

All UniProt accessions (1): Q14520

UniProt curated annotations — full annotation on UniProt →

Function. Cleaves the alpha-chain at multiple sites and the beta-chain between ‘Lys-53’ and ‘Lys-54’ but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly. It does not cleave (activate) prothrombin and plasminogen but converts the inactive single chain urinary plasminogen activator (pro-urokinase) to the active two chain form. Activates coagulation factor VII. May function as a tumor suppressor negatively regulating cell proliferation and cell migration.

Subunit / interactions. Heterodimer; disulfide-linked. Heterodimer of a 50 kDa heavy and a 27 kDa light chain linked by a disulfide bond.

Subcellular location. Secreted.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Proteolytic cleavage at Gly-23 or Met-27 can give rise to the 50 kDa heavy chain (HC) and cleavage at Arg-313 or Lys-319 can give rise to the 27 kDa light chain (LC). The HC can undergo further proteolytic cleavage giving rise to a 26 kDa fragment. The LC can undergo further proteolytic cleavage at Arg-313 leading to a 17-kDa fragment and at Arg-480 leading to a 8-kDa fragment.

Disease relevance. Thyroid cancer, non-medullary, 5 (NMTC5) [MIM:616535] A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14520-1	1	yes
Q14520-2	2

RefSeq proteins (2): NP_001171131, NP_004123* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000001	Kringle	Domain
IPR000742	EGF	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR013806	Kringle-like	Homologous_superfamily
IPR018056	Kringle_CS	Conserved_site
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR038178	Kringle_sf	Homologous_superfamily
IPR043504
IPR050127	Serine_Proteases_S1	Family

Pfam: PF00008, PF00051, PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.B1 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (41 total): disulfide bond 20, domain 5, chain 4, active site 3, sequence variant 3, glycosylation site 2, signal peptide 1, site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14520-F1	77.58	0.38

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 (4): 362 (charge relay system); 411 (charge relay system); 509 (charge relay system); 480–481 (cleavage)

Disulfide bonds (20): 77–88, 82–97, 99–108, 115–125, 120–136, 138–147, 154–165, 159–176, 178–187, 194–276, 215–257, 246–271, 301–435, 301, 347–363, 355–424, 435, 447–515, 477–493, 505–533

Glycosylation sites (2): 54, 207

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 159 (showing top): GNF2_HPN, HNF1_Q6, NKX61_01, TCF4_Q5, RGTTAMWNATT_HNF1_01, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, CAIRO_HEPATOBLASTOMA_DN, OCT1_06, TGACATY_UNKNOWN, GNF2_HPX, GATA1_03, GOMF_GLYCOSAMINOGLYCAN_BINDING, AFP1_Q6, HNF1_C

GO Biological Process (3): proteolysis (GO:0006508), cell adhesion (GO:0007155), blood coagulation (GO:0007596)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), glycosaminoglycan binding (GO:0005539), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
cellular process	1
hemostasis	1
wound healing	1
coagulation	1
endopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
carbohydrate derivative binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3997 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HABP2	FGB	P02675	805
HABP2	FGG	P02679	799
HABP2	KCNIP1	Q9NZI2	774
HABP2	SERPIND1	P05546	738
HABP2	FGA	P02671	729
HABP2	SERPINE1	P05121	720
HABP2	HRG	P04196	707
HABP2	ACAN	P16112	654
HABP2	HAS2	Q92819	640
HABP2	PROS1	P07225	617
HABP2	CD44	P16070	612
HABP2	HAS1	Q92839	547
HABP2	HAS3	O00219	537
HABP2	SRGAP1	Q7Z6B7	535
HABP2	FN1	P02751	531

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PARP2	HABP2	psi-mi:“MI:0557”(adp ribosylation reaction)	0.440
TNFAIP3	KIF5C	psi-mi:“MI:0914”(association)	0.350
TANK	CNOT1	psi-mi:“MI:0914”(association)	0.350
S	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): HABP2 (Affinity Capture-MS), HABP2 (Affinity Capture-MS), HABP2 (Affinity Capture-MS), HABP2 (Co-fractionation), HABP2 (Co-fractionation), HABP2 (Reconstituted Complex)

