PTGIS

Summary

PTGIS (prostaglandin I2 synthase, HGNC:9603) is a protein-coding gene on chromosome 20q13.13, encoding Prostacyclin synthase (Q16647). Catalyzes the biosynthesis and metabolism of eicosanoids.

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. However, this protein is considered a member of the cytochrome P450 superfamily on the basis of sequence similarity rather than functional similarity. This endoplasmic reticulum membrane protein catalyzes the conversion of prostglandin H2 to prostacyclin (prostaglandin I2), a potent vasodilator and inhibitor of platelet aggregation. An imbalance of prostacyclin and its physiological antagonist thromboxane A2 contribute to the development of myocardial infarction, stroke, and atherosclerosis.

Source: NCBI Gene 5740 — RefSeq curated summary.

At a glance

• Gene–disease (curated): essential hypertension, genetic (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 118 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000961

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9603
Approved symbol	PTGIS
Name	prostaglandin I2 synthase
Location	20q13.13
Locus type	gene with protein product
Status	Approved
Aliases	PGIS, CYP8A1
Ensembl gene	ENSG00000124212
Ensembl biotype	protein_coding
OMIM	601699
Entrez	5740

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000244043, ENST00000478971, ENST00000918261

RefSeq mRNA: 1 — MANE Select: NM_000961 NM_000961

CCDS: CCDS13419

Canonical transcript exons

ENST00000244043 — 10 exons

Exon	Start	End
ENSE00001264907	49503874	49508064
ENSE00003034831	49547841	49548019
ENSE00003059789	49568043	49568137
ENSE00003473245	49539570	49539721
ENSE00003484154	49550066	49550189
ENSE00003556284	49514227	49514395
ENSE00003558469	49524058	49524239
ENSE00003579247	49511028	49511179
ENSE00003629664	49513080	49513261
ENSE00003655367	49544305	49544448

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 98.98.

FANTOM5 (CAGE): breadth broad, TPM avg 18.0224 / max 724.9891, expressed in 882 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187768	9.0505	720
187773	4.5573	703
187767	3.9214	505
187770	0.2013	107
187771	0.1322	51
187772	0.1154	40
187748	0.0337	15
187769	0.0062	2
187766	0.0044	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parietal pleura	UBERON:0002400	98.98	gold quality
right coronary artery	UBERON:0001625	98.69	gold quality
blood vessel layer	UBERON:0004797	98.60	gold quality
saphenous vein	UBERON:0007318	98.44	gold quality
pericardium	UBERON:0002407	98.25	gold quality
left uterine tube	UBERON:0001303	97.36	gold quality
descending thoracic aorta	UBERON:0002345	97.29	gold quality
pleura	UBERON:0000977	97.24	gold quality
ascending aorta	UBERON:0001496	97.24	gold quality
thoracic aorta	UBERON:0001515	97.24	gold quality
coronary artery	UBERON:0001621	96.94	gold quality
germinal epithelium of ovary	UBERON:0001304	96.77	gold quality
left coronary artery	UBERON:0001626	96.74	gold quality
vena cava	UBERON:0004087	96.63	gold quality
aorta	UBERON:0000947	96.27	gold quality
myometrium	UBERON:0001296	96.02	gold quality
cauda epididymis	UBERON:0004360	95.78	gold quality
popliteal artery	UBERON:0002250	95.56	gold quality
tibial artery	UBERON:0007610	95.55	gold quality
calcaneal tendon	UBERON:0003701	95.23	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.06	gold quality
body of uterus	UBERON:0009853	94.90	gold quality
superficial temporal artery	UBERON:0001614	94.72	gold quality
smooth muscle tissue	UBERON:0001135	94.70	gold quality
visceral pleura	UBERON:0002401	94.32	gold quality
urinary bladder	UBERON:0001255	94.12	gold quality
heart right ventricle	UBERON:0002080	94.10	gold quality
caput epididymis	UBERON:0004358	93.91	gold quality
mucosa of urinary bladder	UBERON:0001259	93.86	gold quality
decidua	UBERON:0002450	93.67	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	1264.61
E-MTAB-8559	yes	413.67
E-ANND-3	yes	27.95
E-MTAB-9543	yes	12.81
E-GEOD-124858	no	176.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KDM5B, SP1

miRNA regulators (miRDB)

