TFPI2

Summary

TFPI2 (tissue factor pathway inhibitor 2, HGNC:11761) is a protein-coding gene on chromosome 7q21.3, encoding Tissue factor pathway inhibitor 2 (P48307). May play a role in the regulation of plasmin-mediated matrix remodeling.

This gene encodes a member of the Kunitz-type serine proteinase inhibitor family. The protein can inhibit a variety of serine proteases including factor VIIa/tissue factor, factor Xa, plasmin, trypsin, chymotryspin and plasma kallikrein. This gene has been identified as a tumor suppressor gene in several types of cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7980 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 44 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006528

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11761
Approved symbol	TFPI2
Name	tissue factor pathway inhibitor 2
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Aliases	PP5, TFPI-2, REF1
Ensembl gene	ENSG00000105825
Ensembl biotype	protein_coding
OMIM	600033
Entrez	7980

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000222543, ENST00000451238, ENST00000461482, ENST00000647793, ENST00000649913, ENST00000650573, ENST00000898459

RefSeq mRNA: 3 — MANE Select: NM_006528 NM_001271003, NM_001271004, NM_006528

CCDS: CCDS5632

Canonical transcript exons

ENST00000222543 — 5 exons

Exon	Start	End
ENSE00000705482	93887261	93887431
ENSE00000705485	93889035	93889223
ENSE00000705488	93890137	93890319
ENSE00000877340	93885396	93886896
ENSE00003832353	93890591	93890753

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 214.2771 / max 16920.3743, expressed in 1306 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84889	210.8269	1298
84884	1.0743	301
84888	0.7989	250
84886	0.7598	267
84883	0.3408	149
84891	0.2968	166
84885	0.1002	46
84890	0.0405	11
84887	0.0390	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.78	gold quality
parietal pleura	UBERON:0002400	98.32	gold quality
islet of Langerhans	UBERON:0000006	97.53	gold quality
cartilage tissue	UBERON:0002418	97.43	gold quality
pigmented layer of retina	UBERON:0001782	97.01	gold quality
retina	UBERON:0000966	96.99	gold quality
germinal epithelium of ovary	UBERON:0001304	96.89	gold quality
pericardium	UBERON:0002407	96.65	gold quality
placenta	UBERON:0001987	96.37	gold quality
type B pancreatic cell	CL:0000169	94.58	gold quality
pleura	UBERON:0000977	92.76	gold quality
endometrium	UBERON:0001295	91.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.53	gold quality
left adrenal gland cortex	UBERON:0035825	91.39	gold quality
left adrenal gland	UBERON:0001234	91.14	gold quality
peritoneum	UBERON:0002358	91.06	gold quality
omental fat pad	UBERON:0010414	91.06	gold quality
eye	UBERON:0000970	91.03	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.38	gold quality
left ovary	UBERON:0002119	90.17	gold quality
palpebral conjunctiva	UBERON:0001812	89.40	gold quality
epithelial cell of pancreas	CL:0000083	89.25	gold quality
adrenal cortex	UBERON:0001235	89.19	gold quality
left uterine tube	UBERON:0001303	88.66	gold quality
adrenal gland	UBERON:0002369	88.41	gold quality
right adrenal gland	UBERON:0001233	87.84	gold quality
pancreas	UBERON:0001264	87.71	gold quality
ovary	UBERON:0000992	87.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.19	gold quality
right ovary	UBERON:0002118	86.39	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-9154	yes	7095.06
E-HCAD-24	yes	4961.21
E-GEOD-86618	yes	215.25
E-MTAB-10287	yes	49.20
E-MTAB-7316	yes	31.21
E-GEOD-81547	yes	25.18
E-MTAB-6701	yes	13.46
E-MTAB-7249	yes	4.71
E-CURD-10	no	4356.46
E-HCAD-38	no	1391.67
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, EGR1, ESR1, ESR2, JUN, KLF6, MYC, NFIC, NFKB1, SP1, TFCP2

miRNA regulators (miRDB)

100 targeting TFPI2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4745-5P	99.98	65.95	1028
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-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904

Literature-anchored findings (GeneRIF, showing 40)