ESM2 similar proteins: A6H6T1, A6MFK7, A6MFK8, O15393, O19045, O70169, P00741, P00742, P00749, P04185, P15638, P16227, P18292, P19221, P31394, P33587, P49150, P57727, P70375, P98119, P98121, Q05589, Q14520, Q1L658, Q1L659, Q3UQ41, Q4QXT9, Q56VR3, Q58L93, Q58L94, Q58L95, Q58L96, Q5E9Z2, Q5R537, Q5RF29, Q5U405, Q6AXZ6, Q6AY28, Q6DIV5, Q6L711

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	179
Likely benign	40
Benign	52

Top pathogenic / likely-pathogenic (0)

SpliceAI

2154 predictions. Top by Δscore:

Variant	Effect	Δscore
10:113574272:T:TA	acceptor_gain	1.0000
10:113574276:A:AG	acceptor_gain	1.0000
10:113574279:A:AG	acceptor_gain	1.0000
10:113574402:GCTG:G	donor_gain	1.0000
10:113574406:G:GA	donor_loss	1.0000
10:113574406:G:GG	donor_gain	1.0000
10:113574407:T:G	donor_loss	1.0000
10:113576000:GAAAG:G	donor_gain	1.0000
10:113576003:AGG:A	donor_loss	1.0000
10:113576005:G:GA	donor_loss	1.0000
10:113576006:T:A	donor_loss	1.0000
10:113581964:G:GT	donor_gain	1.0000
10:113581987:GCTT:G	donor_gain	1.0000
10:113582132:G:GG	donor_gain	1.0000
10:113583214:A:AG	acceptor_gain	1.0000
10:113583215:G:GG	acceptor_gain	1.0000
10:113583215:GC:G	acceptor_gain	1.0000
10:113583215:GCATA:G	acceptor_gain	1.0000
10:113583335:A:G	donor_gain	1.0000
10:113585788:CACA:C	acceptor_loss	1.0000
10:113585791:A:AG	acceptor_gain	1.0000
10:113585791:A:T	acceptor_loss	1.0000
10:113585792:G:GC	acceptor_loss	1.0000
10:113585792:G:GG	acceptor_gain	1.0000
10:113585792:GGAA:G	acceptor_gain	1.0000
10:113585792:GGAAA:G	acceptor_gain	1.0000
10:113585904:G:GT	donor_gain	1.0000
10:113585905:A:T	donor_gain	1.0000
10:113589660:ACT:A	donor_loss	1.0000
10:113589662:T:TG	donor_loss	1.0000

AlphaMissense

3742 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:113578712:G:C	W218C	0.999
10:113578712:G:T	W218C	0.999
10:113584266:G:C	W452C	0.998
10:113584266:G:T	W452C	0.998
10:113578794:T:A	C246S	0.997
10:113578795:G:C	C246S	0.997
10:113584154:T:C	L415P	0.997
10:113585849:T:A	C477S	0.997
10:113585850:G:C	C477S	0.997
10:113580658:G:C	W268C	0.996
10:113580658:G:T	W268C	0.996
10:113582016:T:A	W327R	0.996
10:113582016:T:C	W327R	0.996
10:113582018:G:C	W327C	0.996
10:113582018:G:T	W327C	0.996
10:113584264:T:A	W452R	0.996
10:113584264:T:C	W452R	0.996
10:113580622:G:C	W256C	0.995
10:113580622:G:T	W256C	0.995
10:113580623:T:A	C257S	0.995
10:113580624:G:C	C257S	0.995
10:113580625:C:G	C257W	0.995
10:113582110:T:C	L358P	0.995
10:113584160:T:C	L417S	0.995
10:113584249:T:C	C447R	0.995
10:113580665:T:A	C271S	0.994
10:113580666:G:C	C271S	0.994
10:113582077:G:A	C347Y	0.994
10:113582124:T:A	C363S	0.994
10:113582125:G:C	C363S	0.994

dbSNP variants (sampled 300 via entrez): RS1000003429 (10:113567049 C>T), RS1000024917 (10:113572136 T>C), RS1000029046 (10:113562570 G>A,T), RS1000053076 (10:113586456 G>T), RS1000202019 (10:113571007 G>A), RS1000203451 (10:113571913 G>C), RS1000292661 (10:113581322 C>T), RS1000409370 (10:113575804 G>A), RS1000560531 (10:113570474 C>T), RS1000567727 (10:113576065 G>T), RS1000569914 (10:113555684 C>G), RS1000634888 (10:113561380 G>A), RS1000729073 (10:113570807 C>T), RS1000760187 (10:113566266 C>G), RS1000905650 (10:113585581 T>C,G)