128 targeting PTGIS, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-3913-3P	99.74	66.53	938

Literature-anchored findings (GeneRIF, showing 40)

• Association study between a novel single nucleotide polymorphism of the promoter region of the prostacyclin synthase gene and essential hypertension. (PMID:11924728)
• NMR and circular dichroism solution structure of microsomal PGIS (PMID:12193162)
• the fallopian tube expresses both COX isoforms and PGIS (PMID:12213900)
• the PGIS gene has a splicing mutation in familial hypertension (PMID:12372404)
• Cyclic mechanical stretch augmented prostacyclin synthase promoter activity, via activation of activator protein-1 site, and prostacyclin synthase mRNA and protein expression in cultured human myometrial cells (PMID:12414894)
• gestational age decrease in the inhibitory prostaglandin I2 synthase is consistent with lessening of its influence in myometrium at the time of labor (PMID:12414902)
• effect of overexpression of this enzyme transfected into vascular smooth muscle cells in rats (PMID:12664597)
• residue(s) within helix F/G loop of PGIS may be involved in forming the substrate access channel and located in a position that influences the membrane-bound PGIS catalytic function (PMID:12741817)
• splicing mutation found in hypertension (PMID:12751759)
• We successfully identified haplotypes of the PGIS gene, and these haplotypes were not associated with essential hypertension. (PMID:12924623)
• results suggest specific VNTR polymorphism in the 5’-upstream promoter region of the PGIS gene regulated prostacyclin production, but did not seem to be associated with development of CTEPH (chronic thromboembolic pulmonary hypertension) (PMID:15182267)
• Epigenetic inactivation of the PTGIS gene is a recurrent alteration in colorectal carcinogenesis (PMID:16007128)
• The two major genetic loci Pgis1 and Pgis2 of murine spondylitis are homologous to chromosome regions in human genome, which control ankylosing spondylitis in human patients. (PMID:16081819)
• PGIS has a typical low-spin heme with a hydrophobic active site. (PMID:16406803)
• Dengue virus could promote the expression of PGIS mRNA in HUVEC and increase the level of PGI(2), which may increase the vascular permeability. (PMID:17210107)
• In vitro shear stress can promote PGI(2 )secretion by human endothelial progenitor cells. (PMID:17221326)
• Adenovirus PGIS gene transfer reduced PPAR delta expression and inhibited neointimal formation after balloon injury in accordance with the reduction in the phosphorylation of p38 MAPK (PMID:17303142)
• PGIS promoter haplotype can play an important role in the predisposition for lung cancer and CpG methylation provides an epigenetic mechanism for the down-regulated PGIS expression. (PMID:17374734)
• An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans. (PMID:17635855)
• These studies have provided the structural information for the interaction of the PGIS with its substrate mimic. (PMID:18081314)
• Populations with both COX-2 -765GG and PGIS CC genotypes were more at risk for myocardial infarction. (PMID:19040046)
• PTGIS genetic variation is associated with incident myocardial infarction. Carriers of rs20417C allele may derive greater benefits from aspirin use. (PMID:19046748)
• The CC genotype and C allele of the prostacyclin synthase gene might be a risk factor of MI in Uigur population in Xinjiang. (PMID:19065539)
• MI is associated with the CC genotype of rs5629 in the human CYP8A1 gene. The A-C-T haplotype appears to be a useful genetic marker and the C-T-T haplotype might be a protective factor of MI in Chinese people. (PMID:19147528)
• Characterization of the recombinant PGIS intermediates is reported in reactions with other peroxides, peracetic acid, and iodosylbenzene, providing a mechanistic model of a peroxidase reaction catalyzed by the class III cytochromes P450. (PMID:19187034)
• rs237484 is in proximity to the potassium voltage gate channel gene (KCNB1) and close to the prostaglandin I2 (prostacyclin) synthase gene (PTGIS). (PMID:19265782)
• The CC genotype of CYP8A1 is associated with myocardial infarction(MI), respectively. (PMID:19327107)
• In the Uigur population CC genotype of rs5629 and the C-T-T haplotype of prostacyclin synthase gene are associated with myocardial infarction but the A-C-T haplotype of prostacyclin synthase gene might be a protective factor. (PMID:19719985)
• PGIS overexpression apparently protects insulin-producing cells against cytokine toxicity via suppression of endoplasmic reticulum and mitochondrial stress-mediated cell death pathways (PMID:20159982)
• diabetes preferentially increases PGIS nitration that is associated with excessive vascular inflammation in atherosclerotic carotid arteries from patients with type 2 diabetes (PMID:20348234)
• Review: PGI2 function depends on the different alleles of the PTGIS gene and that they may influence the risk of cardiovascular disease. (PMID:20357747)
• downregulated in endometriosis tissues (PMID:20452033)
• The CC genotype of C1117A polymorphism is associated with higher risk of LM-CAD (PMID:22072641)
• Overexpression of PTGIS is associated with liver metastasis in colon cancer. (PMID:22109564)
• High PTGIS expression is associated with colorectal cancer hepatic metastasis. (PMID:22219064)
• These findings suggest that PGIS is induced by hypoxia and regulates the expression of VEGF in fibroblasts. (PMID:23807031)
• Type-2 diabetes is associated with higher COX-2 expression, but lower eNOS and PGIS expression in subcutaneous arteries. (PMID:24225501)
• In a case-control study unaffected carriers of a BMPR2 mutation, linked to pulmonary artery hypertension (PAH), were most often found to have prostacyclin synthase promoter sequence variants, which were thought to protect against PAH. (PMID:24605778)
• results indicate that PGIS expression was associated with radiotherapy efficiency (PMID:25256272)
• Based on the predicted crystal structure of CYP8A1( *)5 using the Molecular Operating Environment platform, the distance from CYP8A1 Cys441 to the heme was altered with a significantly changed binding free energy for the mutant protein. (PMID:25623425)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ptgis	ENSDARG00000060094
mus_musculus	Ptgis	ENSMUSG00000017969
rattus_norvegicus	AABR07054614.1	ENSRNOG00000008245

