TFPI

Summary

TFPI (tissue factor pathway inhibitor, HGNC:11760) is a protein-coding gene on chromosome 2q32.1, encoding Tissue factor pathway inhibitor (P10646). Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex.

This gene encodes a Kunitz-type serine protease inhibitor that regulates the tissue factor (TF)-dependent pathway of blood coagulation. The coagulation process initiates with the formation of a factor VIIa-TF complex, which proteolytically activates additional proteases (factors IX and X) and ultimately leads to the formation of a fibrin clot. The product of this gene inhibits the activated factor X and VIIa-TF proteases in an autoregulatory loop. Inhibition of the encoded protein restores hemostasis in animal models of hemophilia. This gene encodes multiple protein isoforms that differ in their inhibitory activity, specificity and cellular localization.

Source: NCBI Gene 7035 — RefSeq curated summary.

At a glance

• GWAS associations: 26
• Clinical variants (ClinVar): 3 total
• Druggable target: yes
• MANE Select transcript: NM_006287

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11760
Approved symbol	TFPI
Name	tissue factor pathway inhibitor
Location	2q32.1
Locus type	gene with protein product
Status	Approved
Aliases	EPI, TFI, TFPI1
Ensembl gene	ENSG00000003436
Ensembl biotype	protein_coding
OMIM	152310
Entrez	7035

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 48 protein_coding, 2 retained_intron

ENST00000233156, ENST00000339091, ENST00000392365, ENST00000409676, ENST00000417013, ENST00000420747, ENST00000421427, ENST00000435414, ENST00000437725, ENST00000453013, ENST00000481132, ENST00000481389, ENST00000897898, ENST00000897899, ENST00000897900, ENST00000897901, ENST00000897902, ENST00000897903, ENST00000897904, ENST00000897905, ENST00000897906, ENST00000897907, ENST00000897908, ENST00000897909, ENST00000897910, ENST00000897911, ENST00000897912, ENST00000897913, ENST00000897914, ENST00000897915, ENST00000897916, ENST00000897917, ENST00000897918, ENST00000897919, ENST00000897920, ENST00000897921, ENST00000897922, ENST00000897923, ENST00000897924, ENST00000897925, ENST00000897926, ENST00000938019, ENST00000938021, ENST00000938022, ENST00000938023, ENST00000971368, ENST00000971369, ENST00000971370, ENST00000971371, ENST00000971372

RefSeq mRNA: 6 — MANE Select: NM_006287 NM_001032281, NM_001318941, NM_001329239, NM_001329240, NM_001329241, NM_006287

CCDS: CCDS2294, CCDS33349

Canonical transcript exons

ENST00000233156 — 8 exons

Exon	Start	End
ENSE00000783643	187484124	187484216
ENSE00001447089	187464230	187467042
ENSE00003474693	187467753	187467932
ENSE00003507057	187503648	187503770
ENSE00003508654	187488337	187488375
ENSE00003665068	187484811	187484987
ENSE00003784034	187496881	187497078
ENSE00003846247	187554200	187554435