Disease associations

OMIM: gene MIM:603924 | disease phenotypes: MIM:616535, MIM:188050

GenCC curated gene-disease

Mondo (2): thyroid cancer, nonmedullary, 5 (MONDO:0014682), thrombophilia due to thrombin defect (MONDO:0008559)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000853	Goiter
HP:0001907	Thromboembolism
HP:0002176	Spinal cord compression
HP:0002204	Pulmonary embolism
HP:0002625	Deep venous thrombosis
HP:0002653	Bone pain
HP:0002730	Chronic noninfectious lymphadenopathy
HP:0002733	Abnormal lymph node morphology
HP:0002757	Recurrent fractures
HP:0002895	Papillary thyroid carcinoma
HP:0003003	Colon cancer
HP:0004419	Recurrent thrombophlebitis
HP:0005305	Cerebral venous thrombosis
HP:0005994	Nodular goiter
HP:0006528	Chronic lung disease
HP:0006731	Follicular thyroid carcinoma
HP:0006766	Papillary renal cell carcinoma
HP:0011463	Childhood onset
HP:0012288	Neoplasm of head and neck
HP:0012531	Pain
HP:0040198	Non-medullary thyroid carcinoma
HP:3000037	Abnormal neck blood vessel morphology

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003324_4	Ischemic stroke	1.000000e-08
GCST004482_53	Peripheral arterial disease (traffic-related air pollution interaction)	2.000000e-07
GCST004518_3	Waist-to-hip ratio adjusted for body mass index	3.000000e-08
GCST004600_94	Eosinophil percentage of white cells	2.000000e-09
GCST004606_196	Eosinophil count	7.000000e-09
GCST005667_21	Central corneal thickness	2.000000e-09
GCST006288_112	Heel bone mineral density	2.000000e-08
GCST006288_640	Heel bone mineral density	2.000000e-10
GCST006417_40	Plasma factor VII activating protease levels	7.000000e-142
GCST008309_14	Cardiac troponin-I levels	8.000000e-08
GCST008972_88	Urate levels	5.000000e-09
GCST010797_12	Breast cancer, ovarian cancer or prostate cancer (pleiotropy)	5.000000e-12
GCST90000654_49	Central corneal thickness	3.000000e-11
GCST90002381_289	Eosinophil count	3.000000e-18
GCST90002382_197	Eosinophil percentage of white cells	3.000000e-21