Paralogs (1): CYP8B1 (ENSG00000180432)

Protein

Protein identifiers

Prostacyclin synthase — Q16647 (reviewed: Q16647)

Alternative names: Hydroperoxy icosatetraenoate dehydratase, Prostaglandin I2 synthase

All UniProt accessions (1): Q16647

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the biosynthesis and metabolism of eicosanoids. Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2), a potent mediator of vasodilation and inhibitor of platelet aggregation. Additionally, displays dehydratase activity, toward hydroperoxyeicosatetraenoates (HPETEs), especially toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE).

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed; particularly abundant in ovary, heart, skeletal muscle, lung and prostate.

Disease relevance. Essential hypertension (EHT) [MIM:145500] A condition in which blood pressure is consistently higher than normal with no identifiable cause. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cytochrome P450 family.

RefSeq proteins (1): NP_000952* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002403	Cyt_P450_E_grp-IV	Family
IPR024204	Cyt_P450_CYP7A1-type	Family
IPR027286	PTGIS	Family
IPR036396	Cyt_P450_sf	Homologous_superfamily

Pfam: PF00067

Enzyme classification (BRENDA):

• EC 5.3.99.4 — prostaglandin-I synthase (BRENDA: 8 organisms, 20 substrates, 36 inhibitors, 7 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PROSTAGLANDIN H2	0.0073–0.03	4
15-HYDROPEROXYEICOSATETRAENOIC ACID	0.059–0.065	2
PROSTAGLANDIN H1	0.0094	1

Catalyzed reactions (Rhea), 4 shown:

• prostaglandin H2 = prostaglandin I2 (RHEA:23580)
• (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate = 15-oxo-(5Z,8Z,11Z,13E)-eicosatetraenoate + H2O (RHEA:48636)
• (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + AH2 = (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoate + A + H2O (RHEA:48856)
• a hydroperoxyeicosatetraenoate = an oxoeicosatetraenoate + H2O (RHEA:55556)

