PLA2G3

Summary

PLA2G3 (phospholipase A2 group III, HGNC:17934) is a protein-coding gene on chromosome 22q12.2, encoding Group 3 secretory phospholipase A2 (Q9NZ20). Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids.

This gene encodes a protein that belongs to the secreted phospholipase A2 family, whose members include the bee venom enzyme. The encoded enzyme functions in lipid metabolism and catalyzes the calcium-dependent hydrolysis of the sn-2 acyl bond of phospholipids to release arachidonic acid and lysophospholipids. This enzyme acts as a negative regulator of ciliogenesis, and may play a role in cancer development by stimulating tumor cell growth and angiogenesis. This gene is associated with oxidative stress, and polymorphisms in this gene are linked to risk for Alzheimer’s disease.

Source: NCBI Gene 50487 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 99 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015715

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17934
Approved symbol	PLA2G3
Name	phospholipase A2 group III
Location	22q12.2
Locus type	gene with protein product
Status	Approved
Aliases	GIII-SPLA2
Ensembl gene	ENSG00000100078
Ensembl biotype	protein_coding
OMIM	611651
Entrez	50487

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000215885, ENST00000927606, ENST00000927607, ENST00000927608, ENST00000927609, ENST00000927610, ENST00000948217

RefSeq mRNA: 1 — MANE Select: NM_015715 NM_015715

CCDS: CCDS13889

Canonical transcript exons

ENST00000215885 — 7 exons

Exon	Start	End
ENSE00000653064	31136683	31136799
ENSE00000653065	31136908	31137040
ENSE00000653066	31137710	31137993
ENSE00000653067	31138276	31138410
ENSE00000653068	31138667	31138799
ENSE00001168391	31134807	31135936
ENSE00001319965	31139841	31140508

Expression profiles

Bgee: expression breadth ubiquitous, 109 present calls, max score 90.54.

FANTOM5 (CAGE): breadth broad, TPM avg 0.3966 / max 28.7605, expressed in 188 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193673	0.2033	117
193674	0.1221	69
193672	0.0712	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	90.54	silver quality
gingival epithelium	UBERON:0001949	87.36	silver quality
gingiva	UBERON:0001828	85.86	silver quality
squamous epithelium	UBERON:0006914	83.25	silver quality
skin of leg	UBERON:0001511	80.64	gold quality
upper arm skin	UBERON:0004263	80.58	gold quality
lower esophagus mucosa	UBERON:0035834	80.20	gold quality
esophagus mucosa	UBERON:0002469	79.42	gold quality
zone of skin	UBERON:0000014	78.89	gold quality
esophagus squamous epithelium	UBERON:0006920	78.79	silver quality
skin of abdomen	UBERON:0001416	78.11	gold quality
hair follicle	UBERON:0002073	77.41	gold quality
olfactory bulb	UBERON:0002264	74.78	gold quality
type B pancreatic cell	CL:0000169	73.84	gold quality
epithelium of nasopharynx	UBERON:0001951	73.79	gold quality
diaphragm	UBERON:0001103	73.75	gold quality
superficial temporal artery	UBERON:0001614	73.67	gold quality
tongue squamous epithelium	UBERON:0006919	72.68	gold quality
germinal epithelium of ovary	UBERON:0001304	72.30	gold quality
epithelial cell of pancreas	CL:0000083	70.62	gold quality
mucosa of paranasal sinus	UBERON:0005030	70.57	gold quality
ventricular zone	UBERON:0003053	69.16	gold quality
mucosa of urinary bladder	UBERON:0001259	68.44	gold quality
lower lobe of lung	UBERON:0008949	67.21	silver quality
upper leg skin	UBERON:0004262	66.96	silver quality
vastus lateralis	UBERON:0001379	66.81	gold quality
orbitofrontal cortex	UBERON:0004167	66.15	gold quality
thymus	UBERON:0002370	65.79	gold quality
quadriceps femoris	UBERON:0001377	65.46	gold quality
epithelium of mammary gland	UBERON:0003244	64.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.24

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting PLA2G3, 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-4673	100.00	66.64	1490
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-3619-5P	99.00	68.87	2308

Literature-anchored findings (GeneRIF, showing 16)