• the villous cytotrophoblast and syncytiotrophoblast are both important sites of TFPI-2 synthesis in the human placenta (PMID:12606321)
• methylation of TFPI-2 gene is not the sole cause of its silencing (PMID:12632077)
• induced by various pathways in human glioma cells (PMID:12738994)
• the minimal TFPI2 promoter is located between -166 and -111 from the translation start site; three transcription initiation sites and several putative transcription factor binding sites were identified, and potential regulatory regions were characterized. (PMID:12757776)
• These data provide evidence that tissue factor pathway inhibitor-2 does not bind to matrix metalloproteinases-2, -9 or -1, or regulate matrix metalloproteinase-1, in the extracellular matrix. (PMID:12787920)
• The expression of TFPI-2 diminishes with an increasing degree of malignancy, which may suggest a role for TFPI-2 in the maintenance of tumor stability and inhibition of the growth of neoplasms. (PMID:12876637)
• These studies establish that TFPI-2 is transcriptionally silenced through promoter methylation in SNB19 cells. (PMID:12881707)
• Bovine TFPI2 was compared to human TFPI2. (PMID:12921785)
• secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis (PMID:14525759)
• Expression of TFPI-2 may strongly inhibit the invasive ability of ovarian tumor cells in vitro, but has no effect on the migratory ability. (PMID:14558946)
• thrombin, through PAR-1 signaling, up-regulates the synthesis of TFPI-2 via a MAPK/COX-2-dependent pathway (PMID:14623891)
• Computer model of the interaction of human TFPI-2 Kunitz-type serine protease inhibitor with human plasmin [letter] (PMID:14678821)
• analysis of the reactive site in the first Kunitz-type domain of TFPI2 (PMID:14970225)
• human and murine TFPI-2 have different functions in liver regulation during inflammation in the two species (PMID:14983234)
• variations in the TFPI-2 gene and its promoter region (PMID:15183047)
• TNF treatment at 41 degrees C significantly reduced clotting activity, TF protein and mRNA as well as TFPI-2 mRNA. (PMID:15221977)
• data suggest that gC1qR may participate in tissue remodeling and inflammation by localizing TFPI-2 to the pericellular environment to modulate local protease activity and regulate High Molecular Weight Kininogen activation (PMID:15467913)
• Restored expression of the TFPI-2 gene in nonexpressing pancreatic cancer cells resulted in marked suppression in their proliferation, migration, and invasive potential. (PMID:15592528)
• These results suggest that silencing of the TFPI-2 gene by hypermethylation might contribute to tumour progression in NSCLC. (PMID:15685245)
• x-ray crystallographic analysis of Kunitz domain 1 of TFPI-2 in complex with trypsin (PMID:15932872)
• Preeclampsia and IUGR showed distinct distributions of TFPI-2. (PMID:16580726)
• role of TFPI-2 as a maintenance factor of extracellular remodeling suggests the indirect function of ADAMTS1 as an additional homeostatic player by its ability to alter the extracellular location of TFPI-2 (PMID:16641089)
• Aberrant methylation of tissue factor pathway inhibitor 2 is associated with pancreatic carcinoma. (PMID:16965396)
• data suggest that VEGF-upregulation of TFPI-2 expression in endothelial cells may represent a mechanism for negative feedback regulation and modulation of its pro-angiogenic action on endothelial cells. (PMID:17023682)
• Our data suggest that TFPI-2 may be an important regulator of aberrant angiogenesis associated with tumor growth/metastasis, cardiovascular diseases, chronic inflammation, or diabetes. (PMID:17138934)
• A new 289-nucleotide splice variant of the TFPI-2 transcript consists of complete exons II & V, fused with several nucleotides derived from exons III & IV, & 6 nucleotides derived from intron C. It lacks either a 5’-TR) or a 3’-poly (A)+ tail. (PMID:17352822)
• Results showed that TFPI-2 is silenced in malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis. (PMID:17372906)
• TFPI-2 is frequently silenced in hepatocellular carcinoma via epigenetic alterations, including promoter methylation and histone deacetylation; ectopic overexpression of TFPI-2 significantly suppressed the proliferation and invasiveness of HCC cells (PMID:17464989)
• The detailed conformational changes of the heated protein observed by fourier transform infrared spectroscopy, circular dichroism and Raman spectroscopy revealed that hTFPI-2/KD1 was thermally stable (PMID:17558445)
• The CpG islands in TFPI-2 promoter was hypermethylated in highly invasive breast cancer cell line, and DNA methylation in the entire promoter region caused TFPI-2 repression by inducing inactive chromatin structure and decreasing KLF6 binding. (PMID:18053161)
• keratoepithelin induces elevated TFPI2 transcript levels in neuroblastoma cells without alterations of MYCN expression. (PMID:18097563)
• Collectively, our results demonstrate that treatment of HT-1080 fibrosarcoma cells exogenously with either TFPI-2 or its first Kunitz domain mutant R24K activates caspase-mediated, pro-apoptotic signaling pathways resulting in apoptosis. (PMID:18401718)
• Results reveals a novel placenta-specific transcript, TFPI2, which is expressed from the maternal allele. (PMID:18480470)
• Genotyping for MspI gene polymorphisms may be clinically relevant to define the predisposition to the major clinical manifestations in mixed cryoglobulinemic syndrome. (PMID:18810851)
• Tissue factor pathway inhibitor-2 gene methylation is associated with low expression in carotid atherosclerotic plaques. (PMID:19081094)
• The expression of TFPI-2 is correlated with clinical stage and differentiation of pancreatic carcinoma. (PMID:19102937)
• Initial description of TFPI-2 internalization and translocation to the nucleus in a number of cells. (PMID:19103149)
• epigallocatechin gallate inhibits growth and induces apoptosis in renal cell carcinoma through TFPI-2 overexpression (PMID:19212621)
• Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma. (PMID:19288010)
• Potential of TFPI2 as a biomarker for the early detection of CRC using stool DNA-based assays. (PMID:19435926)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	tfpi2	ENSDARG00000061351
mus_musculus	Tfpi2	ENSMUSG00000029664
rattus_norvegicus	Tfpi2	ENSRNOG00000010513
drosophila_melanogaster	CG7565	FBGN0035833
caenorhabditis_elegans		WBGENE00010792
caenorhabditis_elegans		WBGENE00015355
caenorhabditis_elegans		WBGENE00021939