UniProt features (55 total): helix 20, strand 14, sequence variant 8, binding site 6, turn 4, chain 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3B6H	X-RAY DIFFRACTION	1.62
2IAG	X-RAY DIFFRACTION	2.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16647-F1	94.57	0.88

Functional residue map

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

Ligand- & substrate-binding residues (6): 106; 112; 287; 358–359; 382; 441 (axial binding residue)

Mutagenesis-validated functional residues (1):

Position	Phenotype
441	abolishes prostaglandin-i synthase activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-211979	Eicosanoids
R-HSA-2162123	Synthesis of Prostaglandins (PG) and Thromboxanes (TX)

MSigDB gene sets: 278 (showing top): MODULE_93, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_INFLAMMATORY_RESPONSE, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_RESPONSE_TO_PEPTIDE, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, MAHADEVAN_IMATINIB_RESISTANCE_DN, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, MODULE_313, GOBP_DECIDUALIZATION, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (20): prostaglandin biosynthetic process (GO:0001516), icosanoid metabolic process (GO:0006690), embryo implantation (GO:0007566), cyclooxygenase pathway (GO:0019371), positive regulation of peroxisome proliferator activated receptor signaling pathway (GO:0035360), negative regulation of nitric oxide biosynthetic process (GO:0045019), positive regulation of angiogenesis (GO:0045766), prostanoid biosynthetic process (GO:0046457), decidualization (GO:0046697), negative regulation of inflammatory response (GO:0050728), cellular response to interleukin-1 (GO:0071347), cellular response to interleukin-6 (GO:0071354), cellular response to hypoxia (GO:0071456), apoptotic signaling pathway (GO:0097190), positive regulation of execution phase of apoptosis (GO:1900119), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), fatty acid biosynthetic process (GO:0006633), prostaglandin metabolic process (GO:0006693), NAD+ biosynthetic process via the salvage pathway (GO:0034355)

GO Molecular Function (10): monooxygenase activity (GO:0004497), iron ion binding (GO:0005506), prostaglandin-I synthase activity (GO:0008116), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), heme binding (GO:0020037), hydroperoxy icosatetraenoate dehydratase activity (GO:0106256), protein binding (GO:0005515), lyase activity (GO:0016829), isomerase activity (GO:0016853), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), caveola (GO:0005901), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cytochrome P450 - arranged by substrate type	1
Arachidonate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
prostanoid metabolic process	2
cellular response to cytokine stimulus	2
oxidoreductase activity	2
catalytic activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
prostaglandin metabolic process	1
prostanoid biosynthetic process	1
carboxylic acid metabolic process	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
prostaglandin biosynthetic process	1
arachidonate metabolic process	1
peroxisome proliferator activated receptor signaling pathway	1
regulation of peroxisome proliferator activated receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
nitric oxide biosynthetic process	1
negative regulation of biosynthetic process	1
regulation of nitric oxide biosynthetic process	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
unsaturated fatty acid biosynthetic process	1
icosanoid biosynthetic process	1
maternal placenta development	1
developmental process involved in reproduction	1
tissue development	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
response to interleukin-1	1
response to interleukin-6	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
apoptotic process	1
signal transduction	1
positive regulation of apoptotic process	1

Protein interactions and networks

STRING

2038 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTGIS	TBXAS1	P24557	861
PTGIS	PTGS2	P35354	843
PTGIS	PTGIR	P43119	829
PTGIS	PTGES	O14684	715
PTGIS	PTGS1	P23219	633
PTGIS	PTGES3	Q15185	626
PTGIS	NOS3	P29474	608
PTGIS	PTGES2	Q9H7Z7	598
PTGIS	PLA2G1B	P04054	593
PTGIS	AKR1C3	P42330	582
PTGIS	GNB3	P16520	579
PTGIS	SLC2A10	O95528	578
PTGIS	PTGDS	P41222	578
PTGIS	ADD1	P35611	574
PTGIS	CYP3A5	P20815	573