• Lys 43 and Asp 46 in rhUG are critical residues for the sPLA2-inhibitory activity of UG (PMID:12127976)
• cellular arachidonate (AA) release and prostaglandin (PG) production are regulated by novel classes of secretory phospholipase A(2)s (sPLA(2)s), groups III and XII (PMID:12522102)
• sPLA(2)-III may have a role in cancer development by stimulating tumor cell growth and angiogenesis (PMID:15863501)
• potential contribution of sPLA2-III to neuronal differentiation and its function under certain conditions (PMID:17868035)
• the biological action of group III sPLA(2) depends on its N-terminal domain (PMID:17980167)
• a potential functional link between PLA2G3 and atherosclerosis, as has recently been proposed for PLA2G5 and PLA2G10. (PMID:18801741)
• This study showed that endogenous group III sPLA2 (PLA2G3) is expressed in mouse skin and that transgenic mice overexpressing human PLA2G3 spontaneously develop skin inflammation. (PMID:19371233)
• Secreted PLA2 III induces apoptosis of primary cortical neurons in culture by suppressing production of Bcl-xl, promoting Bax, augmenting caspase 3 and cleaving alpha-fodrin. (PMID:20492356)
• The availability of the human group III phospholipase A(2) (hIIIPLA(2)) amino acid sequence offers an opportunity to study its structural features by modeling. (PMID:20654644)
• we describe that PLA2G3 gene silencing produced a marked inhibition of xanthine/xanthine oxidase induced cell death, and that PLA2G3 polymorphisms are associated with Alzheimer disease in a Spanish case-control sample. (PMID:20930276)
• Data indicate that the expression of genes encoding hGIIA, hGIII and hGX sPLA2s (PLA2G2A, PLA2G3 and PLA2G10, respectively) in breast tumour biopsies differs from that in normal tissues. (PMID:24508801)
• Studies indicate that phospholipase A2 receptor 1 (PLA2R1) may act as a clearance or signaling receptor for secreted phospholipase A2 (sPLA2s). (PMID:25230085)
• Studies indicate that the expression of secreted phospholipases A2 (sPLA2s), most notably the group IIA, III and X enzymes, is dysregulated in various malignant tissues. (PMID:25286228)
• sPLA2GIII expression may be used as a risk factor for lymph node metastasis and a prognostic marker in colorectal cancer. In addition, sPLA2GIII and sPLA2GX may play opposing roles in colorectal carcinogenesis (PMID:25964585)
• Several hits were discovered, and data have been uploaded to PubChem. This study describes the first high-throughput optical screening assay for secreted phospholipase A2 inhibitors based on a phospholipid vesicle substrate (PMID:27146384)
• Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization. (PMID:34082797)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pla2g3	ENSDARG00000008948
danio_rerio		ENSDARG00000098989
mus_musculus	Pla2g3	ENSMUSG00000034579
rattus_norvegicus	Pla2g3	ENSRNOG00000025121
drosophila_melanogaster	GIIIspla2	FBGN0030013
drosophila_melanogaster	sPLA2	FBGN0033170
drosophila_melanogaster	CG30503	FBGN0050503

Paralogs (1): PROCA1 (ENSG00000167525)

Protein

Protein identifiers

Group 3 secretory phospholipase A2 — Q9NZ20 (reviewed: Q9NZ20)

Alternative names: Group III secretory phospholipase A2, Phosphatidylcholine 2-acylhydrolase 3

All UniProt accessions (1): Q9NZ20

UniProt curated annotations — full annotation on UniProt →

Function. Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids without apparent head group selectivity. Contributes to phospholipid remodeling of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. Hydrolyzes LDL phospholipids releasing unsaturated fatty acids that regulate macrophage differentiation toward foam cells. May act in an autocrine and paracrine manner. Secreted by immature mast cells, acts on nearby fibroblasts upstream to PTDGS to synthesize prostaglandin D2 (PGD2), which in turn promotes mast cell maturation and degranulation via PTGDR. Secreted by epididymal epithelium, acts on immature sperm cells within the duct, modulating the degree of unsaturation of the fatty acyl components of phosphatidylcholines required for acrosome assembly and sperm cell motility. Facilitates the replacement of fatty acyl chains in phosphatidylcholines in sperm membranes from omega-6 and omega-9 to omega-3 polyunsaturated fatty acids (PUFAs). Coupled to lipoxygenase pathway, may process omega-6 PUFAs to generate oxygenated lipid mediators in the male reproductive tract. At pericentrosomal preciliary compartment, negatively regulates ciliogenesis likely by regulating endocytotic recycling of ciliary membrane protein. Coupled to cyclooxygenase pathway provides arachidonate to generate prostaglandin E2 (PGE2), a potent immunomodulatory lipid in inflammation and tumorigenesis. At colonic epithelial barrier, preferentially hydrolyzes phospholipids having arachidonate and docosahexaenoate at sn-2 position, contributing to the generation of oxygenated metabolites involved in colonic stem cell homeostasis. Releases C16:0 and C18:0 lysophosphatidylcholine subclasses from neuron plasma membranes and promotes neurite outgrowth and neuron survival.