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007908	traffic air pollution measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004842	eosinophil count
EFO:0005213	central corneal thickness
EFO:0009270	heel bone mineral density
EFO:0010071	cardiac troponin I measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465370 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
graphene oxide	increases expression	2
sodium arsenite	decreases expression, increases methylation	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Estradiol	decreases expression, affects cotreatment	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Valproic Acid	affects expression, decreases expression, decreases methylation	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
propionaldehyde	decreases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	decreases expression	1
1-nitropyrene	decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
abrine	decreases expression	1
Air Pollutants	decreases expression	1
Aldehydes	decreases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Silicon Dioxide	decreases expression	1
Urethane	increases expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5363425	Binding	Inhibition of spermidine-induced human pro-PHBP autoactivation	Benzo[j]fluoranthene-Derived Natural Products. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00077753	PHASE4	COMPLETED	EXCLAIM:Extended Prophylaxis for Venous ThromboEmbolism (VTE) in Acutely Ill Medical Patients With Prolonged Immobilization
NCT00196118	PHASE4	COMPLETED	Study of IVC Filter Retrieval With the Günther Tulip Vena Cava Filter
NCT00437697	PHASE4	TERMINATED	Thromboprophylaxis in Critically Ill Patients
NCT00445328	PHASE4	TERMINATED	Dalteparin vs Unfractionated Heparin For The Prevention Of Venous Thromboembolism (VTE) In Hospitalized Acutely Ill Medical Patients
NCT00689520	PHASE4	COMPLETED	Long-Term Low-Molecular-Weight Heparin Versus Oral Anticoagulants in Deep Venous Thrombosis
NCT00851864	PHASE4	COMPLETED	Safety and Efficacy of Therapeutic Anticoagulation With Tinzaparin During Pregnancy Via Weight-based Dosing
NCT00966277	PHASE4	COMPLETED	Dalteparin for Primary Venous Thromboembolism (VTE) Prophylaxis in Pancreatic Cancer Patients
NCT00967304	PHASE4	COMPLETED	Clinical Decision Rule Validation Study to Predict Low Recurrent Risk in Patients With Unprovoked Venous Thromboembolism
NCT01119261	PHASE4	COMPLETED	EUropean Pharmacogenetics of AntiCoagulant Therapy - Acenocoumarol
NCT01119274	PHASE4	COMPLETED	EUropean Pharmacogenetics of AntiCoagulant Therapy - Phenprocoumon
NCT01119300	PHASE4	COMPLETED	EUropean Pharmacogenetics of AntiCoagulant Therapy - Warfarin
NCT01210755	PHASE4	COMPLETED	Study in Healthy Volunteers of the Reversion by Haemostatic Drugs of the Anticoagulant Effect of New Anti-thrombotics
NCT01304108	PHASE4	COMPLETED	Improving Venous Thromboembolism Prophylaxis
NCT01467583	PHASE4	COMPLETED	Fondaparinux in Critically Ill Patients With Renal Failure
NCT01916707	PHASE4	UNKNOWN	Weight Based Enoxaparin in Trauma Patients
NCT02095509	PHASE4	COMPLETED	Pharmacokinetics of Enoxaparin in Intensive Care Patients
NCT02396732	PHASE4	TERMINATED	Aspirin and Enoxaparin for VTE in Trauma
NCT02412982	PHASE4	COMPLETED	Evaluation of Venous Thromboembolism Prevention in High-Risk Trauma Patients
NCT02464969	PHASE4	COMPLETED	Apixaban for the Acute Treatment of Venous Thromboembolism in Children
NCT02474212	PHASE4	COMPLETED	: Pharmacokinetics of Enoxaparin After Coronary Artery Bypass Graft Surgery
NCT02559856	PHASE4	COMPLETED	Comparison of Bleeding Risk Between Rivaroxaban and Apixaban: The Pilot Study
NCT02856295	PHASE4	COMPLETED	anti10a Levels in Women Treated With LMWH in the Postpartum Period
NCT02945280	PHASE4	TERMINATED	Apixaban for Routine Management of Upper Extremity Deep Venous Thrombosis
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03006562	PHASE4	TERMINATED	PREvention of VENous ThromboEmbolism Following Radical Prostatectomy
NCT03158792	PHASE4	COMPLETED	Enoxaparin 20mg Versus 30mg Subcutaneously Once Daily in Elderly Patients With Impaired Renal Function
NCT03196349	PHASE4	TERMINATED	Comparison of Oral Anticoagulants for Extended VEnous Thromboembolism
NCT03244020	PHASE4	ENROLLING_BY_INVITATION	LMWH vs Aspirin for VTE Prophylaxis in Orthopaedic Oncology
NCT03266783	PHASE4	COMPLETED	Comparison of Bleeding Risk Between Rivaroxaban and Apixaban for the Treatment of Acute Venous Thromboembolism
NCT03426982	PHASE4	UNKNOWN	Comparision Between Activated Partial Thromboplastin Time Versus Anti-Xa Activity in Heparin Monitoring
NCT03678506	PHASE4	TERMINATED	Apixaban for Extended Anticoagulation (APIDULCIS)
NCT03988101	PHASE4	COMPLETED	Role of Statin in Venous Dysfunction in Patients With Venous Thromboembolism Event
NCT03988231	PHASE4	WITHDRAWN	Enoxaparin Versus Placebo for Venous Thromboembolism Prevention in Low Risk Cancer Patients After Surgical Procedures: a Randomized, Double Blind, Placebo Controlled Clinical Trial Pilot Study
NCT04128254	PHASE4	UNKNOWN	A Prospective Study in Chinese Patients With Lower Extremity Ankle Fracture of Oral Anticoagulants to Prevent Venous Thromboembolism (VTE)
NCT04157881	PHASE4	COMPLETED	A Study on the Impact of Rabeprazole-induced Elevated Stomach pH on APO-Dabigatran Exposure in Healthy Volunteers
NCT04168203	PHASE4	COMPLETED	Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked Venous Thromboembolism
NCT04169269	PHASE4	UNKNOWN	Deep Vein Thrombosis Prophylaxis Adherence: Enoxaparin vs Rivaroxaban
NCT04263038	PHASE4	RECRUITING	Clinical Surveillance vs. Anticoagulation for Low-risk Patients With Isolated Subsegmental Pulmonary Embolism
NCT04352439	PHASE4	COMPLETED	Aspirin for Prevention of Venous Thromboembolism Among Ovarian Cancer Patients Receiving Neoadjuvant Chemotherapy
NCT04409834	PHASE4	COMPLETED	Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients Trial