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PTGIS	VIM	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
SAAL1	TMEM223	psi-mi:“MI:0914”(association)	0.350
TMEM169	PTGES3L-AARSD1	psi-mi:“MI:0914”(association)	0.350
FOS	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): PTGIS (Proximity Label-MS), PTGIS (Protein-peptide), APP (Reconstituted Complex), PTGIS (FRET), PTGIS (FRET), PTGIS (Reconstituted Complex), PTGIS (Affinity Capture-Western), CAV1 (Affinity Capture-Western), PTGIS (Co-fractionation)

ESM2 similar proteins: B2RXA7, E1BHJ4, F1RE08, G3V7X8, O02766, O35074, O35084, O43174, O46491, O46515, O75881, O88962, O93323, P00189, P05108, P0DOX0, P10612, P14137, P15393, P17177, P17178, P18125, P22680, P46634, P51542, P79153, P79202, P97720, Q08D50, Q16647, Q28827, Q29626, Q2XV99, Q4G0S4, Q60991, Q62969, Q63688, Q64408, Q64505, Q6EIG3

Diamond homologs: F1RE08, F1SY71, F1SY99, I1RJR2, O02766, O35074, O46491, O75881, O88962, P0DXV0, P18125, P22680, P46634, P51542, Q16647, Q29626, Q60991, Q62969, Q64505, Q7YRB2, Q9UNU6, A0A0E3D8M1, A0A0G4P2K0, A0A0L1JEW4, A0A140JWT9, A0A4D6Q415, B8N2C8, B8NFL5, B8NUK6, E9QY26, I1RBR4, I1S2M5, O14442, O46420, O48958, P0DKI2, P0DXU9, P10613, P10614, P14263

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	89
Likely benign	4
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
7864	NM_000961.4(PTGIS):c.1358+2T>C	Pathogenic
208402	NM_000961.4(PTGIS):c.824G>A (p.Arg275Gln)	Likely pathogenic

SpliceAI

1738 predictions. Top by Δscore:

Variant	Effect	Δscore
20:49507913:C:CA	donor_gain	1.0000
20:49508060:CAAAT:C	acceptor_gain	1.0000
20:49511026:A:AC	donor_gain	1.0000
20:49511027:C:CC	donor_gain	1.0000
20:49513075:TTTAC:T	donor_loss	1.0000
20:49513076:TTACC:T	donor_loss	1.0000
20:49513077:TACC:T	donor_loss	1.0000
20:49513078:ACC:A	donor_loss	1.0000
20:49513079:CCT:C	donor_gain	1.0000
20:49524236:TCCC:T	acceptor_gain	1.0000
20:49524237:CCC:C	acceptor_gain	1.0000
20:49524237:CCCC:C	acceptor_gain	1.0000
20:49524238:CCC:C	acceptor_gain	1.0000
20:49524240:C:CC	acceptor_gain	1.0000
20:49539568:AC:A	donor_gain	1.0000
20:49539569:CC:C	donor_gain	1.0000
20:49539569:CCCA:C	donor_gain	1.0000
20:49544299:CCTCA:C	donor_loss	1.0000
20:49544300:CTCA:C	donor_loss	1.0000
20:49544301:TCA:T	donor_loss	1.0000
20:49544302:CAC:C	donor_loss	1.0000
20:49544303:A:C	donor_loss	1.0000
20:49544304:C:CG	donor_loss	1.0000
20:49544444:GAGTC:G	acceptor_gain	1.0000
20:49544445:AGTC:A	acceptor_gain	1.0000
20:49544446:GTC:G	acceptor_gain	1.0000
20:49544447:TC:T	acceptor_gain	1.0000
20:49544448:CC:C	acceptor_gain	1.0000
20:49544455:C:CT	acceptor_gain	1.0000
20:49544456:A:T	acceptor_gain	1.0000