Subcellular location. Secreted. Cell membrane. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole. Recycling endosome.

Tissue specificity. Expressed in kidney, heart, liver, and skeletal muscle. Also present in placenta and peripheral blood leukocytes. Not detected in colon, thymus, spleen and small intestine. In lung, expressed in bronchial epithelial cells and alveolar macrophages, but scarcely detected in alveolar epithelium, arterial walls and interstitial fibroblasts (at protein level). In joints of osteoarthritis and rheumatoid arthritis, expressed in endothelial cells (at protein level). In normal heart, detected in some vessels. In myocardial tissues with acute infarction, expressed in vascular endothelial cells adjacent to cardiomyocytes and those in lesions with granulation. Expression in cardiomyocytes is scarce (at protein level). In uterus, breast and colon cancers, detected in tumor cells and neighboring microvascular endothelium, but not in normal glandular tissues (at protein level). Expressed in dermal resting mast cells (at protein level) and pulmonary mast cells. Expressed in neuronal fibers (at protein level). Highly expressed in dorsal root ganglia neurons (at protein level). Expressed in Purkinje cells in cerebellum (at protein level). In stomach is preferentially expressed in neuronal fibers and in microvascular endothelium. Sparsely expressed in normal aorta (at protein level). Highly expressed in macrophages and smooth muscle cells in aorta with atheroma.

Post-translational modifications. N-glycosylation does not affect the catalytic activity, but is required for proper secretion. A nonglycosylated form is observed in several cell types. In several cell types, the N- and C-termini are cleaved off.

Activity regulation. Arachidonic acid release is markedly increased by glypican, a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan.

Cofactor. Binds 1 Ca(2+) ion.

Domain organisation. The phospholipase A2-like domain represents the fully processed form after N- and C-termini are cleaved off. It is the secreted mature form found in biological fluids.

Induction. By IL1B/interleukin-1 beta and TNF in microvascular endothelial cells (at protein level).

Similarity. Belongs to the phospholipase A2 family.

RefSeq proteins (1): NP_056530* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016090	PLA2-like_dom	Domain
IPR033113	PLA2_histidine	Active_site
IPR036444	PLipase_A2_dom_sf	Homologous_superfamily

Pfam: PF05826

Catalyzed reactions (Rhea), 5 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40427)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphoethanolamine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphoethanolamine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40431)
• 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine + H2O = (9Z,12Z)-octadecadienoate + 1-hexadecanoyl-sn-glycero-3-phosphocholine + H(+) (RHEA:40811)
• 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphoethanolamine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphoethanolamine + (9Z,12Z)-octadecadienoate + H(+) (RHEA:40815)

UniProt features (33 total): sequence variant 6, glycosylation site 5, binding site 4, region of interest 4, disulfide bond 4, mutagenesis site 3, compositionally biased region 3, active site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZ20-F1	71.88	0.34

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 (2): 214; 184

Ligand- & substrate-binding residues (4): 158; 160; 162; 185

Disulfide bonds (4): 159–181, 180–220, 187–213, 211–244

Glycosylation sites (5): 167, 280, 325, 396, 439

Mutagenesis-validated functional residues (3):

Position	Phenotype
167	loss of glycosylation.
184	impairs pge2 synthesis. impairs pgd2 synthesis. impairs mast cell degranulation. impairs neurite outgrowth.
280	loss of glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1482788	Acyl chain remodelling of PC
R-HSA-1482839	Acyl chain remodelling of PE
R-HSA-1482925	Acyl chain remodelling of PG

MSigDB gene sets: 316 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_REGULATION_OF_ICOSANOID_SECRETION, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_PROSTAGLANDIN_SECRETION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_DEGRANULATION, GOBP_VESICLE_ORGANIZATION, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_REGULATION_OF_EXOCYTOSIS