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 98.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 83.6761 / max 2043.0902, expressed in 1665 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32815	68.0943	1634
32816	7.7339	1421
32809	3.7566	373
32804	1.0636	545
32799	0.8750	445
32801	0.5342	261
32806	0.4967	281
32800	0.2803	131
32808	0.1812	81
32805	0.1810	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	98.94	gold quality
lower lobe of lung	UBERON:0008949	98.30	gold quality
visceral pleura	UBERON:0002401	98.26	gold quality
placenta	UBERON:0001987	98.04	gold quality
upper lobe of lung	UBERON:0008948	98.04	gold quality
upper lobe of left lung	UBERON:0008952	98.00	gold quality
stromal cell of endometrium	CL:0002255	97.76	gold quality
lung	UBERON:0002048	97.72	gold quality
liver	UBERON:0002107	97.66	gold quality
pericardium	UBERON:0002407	97.38	gold quality
right lobe of liver	UBERON:0001114	97.22	gold quality
superficial temporal artery	UBERON:0001614	96.97	gold quality
jejunal mucosa	UBERON:0000399	96.67	gold quality
gall bladder	UBERON:0002110	96.63	gold quality
adrenal tissue	UBERON:0018303	96.22	gold quality
islet of Langerhans	UBERON:0000006	96.20	gold quality
nephron tubule	UBERON:0001231	96.12	gold quality
duodenum	UBERON:0002114	95.74	gold quality
calcaneal tendon	UBERON:0003701	95.64	gold quality
renal glomerulus	UBERON:0000074	95.58	gold quality
metanephric glomerulus	UBERON:0004736	95.55	gold quality
left coronary artery	UBERON:0001626	95.11	gold quality
mucosa of stomach	UBERON:0001199	95.01	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.00	gold quality
coronary artery	UBERON:0001621	94.91	gold quality
kidney epithelium	UBERON:0004819	94.78	gold quality
right coronary artery	UBERON:0001625	94.75	gold quality
omental fat pad	UBERON:0010414	94.70	gold quality
peritoneum	UBERON:0002358	94.68	gold quality
metanephros	UBERON:0000081	94.51	gold quality

Single-cell (SCXA)

Detected in 37 experiment(s), a significant marker in 33.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	4072.34
E-MTAB-8205	yes	3279.06
E-HCAD-23	yes	2986.67
E-GEOD-124263	yes	2925.46
E-MTAB-6701	yes	2732.54
E-MTAB-8142	yes	2612.27
E-ANND-2	yes	2599.85
E-HCAD-24	yes	2214.21
E-HCAD-1	yes	2183.34
E-MTAB-8410	yes	2061.35
E-MTAB-8271	yes	2045.39
E-CURD-46	yes	1823.49
E-MTAB-6308	yes	1821.73
E-MTAB-9388	yes	1632.01
E-CURD-112	yes	1591.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ADTRP

miRNA regulators (miRDB)

113 targeting TFPI, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-9902	99.89	69.15	2250

Literature-anchored findings (GeneRIF, showing 40)