AlphaMissense

3266 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:49511086:A:G	W434R	0.993
20:49511086:A:T	W434R	0.993
20:49511159:G:C	F409L	0.993
20:49511159:G:T	F409L	0.993
20:49511161:A:G	F409L	0.993
20:49547991:A:T	V76D	0.993
20:49550069:A:C	F65L	0.993
20:49550069:A:T	F65L	0.993
20:49550071:A:G	F65L	0.993
20:49513210:C:G	R359P	0.992
20:49547894:A:C	F108L	0.992
20:49547894:A:T	F108L	0.992
20:49547896:A:G	F108L	0.992
20:49513237:C:G	R350T	0.991
20:49513246:T:A	E347V	0.991
20:49524069:A:G	W282R	0.990
20:49524069:A:T	W282R	0.990
20:49513211:G:T	R359S	0.989
20:49513236:C:A	R350S	0.989
20:49513236:C:G	R350S	0.989
20:49550142:C:T	G41E	0.987
20:49511084:C:A	W434C	0.986
20:49511084:C:G	W434C	0.986
20:49514372:G:C	F293L	0.986
20:49514372:G:T	F293L	0.986
20:49514374:A:G	F293L	0.986
20:49547930:G:C	F96L	0.986
20:49547930:G:T	F96L	0.986
20:49547932:A:G	F96L	0.986
20:49513237:C:A	R350M	0.985

dbSNP variants (sampled 300 via entrez): RS1000041854 (20:49566793 G>A), RS1000108429 (20:49527718 T>G), RS1000141289 (20:49520128 C>G), RS1000166373 (20:49503779 A>G), RS1000201073 (20:49541733 TTAAAATAAAA>T,TTAAAA,TTAAAATAAAATAAAA), RS1000286512 (20:49543677 G>A), RS1000350675 (20:49505716 A>C,G,T), RS1000359121 (20:49545235 G>C), RS1000402932 (20:49506096 A>C), RS1000408902 (20:49534152 C>A,T), RS1000539024 (20:49556667 C>T), RS1000715545 (20:49517748 C>T), RS1000722046 (20:49509686 C>T), RS1000750528 (20:49549646 G>A), RS1000797143 (20:49537884 C>G)

Disease associations

OMIM: gene MIM:601699 | disease phenotypes: MIM:145500

GenCC curated gene-disease

Disease	Classification	Inheritance
essential hypertension, genetic	Limited	Unknown

Mondo (3): essential hypertension (MONDO:0001134), childhood-onset schizophrenia (MONDO:0957430), essential hypertension, genetic (MONDO:0007781)

Orphanet (2): Childhood-onset schizophrenia (Orphanet:641496), NON RARE IN EUROPE: Essential hypertension (Orphanet:243761)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0001426	Non-Mendelian inheritance
HP:0004421	Elevated systolic blood pressure
HP:0004972	Elevated mean arterial pressure
HP:0005117	Elevated diastolic blood pressure

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002539_93	Schizophrenia	5.000000e-08
GCST006803_52	Schizophrenia	1.000000e-07
GCST007201_265	Schizophrenia	8.000000e-09
GCST007201_291	Schizophrenia	1.000000e-07
GCST009600_40	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	3.000000e-09

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000075222	Essential Hypertension	C14.907.489.165

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4428 (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: 314 (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
CHEMBL48092	PIRMAGREL	2	314

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CYP5, CYP7 and CYP8 families

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 7p [PMID: 7861416]	Inhibition	6.0	pIC50

ChEMBL bioactivities

15 potent at pChembl≥5 of 32 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	IC50	2000	nM	CHEMBL163278
5.70	IC50	2000	nM	CHEMBL159876
5.70	IC50	2000	nM	CHEMBL350510
5.60	IC50	2500	nM	CHEMBL355596
5.52	IC50	3000	nM	CHEMBL161608
5.47	IC50	3400	nM	CHEMBL159859
5.40	IC50	4000	nM	CHEMBL162406
5.40	IC50	4000	nM	CHEMBL161357
5.40	IC50	4000	nM	CHEMBL159859
5.30	IC50	5000	nM	CHEMBL159778
5.16	IC50	7000	nM	CHEMBL159851
5.16	IC50	7000	nM	CHEMBL161911
5.10	IC50	8000	nM	CHEMBL159737
5.05	IC50	9000	nM	CHEMBL422719
5.05	IC50	9000	nM	CHEMBL159243