GO Biological Process (33): acrosome assembly (GO:0001675), production of molecular mediator involved in inflammatory response (GO:0002532), phospholipid metabolic process (GO:0006644), phosphatidylserine metabolic process (GO:0006658), sperm axoneme assembly (GO:0007288), negative regulation of gene expression (GO:0010629), positive regulation of macrophage derived foam cell differentiation (GO:0010744), positive regulation of neuron projection development (GO:0010976), lipoxygenase pathway (GO:0019372), positive regulation of prostaglandin biosynthetic process (GO:0031394), positive regulation of prostaglandin secretion (GO:0032308), low-density lipoprotein particle remodeling (GO:0034374), high-density lipoprotein particle remodeling (GO:0034375), macrophage activation (GO:0042116), mast cell degranulation (GO:0043303), negative regulation of neuron apoptotic process (GO:0043524), phosphatidylethanolamine metabolic process (GO:0046337), phosphatidylcholine metabolic process (GO:0046470), phosphatidylglycerol metabolic process (GO:0046471), phosphatidic acid metabolic process (GO:0046473), phosphatidylinositol metabolic process (GO:0046488), cell maturation (GO:0048469), arachidonate secretion (GO:0050482), cilium assembly (GO:0060271), positive regulation of mast cell differentiation (GO:0060376), positive regulation of cytokine production involved in inflammatory response (GO:1900017), negative regulation of amyloid-beta clearance (GO:1900222), positive regulation of histamine secretion by mast cell (GO:1903595), regulation of endocytic recycling (GO:2001135), lipid metabolic process (GO:0006629), cell projection organization (GO:0030030), positive regulation of cell differentiation (GO:0045597), cell development (GO:0048468)

GO Molecular Function (5): metal ion binding (GO:0046872), obsolete calcium-dependent phospholipase A2 activity (GO:0047498), glycerophospholipase activity (GO:0004620), A2-type glycerophospholipase activity (GO:0004623), hydrolase activity (GO:0016787)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), centriole (GO:0005814), plasma membrane (GO:0005886), recycling endosome (GO:0055037), cytoplasm (GO:0005737), endosome (GO:0005768), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	3

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycerophospholipid metabolic process	5
cellular anatomical structure	3
developmental process involved in reproduction	2
plasma lipoprotein particle remodeling	2
intracellular membraneless organelle	2
spermatid development	1
cellular component assembly involved in morphogenesis	1
cellular process involved in reproduction in multicellular organism	1
secretory granule organization	1
organelle assembly	1
inflammatory response	1
multicellular organismal process	1
lipid metabolic process	1
organophosphate metabolic process	1
modified amino acid metabolic process	1
axoneme assembly	1
sperm flagellum assembly	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
macrophage derived foam cell differentiation	1
regulation of macrophage derived foam cell differentiation	1
positive regulation of cell differentiation	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
fatty acid metabolic process	1
icosanoid metabolic process	1
prostaglandin biosynthetic process	1
regulation of prostaglandin biosynthetic process	1
positive regulation of unsaturated fatty acid biosynthetic process	1
positive regulation of icosanoid secretion	1
regulation of prostaglandin secretion	1
prostaglandin secretion	1
positive regulation of secretion by cell	1
myeloid leukocyte activation	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1

Protein interactions and networks

STRING

1602 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLA2G3	PLA2G2D	Q9UNK4	968
PLA2G3	PLA2G10	O15496	945
PLA2G3	PLA2G12A	Q9BZM1	929
PLA2G3	PLA2G2A	P14555	874
PLA2G3	PLA2G2F	Q9BZM2	700
PLA2G3	PLA2G2E	Q9NZK7	696
PLA2G3	PLA2G5	P39877	664
PLA2G3	PLA2G12B	Q9BX93	623
PLA2G3	PTGDS	P41222	581
PLA2G3	PLA2G15	Q8NCC3	570
PLA2G3	PLA2G6	O60733	560
PLA2G3	PLA2G2C	Q5R387	553
PLA2G3	PLAAT3	P53816	499
PLA2G3	PTGS2	P35354	498
PLA2G3	PLA2G1B	P04054	481

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PLA2G3	PCSK1N	psi-mi:“MI:0915”(physical association)	0.400
PVR	PLA2G3	psi-mi:“MI:0915”(physical association)	0.370
PLA2G3	TGFB1I1	psi-mi:“MI:0915”(physical association)	0.370
BTG3	PLA2G3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): PCSK1N (Affinity Capture-MS), PLA2G3 (Two-hybrid), PLA2G3 (Proximity Label-MS), PVR (Two-hybrid), TGFB1I1 (Two-hybrid)