• The purpose of this review is to outline recent developments in the field related to the structural specificity and biology of TFPI. (PMID:11686353)
• protease inhibitor of extrinsic coagulation (PMID:11693665)
• circadian variations in healthy adults and in subjects with type II diabetes; possible role in increased vascular wall uptake of lipoproteins in diabetic subjects (PMID:11697721)
• Bemiparin and fluid flow modulate the expression, activity and release of tissue factor pathway inhibitor in human endothelial cells in vitro. Bemiparin enhanced TFPI mRNA in EC under the arterial flow. (PMID:11776326)
• Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. (PMID:11776329)
• The presence of TFPI in human cardiomyocytes is confirmed in ventricle from cardiac soidosis, myocarditis, and AMI patients. (PMID:11816723)
• The C-terminal domain of TFPI molecule plays a predominant role in the binding to ox-LDL and the binding through the C-terminal part is essential for the ox-LDL-dependent reduction of the anticoagulant activity of TFPI. (PMID:11848461)
• Plasma levels of the Factor Xa (FXa)-TFPI complex were significantly higher in patients with solid tumours, compared to patients with haematological malignancy and healthy controls. (PMID:11864704)
• expression of TF and TFPI in human melanoma (PMID:12028585)
• The tissue factor pathway inhibitor C536T mutation is not associated with the risk of stroke in young adults. (PMID:12038800)
• MMP-8 cleaves TFPI following Ser(174) in the connecting region between the second and third Kunitz domains 75 M(-1).s(-1)) as well as following Lys(20) within the NH(2)-terminal region. MMP-8 cleavage of TFPI decreases the anticoagulant activity of TFPI (PMID:12117418)
• biochemistry, molecular biology, physiology and physiopathology (review) (PMID:12193974)
• The CC genotype of the TFPI intron 7 33T–>C polymorphism is an independent protective factor for venous thromboembolism, an effect probably mediated by increased TFPI levels. (PMID:12195688)
• levels in placenta and myometrium; the concentration seems to be too low to prevent initiation of coagulation (PMID:12270558)
• exploration of active components in oxidized low-density lipoprotein that reduce activity of TFPI (PMID:12408975)
• The intact C-terminus in GPI-anchored TFPI indicates it is not directly attached to a GPI anchor; rather, it most likely associates with placental endothelium by binding to a GPI-anchored protein. (PMID:12482841)
• Transfectants expressing equal levels of GPI-linked TFPI or transmembrane TFPI displayed equal anticoagulant potency as assessed by tissue factor-mediated conversion of factor X to factor Xa. (PMID:12540955)
• High TFPI levels in ovarian follicular fluid underline its physiological importance for maintaining the hypocoagulable state. TFPI in seminal plasma samples of infertile men was reduced, suggesting a correlation between seminal coagulation & fertility. (PMID:12818258)
• Most aPL recognized full-length TFPI, but not a truncated form of TFPI lacking the C-terminus of the molecule; aPL with high titer anti-TFPI limit TFPI action and are associated with the APS. (PMID:12871406)
• TFPI of proximal tubular epithelial cells may act against generation of thrombin and tubular fibrin formation induced by tissue factor activation. (PMID:12893029)
• The TF and TFPI levels depend significantly on the renal function; elevated TF and TFPI levels may be related to thrombosis and atherosclerosis in chronic renal failure patients on peritoneal dialysis (PMID:14610342)
• TFPI is involved in the process of thrombus formation in vivo in patients with ACS, which suggests a potential role for TFPI in modulating coronary thrombosis. (PMID:14656922)
• Immobilized rTFPI slows fibrin deposition on vascular graft material by inhibiting contact pathway and blood borne tissue factor procoagulant arising from either alternatively spliced form of tissue factor or from tissue factor containing microparticles. (PMID:15307537)
• Immunoglobulin G fractions from subjects with antiphospholipid syndrome have inhibitory activity against tissue factor pathway inhibitor (TFPI). (PMID:15339683)
• results suggest that the inhibitory effect of the LMWH tinzaparin on endothelial tube formation is associated with stimulation of the release of TFPI, but not to anti-Factor Xa activity (PMID:15351861)
• TF and TFPI mRNA expression, protein levels and activity in trophoblast cells were determined and compared to human umbilical vein endothelial cells (PMID:15467908)
• both in humans and mice, there are temporal variations in TFPI activity (PMID:15604416)
• caveolin regulates the inhibition by cell-bound TFPI of the active protease production by the extrinsic pathway of coagulation (PMID:15817451)
• polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels (PMID:15845911)
• TFPI may regulate the activity of abundant Tissue Factor in human semen (PMID:15886798)
• a rapid and economic alternative to the determination of total TFPI antigen by ELISA in plasma samples after heparin application (PMID:16113753)
• glycosylation and gene expression induced by stimulation of cells with inflammatory stimuli were compared for the 2 isoforms; Although TFPIalpha comprises 80% of the surface-TFPI, TFPIbeta was responsible for the bulk of the FVIIa/TF inhibitory activity (PMID:16246254)
• thrombosis patients with low levels of free TFPI are at an increased risk of recurrent venous thromboembolism (PMID:16270631)
• changes in circulating tissue factor procoagulant activity (PCA) and other procoagulation proteins in healthy volunteers exposed to 24 h of selective hyperinsulinemia, selective hyperglycemia, or combined hyperinsulinemia and hyperglycemia (PMID:16380494)
• Versican G3 domain promotes blood coagulation through suppressing the activity of tissue factor pathway inhibitor-1 (PMID:16431924)
• data suggest that protein S deficiency not only increases the risk of thrombosis by impairing the protein C system but also by reducing the ability of TFPI to down-regulate the extrinsic coagulation pathway (PMID:16488980)
• TF induction in conjunction with TFPI suppression may be relevant for the increased frequency of myocardial infarction observed in cocaine consumers (PMID:16516912)
• circadian rhythms affect expression of melatonin and tissue factor pathway inhibitor type (PMID:16879232)
• platelets TFPI is also released in microvesicles or as a soluble protein (PMID:17082321)
• TFPI-1 is expressed by breast cancer and other cancer cell lines maintained in cell culture. (PMID:17180732)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfpia	ENSDARG00000034718
mus_musculus	Tfpi	ENSMUSG00000027082
rattus_norvegicus	Tfpi	ENSRNOG00000005039
drosophila_melanogaster	CG7565	FBGN0035833
caenorhabditis_elegans		WBGENE00008449
caenorhabditis_elegans		WBGENE00010792
caenorhabditis_elegans		WBGENE00015355
caenorhabditis_elegans		WBGENE00021939