Paralogs (13): TFPI (ENSG00000003436), EPPIN (ENSG00000101448), 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 2 — P48307 (reviewed: P48307)

Alternative names: Placental protein 5

All UniProt accessions (5): P48307, A0A3B3IRW1, A0A3B3IS67, A0A3B3ISY1, H7C4A3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in the regulation of plasmin-mediated matrix remodeling. Inhibits trypsin, plasmin, factor VIIa/tissue factor and weakly factor Xa. Has no effect on thrombin.

Subunit / interactions. Finds in a complex with ABCB1, TFPI2 and PPP2R3C; leading to the dephosphorylation of ABCB1.

Subcellular location. Secreted.

Tissue specificity. Umbilical vein endothelial cells, liver, placenta, heart, pancreas, and maternal serum at advanced pregnancy.

Domain organisation. This inhibitor contains three inhibitory domains.

Isoforms (2)

UniProt ID	Names	Canonical?
P48307-1	1	yes
P48307-2	2

RefSeq proteins (3): NP_001257932, NP_001257933, NP_006519* (*=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 (32 total): disulfide bond 9, sequence conflict 4, domain 3, strand 3, site 3, sequence variant 2, helix 2, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1ZR0	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48307-F1	84.15	0.64

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 (3): 46–47 (reactive bond); 107–108 (reactive bond); 168–169 (reactive bond)

Disulfide bonds (9): 36–86, 45–69, 61–82, 96–149, 106–130, 122–145, 158–208, 167–191, 183–204

Glycosylation sites (2): 116, 170

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells

MSigDB gene sets: 245 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_255, BECKER_TAMOXIFEN_RESISTANCE_UP, MODULE_317, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, KYNG_DNA_DAMAGE_DN, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_WOUND_HEALING, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, ONKEN_UVEAL_MELANOMA_UP, UEDA_PERIFERAL_CLOCK, MARTINEZ_RB1_TARGETS_DN

GO Biological Process (3): blood coagulation (GO:0007596), hemostasis (GO:0007599), negative regulation of peptidase activity (GO:0010466)