ESM2 similar proteins: A0A1W2PP97, A6NLX4, A6QNY1, P0DJK0, P12838, P13207, P22389, P22749, P23943, P29473, P29474, P55056, P70313, P79209, P97270, P98162, Q1RMT9, Q28969, Q2TAL6, Q2VPJ9, Q4TUC0, Q566C8, Q5BIR3, Q5JTB6, Q5NRP8, Q5RCS3, Q5SPX3, Q5XIX0, Q62600, Q64322, Q7TMJ8, Q7TPD7, Q7TSF4, Q80TT8, Q867D0, Q8BZT7, Q8C8N3, Q8K1T4, Q8K4Z2, Q8MJW9

Diamond homologs: A0A1L4BJ46, I7GQA7, P00630, P04362, P0C8L9, P0DKU2, P0DMI6, P0DXZ6, P16354, P59888, P80003, P82971, P86780, Q3YAU5, Q6PXP0, Q6T178, Q7M4I5, Q7M4I6, Q8BZT7, Q9BMK4, Q9NZ20, Q9XG80, P43318, Q1JPB9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	14
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1361 predictions. Top by Δscore:

Variant	Effect	Δscore
22:31135934:CAG:C	acceptor_gain	1.0000
22:31135937:C:CC	acceptor_gain	1.0000
22:31136679:TTACT:T	donor_loss	1.0000
22:31136681:A:AC	donor_gain	1.0000
22:31136681:ACTT:A	donor_loss	1.0000
22:31136682:C:CT	donor_gain	1.0000
22:31136682:CT:C	donor_gain	1.0000
22:31136682:CTT:C	donor_gain	1.0000
22:31136682:CTTT:C	donor_gain	1.0000
22:31136682:CTTTT:C	donor_gain	1.0000
22:31136795:CCAGA:C	acceptor_gain	1.0000
22:31136796:CAGA:C	acceptor_gain	1.0000
22:31136796:CAGAC:C	acceptor_gain	1.0000
22:31136798:GA:G	acceptor_gain	1.0000
22:31136800:C:CC	acceptor_gain	1.0000
22:31136902:CCTCA:C	donor_loss	1.0000
22:31136903:CTCAC:C	donor_loss	1.0000
22:31136904:TCA:T	donor_loss	1.0000
22:31136905:CA:C	donor_loss	1.0000
22:31136906:A:AC	donor_gain	1.0000
22:31136906:A:T	donor_loss	1.0000
22:31136907:C:CA	donor_loss	1.0000
22:31136907:C:CC	donor_gain	1.0000
22:31136907:CCGG:C	donor_gain	1.0000
22:31138306:T:TA	donor_gain	1.0000
22:31138410:CCT:C	acceptor_loss	1.0000
22:31138411:C:CA	acceptor_loss	1.0000
22:31138678:G:C	donor_gain	1.0000
22:31138795:GACCC:G	acceptor_gain	1.0000
22:31138796:ACCC:A	acceptor_gain	1.0000

AlphaMissense

3298 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:31138324:A:C	F245C	0.994
22:31138408:A:C	F217C	0.993
22:31139879:C:G	C159S	0.993
22:31139880:A:T	C159S	0.993
22:31139881:C:A	W158C	0.993
22:31139881:C:G	W158C	0.993
22:31138708:G:C	N202K	0.992
22:31138708:G:T	N202K	0.992
22:31138347:G:C	F237L	0.991
22:31138347:G:T	F237L	0.991
22:31138349:A:G	F237L	0.991
22:31138350:G:C	F236L	0.990
22:31138350:G:T	F236L	0.990
22:31138352:A:G	F236L	0.990
22:31138323:A:C	F245L	0.988
22:31138323:A:T	F245L	0.988
22:31138324:A:G	F245S	0.988
22:31138325:A:G	F245L	0.988
22:31138408:A:G	F217S	0.988
22:31138772:C:G	C181S	0.986
22:31138773:A:T	C181S	0.986
22:31138775:C:G	C180S	0.986
22:31138776:A:T	C180S	0.986
22:31138676:C:G	C213S	0.985
22:31138677:A:T	C213S	0.985
22:31138682:C:G	C211S	0.985
22:31138683:A:T	C211S	0.985
22:31138754:C:G	C187S	0.985
22:31138755:A:T	C187S	0.985
22:31138399:C:G	C220S	0.984

dbSNP variants (sampled 300 via entrez): RS1000061082 (22:31136016 C>G), RS1000159644 (22:31141176 G>A), RS1001098417 (22:31137115 G>A), RS1001645001 (22:31136512 A>C,G), RS1001729228 (22:31135086 G>C), RS1004723092 (22:31141271 G>C,T), RS1005022788 (22:31136478 A>G), RS1005122738 (22:31141930 T>C), RS1005964227 (22:31137623 G>A,C), RS1005996986 (22:31137865 T>C), RS1006287046 (22:31135188 C>A,T), RS1006751170 (22:31135030 A>G), RS1007571602 (22:31139257 A>C), RS1008471535 (22:31142412 T>A), RS1008769583 (22:31134571 G>A,C)