Paralogs (13): EPPIN (ENSG00000101448), TFPI2 (ENSG00000105825), AMBP (ENSG00000106927), LRP11 (ENSG00000120256), WFIKKN1 (ENSG00000127578), KIAA0319 (ENSG00000137261), KIAA0319L (ENSG00000142687), SPINT4 (ENSG00000149651), WFDC8 (ENSG00000158901), SPINT1 (ENSG00000166145), SPINT2 (ENSG00000167642), WFIKKN2 (ENSG00000173714), WFDC6 (ENSG00000243543)

Protein

Protein identifiers

Tissue factor pathway inhibitor — P10646 (reviewed: P10646)

Alternative names: Extrinsic pathway inhibitor, Lipoprotein-associated coagulation inhibitor

All UniProt accessions (6): P10646, C9J103, C9JKV3, C9JP39, C9JQ14, C9JT76

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits factor X (X(a)) directly and, in a Xa-dependent way, inhibits VIIa/tissue factor activity, presumably by forming a quaternary Xa/LACI/VIIa/TF complex. It possesses an antithrombotic action and also the ability to associate with lipoproteins in plasma.

Subcellular location. Secreted Microsome membrane.

Tissue specificity. Mostly in endothelial cells.

Post-translational modifications. O-glycosylated.

Domain organisation. This inhibitor contains three inhibitory domains. The first domain interacts with VIIa and TF, the second one with Xa.

Miscellaneous. GPI-anchored.

Isoforms (2)

UniProt ID	Names	Canonical?
P10646-1	Alpha, TFPIalpha	yes
P10646-2	Beta, TFPIbeta

RefSeq proteins (6): NP_001027452, NP_001305870, NP_001316168, NP_001316169, NP_001316170, NP_006278* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002223	Kunitz_BPTI	Domain
IPR008296	TFPI-like	Family
IPR020901	Prtase_inh_Kunz-CS	Conserved_site
IPR036880	Kunitz_BPTI_sf	Homologous_superfamily
IPR050098	TFPI/VKTCI-like	Family

Pfam: PF00014

UniProt features (57 total): strand 17, disulfide bond 9, mutagenesis site 6, glycosylation site 5, helix 5, site 4, domain 3, turn 3, splice variant 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5NMV	X-RAY DIFFRACTION	1.65
4DTG	X-RAY DIFFRACTION	1.8
6BX8	X-RAY DIFFRACTION	1.98
4BQD	X-RAY DIFFRACTION	2.48
1TFX	X-RAY DIFFRACTION	2.6
7V1N	ELECTRON MICROSCOPY	3.2
9P0X	ELECTRON MICROSCOPY	3.7
1ADZ	SOLUTION NMR
1IRH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10646-F1	74.04	0.48

Antibody-complex structures (SAbDab): 3 — 4DTG, 5NMV, 9P0X

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): 64–65 (reactive bond); 135–136 (reactive bond); 227–228 (reactive bond); 256 (not glycosylated)

Disulfide bonds (9): 54–104, 63–87, 79–100, 125–175, 134–158, 150–171, 217–267, 226–250, 242–263

Glycosylation sites (5): 145, 195, 202, 203, 42

Mutagenesis-validated functional residues (6):