GO Molecular Function (3): serine-type endopeptidase inhibitor activity (GO:0004867), extracellular matrix structural constituent (GO:0005201), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
peptidase activity	2
hemostasis	1
wound healing	1
coagulation	1
regulation of body fluid levels	1
negative regulation of proteolysis	1
negative regulation of hydrolase activity	1
regulation of peptidase activity	1
serine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
structural molecule activity	1
extracellular matrix	1
enzyme inhibitor activity	1
peptidase regulator activity	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1826 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TFPI2	F3	P13726	898
TFPI2	BMP3	P12645	695
TFPI2	RASSF1	Q9NS23	643
TFPI2	PLG	P00747	601
TFPI2	NDRG4	Q9ULP0	598
TFPI2	KLKB1	P03952	597
TFPI2	IGF2	P01344	542
TFPI2	FGFBP1	Q14512	509
TFPI2	THBD	P07204	506
TFPI2	RELN	P78509	505
TFPI2	THBS1	P07996	491
TFPI2	SFRP1	Q8N474	482
TFPI2	SFRP2	Q96HF1	479
TFPI2	SEPTIN9	Q9UHD8	476
TFPI2	ENTPD1	P49961	475
TFPI2	PSG3	Q16557	475

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TFPI2	SKIL	psi-mi:“MI:0915”(physical association)	0.370
SMURF2	TFPI2	psi-mi:“MI:0915”(physical association)	0.370
TFPI2	AP3B1	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): TFPI2 (Affinity Capture-MS), TFPI2 (Affinity Capture-Western), TFPI2 (Affinity Capture-Western), TFPI2 (Proximity Label-MS), SORL1 (Affinity Capture-MS), DCAF5 (Affinity Capture-MS), IFT172 (Affinity Capture-MS), NAP1L1 (Affinity Capture-MS), IFT88 (Affinity Capture-MS), KBTBD7 (Affinity Capture-MS), IFT57 (Affinity Capture-MS), WDR89 (Affinity Capture-MS), C18orf25 (Affinity Capture-MS), CENPB (Affinity Capture-MS), TRIM26 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D0BND9, A0A6B7FBD3, A6MFL4, B2G331, B5KL27, B5KL28, B5KL29, B5KL30, B5KL32, B5KL33, B5KL34, B5KL35, B5KL37, B5KL38, B5KL39, B5KL40, B5KL41, B5L5Q1, B5L5Q3, B5L5Q6, E7FL13, G9I929, O35536, P0DJ45, P0DJ50, P0DJ80, P0DJ85, P0DMJ1, P0DMJ5, P0DN06, P0DN07, P0DN09, P0DN10, P0DN11, P0DN12, P0DN13, P0DN14, P0DN15, P0DN16, P0DN17

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

549 predictions. Top by Δscore:

Variant	Effect	Δscore
7:93886892:CAAAG:C	acceptor_gain	1.0000
7:93886897:C:CC	acceptor_gain	1.0000
7:93887432:C:CC	acceptor_gain	1.0000
7:93887434:T:C	acceptor_gain	1.0000
7:93889030:TTTA:T	donor_loss	1.0000
7:93889031:TTACT:T	donor_loss	1.0000
7:93889032:TACTT:T	donor_loss	1.0000
7:93889033:A:AC	donor_gain	1.0000
7:93889033:A:AT	donor_loss	1.0000
7:93889034:C:CT	donor_gain	1.0000
7:93889034:CT:C	donor_gain	1.0000
7:93889034:CTTTT:C	donor_gain	1.0000
7:93889113:C:CT	acceptor_gain	1.0000
7:93889114:G:T	acceptor_gain	1.0000
7:93889219:AACTT:A	acceptor_gain	1.0000
7:93889220:ACTT:A	acceptor_loss	1.0000
7:93889220:ACTTC:A	acceptor_gain	1.0000
7:93889221:CTT:C	acceptor_gain	1.0000
7:93889221:CTTCT:C	acceptor_gain	1.0000
7:93889222:TT:T	acceptor_gain	1.0000
7:93889223:TCT:T	acceptor_loss	1.0000
7:93889224:C:CC	acceptor_gain	1.0000
7:93889224:C:G	acceptor_loss	1.0000
7:93889225:T:C	acceptor_loss	1.0000
7:93890133:TTACT:T	donor_loss	1.0000
7:93890135:A:AC	donor_gain	1.0000
7:93890136:C:CC	donor_gain	1.0000
7:93890136:CT:C	donor_gain	1.0000
7:93890136:CTT:C	donor_gain	1.0000
7:93890136:CTTT:C	donor_gain	1.0000