Disease associations

OMIM: gene MIM:611651 | disease phenotypes: MIM:190300

GenCC curated gene-disease

Mondo (1): essential tremor (MONDO:0003233)

Orphanet (1): NON RARE IN EUROPE: Hereditary essential tremor (Orphanet:862)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002074_2	Paclitaxel-induced neuropathy	3.000000e-06
GCST003876_1	Gut microbiota (beta diversity)	5.000000e-08
GCST010135_20	Oily fish consumption	3.000000e-10
GCST010135_5	Oily fish consumption	1.000000e-15
GCST010140_12	Pork consumption	3.000000e-10
GCST010140_49	Pork consumption	1.000000e-15
GCST010142_11	Fish- and plant-related diet	1.000000e-11
GCST90000025_707	Appendicular lean mass	4.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0008111	diet measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020329	Essential Tremor	C10.228.662.350

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4524005 (PROTEIN FAMILY), CHEMBL4667 (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: 272 (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
CHEMBL148674	VARESPLADIB	2	272

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phospholipase A₂

Binding affinities (BindingDB)

201 measured of 211 human assays (238 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-(3-chlorophenyl)-4-N-methyltriazole-4,5-diamine	EC50	0.325 nM
5-(6-Methyl-benzooxazol-2-yl)-benzene-1,3-diamine	EC50	1570 nM
1-[[(E)-[4-(diethylamino)-6-keto-cyclohexa-2,4-dien-1-ylidene]methyl]amino]-3-methyl-thiourea	EC50	1980 nM
(4E)-4-[[[2-allylimino-4-(2-furyl)-4-thiazolin-3-yl]amino]methylene]-2,3-dihydroxy-cyclohexa-2,5-dien-1-one	IC50	2810 nM
5-Acetoxy-6-bromo-2-carbamimidoylsulfanylmethyl-1-phenyl-1H-indole-3-carboxylic acid ethyl ester	IC50	3230 nM
2-N,6-N-bis[4-(dimethylamino)phenyl]pyridine-2,6-dicarboxamide	IC50	3330 nM
4-keto-5-methyl-N-(4-methylthiazol-2-yl)-2-[(methylthio)methyl]-3H-thieno[2,3-d]pyrimidine-6-carboxamide	IC50	3890 nM
1-[5-[(E)-2-(dimethylamino)vinyl]-3-methyl-isoxazol-4-yl]sulfonyl-N-(2-furfuryl)nipecotamide	EC50	5600 nM
N,N-dimethyl-4-[(1-methyl-6-nitro-2-phenylpyrazolo[1,5-a]indol-1-ium-4-ylidene)methyl]aniline;trifluoromethanesulfonate	IC50	6130 nM
SMR000477542	IC50	6290 nM
N-[[(4-methylphenyl)carbonylamino]carbamothioyl]furan-2-carboxamide	EC50	7870 nM
4-[(1,5-dimethyl-4-nitro-3-pyrazolyl)azo]-N,N-diethylaniline	EC50	8190 nM
2-chloro-N-[[[(3-nitrophenyl)-oxomethyl]hydrazo]-sulfanylidenemethyl]benzamide	EC50	11200 nM
MLS000703259	EC50	12700 nM
(4-chloro-2,5-dimethoxy-phenyl)-(4-chlorodithiazol-5-ylidene)amine	IC50	15200 nM
1-[(2-bromophenyl)carbonylamino]-3-cyclohexyl-thiourea	EC50	16400 nM
cid_2211008	IC50	18800 nM
24-methyl-5,7,18,20-tetraoxa-24-azahexacyclo[11.11.0.0^{2,10}.0^{4,8}.0^{14,22}.0^{17,21}]tetracosa-1(13),2,4(8),9,11,14(22),15,17(21),23-nonaen-24-ium	IC50	19000 nM
N’-(4,6-dimethyl-1,3-benzothiazol-2-yl)-4-piperidin-1-ylsulfonyl-benzohydrazide	IC50	19000 nM
SMR000235767	IC50	21300 nM
4-methoxy-N-[[(5-methyl-3-phenyl-1,2-oxazole-4-carbonyl)amino]carbamothioyl]benzamide	IC50	24200 nM
4-[(E)-2-(1-ethyl-4-quinolin-1-iumyl)ethenyl]-N,N-dimethylaniline;iodide	IC50	24600 nM
cid_12006166	IC50	24600 nM
cid_395175	IC50	24900 nM
MLS000389664	IC50	25000 nM
cid_45281797	IC50	25500 nM
MLS000704246	IC50	25800 nM
MLS000696569	IC50	25900 nM
MLS000724624	IC50	26200 nM
N,N-dimethyl-4-[(E)-2-(1-methylquinolin-1-ium-4-yl)ethenyl]aniline;perchlorate	IC50	28600 nM
3-(4-chlorophenyl)-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-1H-1,2,4-triazole-5-thione	EC50	30000 nM
carbazol-9-yl-(4-methylphenyl)methanone	IC50	30300 nM
SMR000377934	IC50	31800 nM
Hydrazinecarbothioamide, 2-[[5-(heptafluoropropyl)-1-isoquinolinyl]methylene]-	IC50	31900 nM
cid_45281794	IC50	32000 nM
MLS000527215	IC50	34900 nM
1-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]amino]-3-(3-pyridinyl)thiourea	IC50	35300 nM
1-(4-fluorophenyl)-3-(1,3-thiazol-2-yl)thiourea	EC50	35600 nM
cid_395179	IC50	36100 nM
(E)-3-thiophen-2-yl-N-[[(2-thiophen-2-ylacetyl)amino]carbamothioyl]prop-2-enamide	IC50	37000 nM
MLS003128403	IC50	40600 nM
SMR000242662	IC50	40600 nM
1-[[2-[[5-(4-chlorophenyl)-4-cyclohexyl-1,2,4-triazol-3-yl]sulfanyl]acetyl]amino]-3-(4-methylphenyl)thiourea	IC50	40600 nM
MLS002702422	IC50	40600 nM
MLS000589117	IC50	40600 nM
N,N-dimethyl-4-[(1E,3E)-4-(3-methyl-1,3-benzothiazol-3-ium-2-yl)buta-1,3-dienyl]aniline;perchlorate	IC50	41600 nM
cid_3113865	IC50	42500 nM
SMR000178281	IC50	43200 nM
cid_1933177	IC50	44000 nM
MLS000554134	IC50	46200 nM