Position	Phenotype
49	results in resistance to mmp9-mediated cleavage.
64	abolishes inhibition of vii(a)/tf.
115	results in resistant to elane-mediated cleavage. results in resistant to elane- and ctsg-mediated cleavage; when associa
117	results in resistant to elane- and ctsg-mediated cleavage; when associated with a-115.
135	abolishes inhibition of x(a).
227	abolishes inhibition of vii(a)/tf.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-140834
R-HSA-9769735	Initiation of coagulation cascade
R-HSA-9769739	Regulation of clotting cascade
R-HSA-109582	Hemostasis
R-HSA-140877

MSigDB gene sets: 320 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_COAGULATION, GOZGIT_ESR1_TARGETS_DN, GOCC_CELL_SURFACE, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, KORKOLA_CHORIOCARCINOMA, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, GOBP_NEGATIVE_REGULATION_OF_COAGULATION, GOBP_WOUND_HEALING, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP

GO Biological Process (6): blood coagulation (GO:0007596), negative regulation of blood coagulation (GO:0030195), cellular response to steroid hormone stimulus (GO:0071383), hemostasis (GO:0007599), negative regulation of peptidase activity (GO:0010466), cellular response to lipid (GO:0071396)

GO Molecular Function (3): endopeptidase inhibitor activity (GO:0004866), serine-type endopeptidase inhibitor activity (GO:0004867), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), caveola (GO:0005901), cell surface (GO:0009986), side of membrane (GO:0098552), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Coagulation pathway	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
peptidase activity	2
membrane	2
hemostasis	1
wound healing	1
coagulation	1
blood coagulation	1
regulation of blood coagulation	1
negative regulation of coagulation	1
negative regulation of wound healing	1
negative regulation of hemostasis	1
cellular response to hormone stimulus	1
response to steroid hormone	1
cellular response to lipid	1
regulation of body fluid levels	1
negative regulation of proteolysis	1
negative regulation of hydrolase activity	1
regulation of peptidase activity	1
response to lipid	1
cellular response to chemical stimulus	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
enzyme inhibitor activity	1
peptidase regulator activity	1
cell periphery	1
plasma membrane raft	1
leaflet of membrane bilayer	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1734 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFPI	F3	P13726	999
TFPI	F10	P00742	996
TFPI	THBD	P07204	963
TFPI	F7	P08709	949
TFPI	SERPINC1	P01008	935
TFPI	F2	P00734	919
TFPI	SERPIND1	P05546	873
TFPI	PROCR	Q9UNN8	853
TFPI	CLMP	Q9H6B4	774
TFPI	PLG	P00747	766
TFPI	F2R	P25116	728
TFPI	VWF	P04275	727
TFPI	PLAT	P00750	725
TFPI	THBS1	P07996	718
TFPI	ADCY10	Q96PN6	708

IntAct

10 interactions, top by confidence:

A	B	Type	Score
MASP2	TFPI	psi-mi:“MI:0194”(cleavage reaction)	0.440
TFPI	KCNIP4	psi-mi:“MI:0915”(physical association)	0.400
	POLR3A	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
	GTPBP10	psi-mi:“MI:0914”(association)	0.350
	POLRMT	psi-mi:“MI:0914”(association)	0.350
	GTPBP1	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): TFPI (Reconstituted Complex), KCNIP4 (Affinity Capture-MS), TFPI (Proximity Label-MS), TFPI (Affinity Capture-MS), THBS1 (Reconstituted Complex), KCNIP4 (Affinity Capture-MS), TFPI (Co-crystal Structure), TFPI (Affinity Capture-Western), TFPI (Reconstituted Complex), TFPI (Affinity Capture-MS), TFPI (Affinity Capture-MS), TFPI (Affinity Capture-MS), TFPI (Proximity Label-MS), TFPI (Cross-Linking-MS (XL-MS)), FLNA (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A3G5BID2, B4QW11, B5M0W4, D0MVC9, D2CFI7, D3GGZ8, D3ZVP0, E9Q6D8, F5GTK6, O54819, O62247, O97176, P01002, P01003, P01005, P04542, P07701, P08481, P09036, P09655, P09656, P0C7L1, P0DN15, P0DN16, P0DQG8, P10646, P13671, P15358, P19761, P26461, P61134, P61135, P83579, Q02445, Q09TK7, Q11101, Q177W0, Q18206, Q1W4C9, Q20930