PubChem BioAssay actives

18 with measured affinity, of 105 total; 16 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
(Z)-6-[2-[2-(4-bromophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	1.0000	uM
(Z)-6-[2-[2-(2-nitrophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	1.0000	uM
(Z)-6-[2-[2-(2-fluorophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	1.0000	uM
(Z)-6-[2-[2-(2-methylsulfonylphenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	2.0000	uM
(Z)-6-[2-[1-(4-fluorophenyl)-2-methylpropan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	2.0000	uM
(Z)-6-[2-[2-(4-fluorophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	2.0000	uM
(Z)-6-[2-(2,4-dichlorophenyl)-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	2.5000	uM
(Z)-6-[2-[2-(2-cyanophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	3.0000	uM
(Z)-6-[2-[2-(4-cyanophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	4.0000	uM
(Z)-6-[2-[2-(4-acetyl-2-nitrophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	4.0000	uM
(Z)-6-[2-[2-(4-methylsulfanyl-2-nitrophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	5.0000	uM
(Z)-6-[2-[1-(2-cyano-4-fluorophenyl)-2-methylpropan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	7.0000	uM
(Z)-6-[2-[2-(2-bromophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	7.0000	uM
(Z)-6-[2-[2-(4-methylsulfonylphenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	8.0000	uM
(Z)-6-[2-(3,4-dichlorophenyl)-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	9.0000	uM
(Z)-6-[2-[2-(4-fluoro-2-nitrophenoxy)propan-2-yl]-4-pyridin-3-yl-1,3-dioxan-5-yl]hex-4-enoic acid	160761: In vitro inhibition of Prostaglandin I2 synthase from human blood platelet microsomes	ic50	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	8
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
entinostat	decreases expression, increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
bisphenol F	increases expression	1
lasiocarpine	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
senecionine	decreases expression	1
senkirkine	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
rofecoxib	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
tricetin	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Dasatinib	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acrolein	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Asbestos	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methotrexate	decreases expression	1
Oxygen	increases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1100229	Binding	Inhibition of human prostacyclin synthase in IL-1-beta-stimulated human RASF cells assessed as PGF1alpha levels after 50 mins by ELISA	Selective inducible microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitors derived from an oxicam template. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4EL	PUMCHi006-A	Induced pluripotent stem cell	Female
CVCL_ZL87	PUMCHi003-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00157963	PHASE4	COMPLETED	Hydrochlorothiazide (+) Losartan Potassium vs. Amlodipine Comparative Study (0954A-314)
NCT00295555	PHASE4	COMPLETED	Doxazosin Effects on ABPM in Hypertensive Patients With Diabetic Nephropathy
NCT00311155	PHASE4	COMPLETED	Olmesartan and an add-on Treatment in Patients With Mild to Moderate Hypertension
NCT00328965	PHASE4	COMPLETED	Lacidipine In Mild To Moderate Essential Hypertension Patients With Type 2 Diabetes In Korea
NCT00366119	PHASE4	UNKNOWN	Safety and Efficacy of Ramipril in the Treatment of Essential Hypertension
NCT00408512	PHASE4	COMPLETED	Pharmacosurveillance and Pharmacogenetics of First-line Diuretics in Hypertension: The StayOnDiur Study
NCT00438945	PHASE4	COMPLETED	The Effect of Eprosartan on Hormones and Kidney Function in Patients With Essential Hypertension