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.25	IC50	56	nM	CHEMBL4593409
6.94	IC50	114	nM	VARESPLADIB
6.88	IC50	131	nM	VARESPLADIB

PubChem BioAssay actives

4 with measured affinity, of 58 total; 2 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
(2R)-3-[3-(5-benzyl-2-carbamoylphenyl)phenyl]-2-methylpropanoic acid	1631141: Inhibition of sPLA2 in human HepG2 cells	ic50	0.0140	uM
2-(1-benzyl-2-ethyl-3-oxamoylindol-4-yl)oxyacetic acid	1614038: Inhibition of human recombinant sPLA2 assessed as reduction in 16:0 LPC formation after 30 mins by HPLC-MS analysis	ic50	0.1140	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
entinostat	affects cotreatment, increases expression	2
Nickel	increases expression	2
Valproic Acid	affects expression, decreases expression	2
bisphenol A	affects cotreatment, decreases methylation	1
o,p’-DDT	decreases expression	1
coumarin	increases phosphorylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Estradiol	decreases expression	1
Folic Acid	decreases expression	1
Mustard Gas	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1
Aflatoxin B1	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	increases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4383327	Binding	Inhibition of human sPLA2	1-(2-Hydroxybenzoyl)-thiosemicarbazides are promising antimicrobial agents targeting d-alanine-d-alanine ligase in bacterio. — Eur J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00439699	PHASE4	COMPLETED	A Pilot Clinical Trial Of Memantine for Essential Tremor
NCT00584376	PHASE4	COMPLETED	Pregabalin (Lyrica) for the Treatment of Essential Tremor
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02111369	PHASE4	COMPLETED	Propranolol and Botulinum Toxin for Essential Vocal Tremor
NCT02495883	PHASE4	COMPLETED	Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
NCT00018564	PHASE3	COMPLETED	Novel Therapies for Essential Tremor
NCT00236496	PHASE3	COMPLETED	A Comparison of the Efficacy and Safety of Topiramate Versus Placebo in Treating Tremor of Unknown Cause.
NCT01441284	PHASE3	WITHDRAWN	Efficacy of Pramipexole Extended Release in the Treatment of Essential Tremor
NCT04193527	PHASE3	COMPLETED	A Study to Evaluate the Diagnostic Efficacy of DaTSCAN™ Ioflupane (123I) Injection in Single Photon Emission Computed Tomography (SPECT) for the Diagnosis of Parkinsonian Syndrome (PS) in Chinese Patients
NCT04265209	PHASE3	COMPLETED	[18F] LBT-999 PET Compared to [123I]-FP/CIT SPECT to Distinguish Between Parkinson’s Diseases and Essential Tremor
NCT06087276	PHASE3	ENROLLING_BY_INVITATION	Essential 3 - Decentralized, Phase 3 Study Evaluating the Safety and Efficacy of Ulixacaltamide in Essential Tremor (ET)
NCT00080366	PHASE2	COMPLETED	Octanol to Treat Essential Tremor