Diamond homologs: A0A1D0BND9, A0A3G2FQK2, A0A6B7FA07, A0A6B7FBD3, A0A6B7FEJ3, A0A6P8HC43, A5X2X1, A6MFL3, A8Y7N5, A8Y7P3, A8Y7P4, B1B5I8, B2G331, B6ZIW0, C0HJF3, C0HJF4, C0HJU6, C0HJU7, C0HK72, C0HK73, C0HK74, C0HMC7, C1IBY4, C1IC51, C1IC52, C8YJ94, C8YJ95, C8YJ96, C8YJ97, D4A2Z2, F6ULY1, H2A0N5, H2A0P0, H6VC06, O35536, O54819, O62845, O76840, P00978, P00993

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TFPI	up-regulates	VLDLR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1393 predictions. Top by Δscore:

Variant	Effect	Δscore
2:187467827:A:C	donor_gain	1.0000
2:187484118:TCTTA:T	donor_loss	1.0000
2:187484119:CTTA:C	donor_loss	1.0000
2:187484120:TTA:T	donor_loss	1.0000
2:187484121:TACCA:T	donor_loss	1.0000
2:187484122:A:AC	donor_gain	1.0000
2:187484122:A:C	donor_loss	1.0000
2:187484123:C:CC	donor_gain	1.0000
2:187484212:ATTCG:A	acceptor_gain	1.0000
2:187484213:TTCG:T	acceptor_gain	1.0000
2:187484214:TCG:T	acceptor_gain	1.0000
2:187484215:CG:C	acceptor_gain	1.0000
2:187484215:CGC:C	acceptor_gain	1.0000
2:187484217:C:CC	acceptor_gain	1.0000
2:187484227:A:AC	acceptor_gain	1.0000
2:187484227:A:C	acceptor_gain	1.0000
2:187484234:CAAT:C	acceptor_gain	1.0000
2:187484809:A:AC	donor_gain	1.0000
2:187484809:ACGAC:A	donor_gain	1.0000
2:187484810:C:CC	donor_gain	1.0000
2:187484810:CG:C	donor_gain	1.0000
2:187484810:CGA:C	donor_gain	1.0000
2:187484810:CGACC:C	donor_gain	1.0000
2:187484983:CTTTT:C	acceptor_gain	1.0000
2:187484984:TTTT:T	acceptor_gain	1.0000
2:187484985:TTT:T	acceptor_gain	1.0000
2:187484986:TT:T	acceptor_gain	1.0000
2:187484988:C:CC	acceptor_gain	1.0000
2:187484989:T:G	acceptor_loss	1.0000
2:187467041:ACC:A	acceptor_loss	0.9900

AlphaMissense

2035 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:187484834:C:G	C171S	0.997
2:187484835:A:T	C171S	0.997
2:187484857:G:C	N163K	0.996
2:187484857:G:T	N163K	0.996
2:187484873:C:G	C158S	0.996
2:187484874:A:T	C158S	0.996
2:187484897:C:G	C150S	0.996
2:187484898:A:T	C150S	0.996
2:187484945:C:G	C134S	0.996
2:187484946:A:T	C134S	0.996
2:187496964:C:G	C79S	0.996
2:187496965:A:T	C79S	0.996
2:187467796:G:C	N255K	0.995
2:187467796:G:T	N255K	0.995
2:187467911:C:G	C217S	0.995
2:187467912:A:T	C217S	0.995
2:187484858:T:A	N163I	0.995
2:187496901:C:G	C100S	0.995
2:187496902:A:T	C100S	0.995
2:187497039:C:G	C54S	0.995
2:187497040:A:T	C54S	0.995
2:187467790:A:C	F257L	0.994
2:187467790:A:T	F257L	0.994
2:187467792:A:G	F257L	0.994
2:187467836:C:G	C242S	0.994
2:187467837:A:T	C242S	0.994
2:187484946:A:G	C134R	0.994
2:187496889:C:G	C104S	0.994
2:187496890:A:T	C104S	0.994
2:187496924:A:C	N92K	0.994