AlphaMissense

1551 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:93889208:C:G	C96S	0.996
7:93889209:A:T	C96S	0.996
7:93890163:C:G	C82S	0.996
7:93890164:A:T	C82S	0.996
7:93890180:G:C	F76L	0.996
7:93890180:G:T	F76L	0.996
7:93890182:A:G	F76L	0.996
7:93890151:C:T	C86Y	0.995
7:93890163:C:T	C82Y	0.995
7:93890181:A:C	F76C	0.995
7:93887374:C:G	R173P	0.994
7:93889049:C:G	C149S	0.994
7:93889050:A:T	C149S	0.994
7:93889079:A:C	F139C	0.994
7:93890226:C:G	C61S	0.994
7:93890227:A:T	C61S	0.994
7:93887334:G:C	F186L	0.993
7:93887334:G:T	F186L	0.993
7:93887335:A:C	F186C	0.993
7:93887336:A:G	F186L	0.993
7:93889061:C:G	C145S	0.993
7:93889062:A:T	C145S	0.993
7:93889078:A:C	F139L	0.993
7:93889078:A:T	F139L	0.993
7:93889080:A:G	F139L	0.993
7:93889208:C:T	C96Y	0.993
7:93890151:C:G	C86S	0.993
7:93890152:A:T	C86S	0.993
7:93890186:G:C	N74K	0.993
7:93890186:G:T	N74K	0.993

dbSNP variants (sampled 300 via entrez): RS1000218731 (7:93888916 T>C), RS1000512824 (7:93890249 G>A,T), RS1000586619 (7:93889939 T>C), RS1000716037 (7:93888649 G>A,C), RS1000956366 (7:93890390 A>G), RS1002082418 (7:93890455 C>A,G,T), RS1003603423 (7:93885732 C>T), RS1004066731 (7:93885421 G>A,T), RS1004159969 (7:93891613 A>G), RS1004388080 (7:93889289 A>G), RS1004510227 (7:93889260 A>C), RS1004626156 (7:93890999 C>G), RS1004699553 (7:93889598 A>G), RS1005151359 (7:93889555 C>A,T), RS1005185716 (7:93891629 A>G)

Disease associations

OMIM: gene MIM:600033 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005846_6	Heart rate response to recovery post exercise (10 sec)	7.000000e-12
GCST005847_8	Heart rate response to recovery post exercise (20 sec)	9.000000e-11
GCST005848_14	Heart rate response to recovery post exercise (50 sec)	4.000000e-11
GCST005849_13	Heart rate response to recovery post exercise (40 sec)	2.000000e-12
GCST005850_5	Heart rate response to recovery post exercise (30 sec)	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009185	heart rate response to recovery post exercise

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066240 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,679 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL48449	CANTHARIDIN	4	4,679

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

ChEMBL bioactivities

17 potent at pChembl≥5 of 25 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	MICROCYSTIN-LR
8.46	IC50	3.5	nM	OKADAIC ACID
8.40	IC50	4	nM	NODULARIN
6.30	IC50	500	nM	CANTHARIDIN
6.05	IC50	900	nM	CHEMBL5597580
6.01	IC50	970	nM	DEMETHYL-CANTHARIDIN
5.51	IC50	3100	nM	ENDOTHALL
5.44	IC50	3600	nM	CHEMBL5596734
5.39	IC50	4100	nM	CHEMBL5596696
5.27	IC50	5400	nM	CHEMBL5597886
5.21	IC50	6100	nM	CHEMBL5596039
5.21	IC50	6200	nM	CHEMBL5598389
5.17	IC50	6700	nM	CHEMBL5597987
5.14	IC50	7200	nM	CHEMBL5597468
5.11	IC50	7700	nM	CHEMBL5598075
5.11	IC50	7700	nM	CHEMBL5598083
5.07	IC50	8500	nM	CHEMBL5597434