NCT00102596	PHASE2	COMPLETED	Clinical Trial Characterizing the Bioavailability of 1-Octanol in Adults With Ethanol-responsive Essential Tremor
NCT00223743	PHASE2	COMPLETED	A Safety/Efficacy Trial of Zonisamide for Essential Tremor
NCT00321087	PHASE2	TERMINATED	A Study of T2000 in Essential Tremor
NCT00598078	PHASE2	COMPLETED	Multiple-dose,Double-blind,Placebo-controlled Study of Sodium Oxybate in Patients With Essential Tremor
NCT00655278	PHASE2	TERMINATED	T2000 in Essential Tremor - Open Label Continuation
NCT01332695	PHASE2	COMPLETED	A Pilot Efficacy and Safety Study of ST101 in Essential Tremor
NCT02277106	PHASE2	COMPLETED	Evaluate SAGE-547 in Participants With Essential Tremor
NCT02551848	PHASE2	UNKNOWN	Kinematic-based BoNT-A Injections for Bilateral ET
NCT02668146	PHASE2	UNKNOWN	An Efficacy/Safety Study of Perampanel for Reducing Essential Tremor
NCT02978781	PHASE2	COMPLETED	A Study to Evaluate SAGE-217 in Participants With Essential Tremor
NCT03101241	PHASE2	COMPLETED	A Phase 2 RCT Study of CX-8998 for Essential Tremor
NCT03688685	PHASE2	COMPLETED	A Clinical Study to Evaluate CAD-1883 in Essential Tremor
NCT03780426	PHASE2	COMPLETED	tSMS in Essential Tremor
NCT04305275	PHASE2	COMPLETED	A Study to Evaluate the Efficacy, Safety, and Tolerability of SAGE-324 in Participants With Essential Tremor
NCT04727658	PHASE2	TERMINATED	Linac FRACtionated Radiosurgical THALamotomie in Tremors (FRACTHAL)
NCT04880616	PHASE2	COMPLETED	Safety, Efficacy, and Tolerability of NBI-827104 for the Treatment of Essential Tremor
NCT05021978	PHASE2	COMPLETED	A Clinical Trial of PRAX-944 in Participants With Essential Tremor
NCT05021991	PHASE2	COMPLETED	A Clinical Trial of 2 Doses of PRAX-944 in Participants With Essential Tremor
NCT05122650	PHASE2	COMPLETED	A Study To Assess the Safety and Efficacy of JZP385 in the Treatment of Adults With Moderate to Severe Essential Tremor (ET)
NCT05173012	PHASE2	COMPLETED	Study to Evaluate SAGE-324 in Participants With Essential Tremor
NCT05387642	PHASE2	WITHDRAWN	A Clinical Trial of PRAX-114 in Participants With Essential Tremor
NCT06312800	PHASE2	WITHDRAWN	Acamprosate and Methazolamide for Essential Tremor
NCT06821906	PHASE2	RECRUITING	Stereotactic Radiosurgery in the Treatment of Essential Tremor
NCT07074002	PHASE2	RECRUITING	Proof of Concept Study on BP1.4979 Effect on Essential Tremor
NCT07103265	PHASE2	NOT_YET_RECRUITING	Developing a New LIFU Neuromodulation Method to Suppress Tremor
NCT00001986	PHASE1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT00016679	PHASE1	COMPLETED	1-Octanol to Treat Essential Tremor
NCT01304758	PHASE1	COMPLETED	ExAblate Transcranial MR Guided Focused Ultrasound in the Treatment of Essential Tremor