dbSNP variants (sampled 300 via entrez): RS1000078341 (2:187514474 C>A), RS1000100105 (2:187504575 AAAAAAG>A), RS1000180177 (2:187515472 A>G), RS1000341928 (2:187529250 A>G), RS1000345861 (2:187532905 C>T), RS1000417592 (2:187532694 T>C), RS1000426161 (2:187487717 A>T), RS1000518186 (2:187474637 G>A), RS1000544685 (2:187550527 A>G), RS1000548927 (2:187492784 T>C), RS1000562228 (2:187477634 T>C), RS1000667130 (2:187538769 T>A), RS1000732724 (2:187524060 A>C), RS1000793264 (2:187486170 A>G), RS1000800584 (2:187525911 A>G)

Disease associations

OMIM: gene MIM:152310 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST001969_1	Heart rate	5.000000e-08
GCST004744_26	Lung adenocarcinoma	6.000000e-06
GCST007483_12	Waist-to-hip ratio adjusted for BMI (additive genetic model)	3.000000e-12
GCST007487_29	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-14
GCST007492_7	Waist-to-hip ratio adjusted for BMI (additive genetic model)	3.000000e-06
GCST007494_11	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-07
GCST007500_21	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5.000000e-08
GCST007502_16	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-09
GCST007637_7	Diffusing capacity of carbon monoxide	7.000000e-06
GCST010146_8	Serum immune biomarker levels	9.000000e-10
GCST010241_321	Apolipoprotein A1 levels	2.000000e-08
GCST010698_54	Subcortical volume (min-P)	3.000000e-10
GCST010699_61	Brain morphology (min-P)	9.000000e-27
GCST010700_8	Cortical thickness (MOSTest)	5.000000e-14
GCST010701_89	Cortical surface area (MOSTest)	3.000000e-14
GCST010702_58	Subcortical volume (MOSTest)	4.000000e-12
GCST010703_316	Brain morphology (MOSTest)	5.000000e-22
GCST012227_1240	Hip circumference adjusted for BMI	3.000000e-09
GCST012227_1241	Hip circumference adjusted for BMI	4.000000e-08
GCST012229_41	Hip index	1.000000e-08
GCST90020024_1164	A body shape index	3.000000e-09
GCST90020024_1165	A body shape index	1.000000e-10
GCST90020025_1742	Waist-to-hip ratio adjusted for BMI	4.000000e-12
GCST90020027_447	Waist-hip index	1.000000e-11
GCST90020029_851	Waist circumference adjusted for body mass index	1.000000e-08
GCST90020029_852	Waist circumference adjusted for body mass index	2.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0004869	YKL40 measurement
EFO:0004872	inflammatory biomarker measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713062 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs116350534	TFPI		0.00	0