NCT00457483	PHASE4	COMPLETED	Nijmegen Antihypertensive Management Improvement Study
NCT00509470	PHASE4	COMPLETED	Evaluation of Effect of Combination With Telmisartan and Hydrochlorothiazide in Hypertensives Uncontrolled on Amlodipine
NCT00654875	PHASE4	COMPLETED	Efficacy and Safety of Once Daily Dosing of Aliskiren (300 mg (qd) Once a Day) to Twice Daily Dosing of Aliskiren (150 mg (Bid) Twice a Day) in Treating Moderate Hypertension.
NCT00716950	PHASE4	UNKNOWN	Valsartan and Amlodipine Compared to Losartan and Amlodipine in Hypertensive Patients
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00765947	PHASE4	COMPLETED	Efficacy and Tolerability of an Aliskiren-based Treatment Algorithm in Patients With Mild to Moderate Hypertension
NCT00794885	PHASE4	COMPLETED	China Stroke Primary Prevention Trial
NCT00819104	PHASE4	COMPLETED	A Study to Compare the Efficacy, Safety and Tolerability of Selomax With Its Individual Components
NCT00841308	PHASE4	UNKNOWN	Home Blood Pressure in Hypertension Management
NCT00890591	PHASE4	COMPLETED	Efficacy and Safety of Olmesartan Medoxomil in Stage 1 and 2 Essential Hypertension
NCT00994617	PHASE4	UNKNOWN	Monotherapy Versus Dual Therapy for Initial Treatment for Hypertension
NCT01011660	PHASE4	UNKNOWN	Effects of Angiotensin II Receptor Blocker Compared With Diuretics in High-risk Hypertensive Patients
NCT01042392	PHASE4	COMPLETED	Efficacy of Aliskiren Compared to Ramipril in the Treatment of Moderate Systolic Hypertensive Patients
NCT01120990	PHASE4	COMPLETED	Hybrid Blood Pressure Monitor Validation
NCT01131546	PHASE4	COMPLETED	Efficacy and Safety of Levamlodipine Besylate Compared to Amlodipine Maleate in Patients With Essential Hypertension
NCT01132768	PHASE4	TERMINATED	The Confirmatory Olmesartan Plaque Regression Study
NCT01180413	PHASE4	COMPLETED	Intensive Vasodilator Therapy in Patients With Essential Hypertension
NCT01241487	PHASE4	COMPLETED	A National Multicentre Study to Assess the Efficacy of the Fixed Combination of Valsartan and Amlodipine in Hypertensive Patients Not Controlled by Monotherapy
NCT01629225	PHASE4	UNKNOWN	GRK4 Polymorphisms Blood Pressure Response to Candesartan
NCT01825759	PHASE4	UNKNOWN	Danshen Dropping Pill for Coronary Heart Disease Heart and Artery Structure and Function
NCT02031861	PHASE4	COMPLETED	Efficacy Study of Nifedipine Controlled-Release Tablets (Xin Ran) to Treat Mild to Moderate Essential Hypertension
NCT02058446	PHASE4	COMPLETED	PMS Study of Amlodipine/Valsartan for the Treatment of Hypertension
NCT02062645	PHASE4	COMPLETED	Study of Efficacy and Safety of CVAA489 in Hypertensive Patients
NCT02184858	PHASE4	COMPLETED	Dose Titration of Lisinopril in Children Aged 1 to 18 Years With Primary or Secondary Hypertension
NCT02214498	PHASE4	UNKNOWN	Treatment of HYpertension: Morning Versus Evening
NCT02357615	PHASE4	UNKNOWN	Efficacy Study of Nifedipine Controlled-Release Tablets (Xin Ran) to Treat Early Morning Blood Pressure and Central Arterial Pressure
NCT02517866	PHASE4	COMPLETED	Azilsartan Medoxomil in the Treatment of Essential Hypertension and Type 2 Diabetes in Asia
NCT02612298	PHASE4	COMPLETED	Efficacy and Safety of Arotinolol Hydrochloride on Morning Blood Pressure and Heart Rate
NCT02687178	PHASE4	COMPLETED	Canrenone as Add-on in Patients With Essential Hypertension
NCT03226340	PHASE4	UNKNOWN	S-amlodipine+Chlorthalidone vs S-amlodipine+Telmisartan in Hypertension
NCT04306627	PHASE4	UNKNOWN	Effect of Atorvastatin on Carotid Intima Media Thickness
NCT05683301	PHASE4	COMPLETED	Treatment Optimisation for Blood Pressure With Single-Pill Combinations in India
NCT05843162	PHASE4	UNKNOWN	A Clinical Trial to Evaluate the Blood Pressure Control of Telmisartan or Losartan in Essential Hypertensive Patients With Metabolic Syndrome