PubChem BioAssay actives

17 with measured affinity, of 31 total; 17 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
(5R,8S,11R,12S,15S,18S,19S,22R)-15-[3-(diaminomethylideneamino)propyl]-18-[(1E,3E,5S,6S)-6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dienyl]-1,5,12,19-tetramethyl-2-methylidene-8-(2-methylpropyl)-3,6,9,13,16,20,25-heptaoxo-1,4,7,10,14,17,21-heptazacyclopentacosane-11,22-dicarboxylic acid	2121549: Inhibition of PP5 (unknown origin)	ic50	0.0010	uM
(2R)-3-[(2S,6R,8S,11R)-2-[(E,2R)-4-[(2S,2’R,4R,4aS,6R,8aR)-4-hydroxy-2-[(1S,3S)-1-hydroxy-3-[(2S,3R,6S)-3-methyl-1,7-dioxaspiro[5.5]undecan-2-yl]butyl]-3-methylidenespiro[4a,7,8,8a-tetrahydro-4H-pyrano[3,2-b]pyran-6,5’-oxolane]-2’-yl]but-3-en-2-yl]-11-hydroxy-4-methyl-1,7-dioxaspiro[5.5]undec-4-en-8-yl]-2-hydroxy-2-methylpropanoic acid	2121549: Inhibition of PP5 (unknown origin)	ic50	0.0035	uM
(2Z,5R,6S,9S,12S,13S,16R)-9-[3-(diaminomethylideneamino)propyl]-2-ethylidene-12-[(1E,3E,5S,6S)-6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dienyl]-1,6,13-trimethyl-3,7,10,14,19-pentaoxo-1,4,8,11,15-pentazacyclononadecane-5,16-dicarboxylic acid	2121549: Inhibition of PP5 (unknown origin)	ic50	0.0040	uM
Cantharidin	2121549: Inhibition of PP5 (unknown origin)	ic50	0.5000	uM
(1S,2R,3S,4R)-3-(indole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	0.9000	uM
4,10-dioxatricyclo[5.2.1.02,6]decane-3,5-dione	2121549: Inhibition of PP5 (unknown origin)	ic50	0.9700	uM
(1S,2R,3S,4R)-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	3.1000	uM
(1S,2R,3S,4R)-3-([1,3]dioxolo[4,5-f]indole-5-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	3.6000	uM
(1S,2R,3S,4R)-3-(6-methoxyindole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	4.1000	uM
(1S,2R,3S,4R)-3-(5-fluoroindole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	5.4000	uM
(1R,2S,3R,4S)-3-(cyclopentylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	6.1000	uM
(1S,2R,3S,4R)-3-(3-methylindole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	6.2000	uM
(1R,2S,3R,4S)-3-(4-methylpiperazine-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	6.7000	uM
(1S,2R,3S,4R)-3-(5-propan-2-yloxyindole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	7.2000	uM
(1S,2R,3S,4R)-3-(5,6-dimethoxyindole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	7.7000	uM
(1S,2R,3S,4R)-3-(5-methylindole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	7.7000	uM
(1S,2R,3S,4R)-3-(indazole-1-carbonyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid	2121476: Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	ic50	8.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Asbestos, Crocidolite	affects expression, increases expression, increases secretion, decreases reaction, affects reaction	5
bisphenol A	decreases expression, increases expression, increases methylation, affects cotreatment	4
Benzo(a)pyrene	decreases methylation, increases expression	4
Estradiol	affects cotreatment, increases expression, decreases expression	4
trichostatin A	affects cotreatment, affects methylation, affects expression, increases expression	3
Doxorubicin	decreases expression, increases expression, affects response to substance	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Tretinoin	decreases expression, increases expression	3
cobaltous chloride	decreases expression	2
entinostat	increases expression, affects cotreatment	2
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	2
Resveratrol	increases expression	2
Temozolomide	decreases expression, affects response to substance	2
Decitabine	affects methylation, affects expression, decreases methylation, increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression, decreases response to substance, increases expression	2
Dexamethasone	decreases expression, affects cotreatment	2
Lipopolysaccharides	increases expression, affects expression, affects response to substance, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
8-Bromo Cyclic Adenosine Monophosphate	increases expression	2
aristolochic acid I	decreases expression	1
Glupearl 19S	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5587075	Binding	Inhibition of His-tagged PP5 (169 to 499 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using pNPP as substrate incubated for 30 mins	Design and Synthesis of 7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Derivatives as PP5 Inhibitors To Reverse Temozolomide Resistance in Glioblastoma Multiforme. — J Med Chem

Clinical trials (associated diseases)

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