ChEMBL bioactivities

3466 potent at pChembl≥5 of 3573 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.27	Kd	0.054	nM	CHEMBL4545581
10.22	EC50	0.06	nM	CHEMBL4543933
9.52	Kd	0.3	nM	CHEMBL3894172
9.47	IC50	0.337	nM	CHEMBL4473203
9.28	IC50	0.52	nM	CHEMBL4473203
9.25	IC50	0.56	nM	CHEMBL4447126
9.24	IC50	0.57	nM	CHEMBL4467258
9.24	IC50	0.58	nM	CHEMBL4515587
9.24	IC50	0.57	nM	CHEMBL4544981
9.22	IC50	0.6	nM	CHEMBL4570697
9.21	IC50	0.61	nM	CHEMBL4450425
9.21	IC50	0.61	nM	CHEMBL4517882
9.19	IC50	0.65	nM	CHEMBL4476135
9.19	IC50	0.64	nM	CHEMBL4470799
9.18	IC50	0.66	nM	CHEMBL4555480
9.18	IC50	0.66	nM	CHEMBL4449476
9.15	IC50	0.71	nM	CHEMBL4443775
9.14	IC50	0.72	nM	CHEMBL4556108
9.14	IC50	0.72	nM	CHEMBL4463366
9.13	IC50	0.74	nM	CHEMBL4574858
9.11	IC50	0.78	nM	CHEMBL4439410
9.06	IC50	0.87	nM	CHEMBL4527541
9.06	IC50	0.88	nM	CHEMBL4515393
9.04	IC50	0.92	nM	CHEMBL4448457
9.03	IC50	0.94	nM	CHEMBL4475900
9.02	IC50	0.96	nM	CHEMBL4581025
9.00	IC50	1.01	nM	CHEMBL4476540
8.98	IC50	1.04	nM	CHEMBL4563370
8.97	IC50	1.06	nM	CHEMBL4513672
8.96	Kd	1.1	nM	CHEMBL3958046
8.94	IC50	1.14	nM	CHEMBL4451907
8.92	EC50	1.2	nM	CHEMBL4445250
8.91	IC50	1.22	nM	CHEMBL4593874
8.88	IC50	1.32	nM	CHEMBL4436906
8.87	IC50	1.34	nM	CHEMBL4529807
8.82	EC50	1.5	nM	CHEMBL4589534
8.80	Kd	1.6	nM	CHEMBL4451698
8.79	IC50	1.63	nM	CHEMBL4588428
8.79	IC50	1.63	nM	CHEMBL4440879
8.76	IC50	1.75	nM	CHEMBL4472115
8.73	IC50	1.86	nM	CHEMBL4520832
8.71	IC50	1.94	nM	CHEMBL4442890
8.71	IC50	1.94	nM	CHEMBL4462279
8.70	IC50	1.99	nM	CHEMBL4434734
8.70	EC50	2	nM	CHEMBL4548806
8.69	IC50	2.03	nM	CHEMBL4454494
8.69	IC50	2.05	nM	CHEMBL4576960
8.69	IC50	2.06	nM	CHEMBL4448017
8.69	IC50	2.04	nM	CHEMBL4564338
8.68	EC50	2.1	nM	CHEMBL4447812

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases secretion, decreases expression, decreases reaction, affects expression, affects cotreatment (+1 more)	10
Valproic Acid	decreases expression, increases expression, affects cotreatment	6
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	4
methylmercuric chloride	decreases expression, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
(+)-JQ1 compound	affects cotreatment, decreases expression	3
Acetaminophen	decreases expression, affects cotreatment	3
Cyclosporine	decreases expression, affects cotreatment, increases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	3
graphene oxide	increases expression	2
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
mercuric bromide	affects cotreatment, increases expression	2
chromium hexavalent ion	increases expression, increases abundance	2
belinostat	increases expression, affects cotreatment	2
Fulvestrant	decreases reaction, decreases secretion, increases expression, affects cotreatment, increases secretion (+1 more)	2
Vorinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases oxidation, affects cotreatment	2
Ethanol	decreases expression, affects cotreatment, increases abundance	2
Arsenic	increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Copper	affects cotreatment, increases expression, affects binding	2
Doxorubicin	decreases expression, affects response to substance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Genistein	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Raloxifene Hydrochloride	affects cotreatment, increases secretion, decreases expression, decreases reaction, decreases secretion (+1 more)	2

ChEMBL screening assays

116 unique, capped per target: 116 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4419588	Binding	Binding affinity to TFPI (unknown origin) incubated for 1.5 hrs using tracer peptide JBT0131 by competition ELISA	TFPI inhibitors and methods of use

Clinical trials (associated diseases)

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