PLA2G6

Summary

PLA2G6 (phospholipase A2 group VI, HGNC:9039) is a protein-coding gene on chromosome 22q13.1, encoding 85/88 kDa calcium-independent phospholipase A2 (O60733). Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.

The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date.

Source: NCBI Gene 8398 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PLA2G6-associated neurodegeneration (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 31
• Clinical variants (ClinVar): 1,223 total — 91 pathogenic, 54 likely-pathogenic
• Phenotypes (HPO): 133
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_003560

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9039
Approved symbol	PLA2G6
Name	phospholipase A2 group VI
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	iPLA2, PNPLA9, PARK14, iPLA2beta, NBIA2
Ensembl gene	ENSG00000184381
Ensembl biotype	protein_coding
OMIM	603604
Entrez	8398

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 27 protein_coding, 12 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay, 6 retained_intron

ENST00000332509, ENST00000335539, ENST00000402064, ENST00000417303, ENST00000420435, ENST00000426674, ENST00000427114, ENST00000427453, ENST00000430886, ENST00000435484, ENST00000436218, ENST00000445591, ENST00000447598, ENST00000448094, ENST00000452542, ENST00000452794, ENST00000452972, ENST00000454670, ENST00000455341, ENST00000463287, ENST00000471636, ENST00000479641, ENST00000480154, ENST00000490473, ENST00000491986, ENST00000496409, ENST00000498338, ENST00000594306, ENST00000655142, ENST00000660610, ENST00000663895, ENST00000664587, ENST00000665987, ENST00000667521, ENST00000668208, ENST00000668499, ENST00000668949, ENST00000671093, ENST00000673413, ENST00000885143, ENST00000885144, ENST00000885145, ENST00000885146, ENST00000885147, ENST00000885148, ENST00000885149, ENST00000931333, ENST00000955628, ENST00000955629, ENST00000955630, ENST00000955631, ENST00000955632

RefSeq mRNA: 9 — MANE Select: NM_003560 NM_001004426, NM_001199562, NM_001349864, NM_001349865, NM_001349866, NM_001349867, NM_001349868, NM_001349869, NM_003560

CCDS: CCDS13967, CCDS33645

Canonical transcript exons

ENST00000332509 — 17 exons

Exon	Start	End
ENSE00001691504	38132831	38133013
ENSE00001748821	38115527	38115681
ENSE00001759648	38113487	38113654
ENSE00001760874	38112504	38112577
ENSE00001837460	38111495	38112305
ENSE00001955932	38181664	38181830
ENSE00002210330	38128269	38128430
ENSE00002251199	38129454	38129562
ENSE00003070499	38139982	38140169
ENSE00003503664	38169218	38169471
ENSE00003510284	38145438	38145653
ENSE00003531265	38116075	38116211
ENSE00003576128	38143105	38143288
ENSE00003576539	38123095	38123258
ENSE00003585530	38126371	38126449
ENSE00003590715	38120759	38120909
ENSE00003785588	38134988	38135084

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 99.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7710 / max 128.3385, expressed in 1549 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194126	4.6440	1409
194125	1.7496	785
194123	0.0798	29
194124	0.0758	32
194127	0.0753	27
194122	0.0563	20
194119	0.0405	9
194128	0.0247	14
194117	0.0144	7
194118	0.0105	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.25	gold quality
right lobe of thyroid gland	UBERON:0001119	98.25	gold quality
left lobe of thyroid gland	UBERON:0001120	98.17	gold quality
gall bladder	UBERON:0002110	97.41	gold quality
thyroid gland	UBERON:0002046	96.97	gold quality
right adrenal gland cortex	UBERON:0035827	96.60	gold quality
right adrenal gland	UBERON:0001233	96.27	gold quality
sural nerve	UBERON:0015488	96.09	gold quality
granulocyte	CL:0000094	96.05	gold quality
right testis	UBERON:0004534	95.94	gold quality
left ovary	UBERON:0002119	95.76	gold quality
left testis	UBERON:0004533	95.66	gold quality
right ovary	UBERON:0002118	94.76	gold quality
metanephros cortex	UBERON:0010533	94.75	gold quality
left uterine tube	UBERON:0001303	94.73	gold quality
endocervix	UBERON:0000458	94.63	gold quality
left adrenal gland	UBERON:0001234	94.44	gold quality
left adrenal gland cortex	UBERON:0035825	94.40	gold quality
skin of abdomen	UBERON:0001416	94.18	gold quality
body of uterus	UBERON:0009853	94.06	gold quality
body of pancreas	UBERON:0001150	93.92	gold quality
tibial nerve	UBERON:0001323	93.75	gold quality
skin of leg	UBERON:0001511	93.63	gold quality
minor salivary gland	UBERON:0001830	93.59	gold quality
mucosa of stomach	UBERON:0001199	93.53	gold quality
omental fat pad	UBERON:0010414	93.53	gold quality
adrenal cortex	UBERON:0001235	93.52	gold quality
peritoneum	UBERON:0002358	93.47	gold quality
ectocervix	UBERON:0012249	92.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.96

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KAT5, PITX2, SREBF2

miRNA regulators (miRDB)

56 targeting PLA2G6, 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-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-5001-5P	99.05	66.76	1972

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation (PMID:12208880)
• stimulation of three isoforms of PLA2 by thapsigargin liberates free AA that, in turn, induces capacitative calcium influx in human T-cells (PMID:12423354)
• Arachidonic acid produced by iPLA(2)beta-catalyzed hydrolysis of their substrates induces release of Ca(2+) from ER stores, an event thought to participate in glucose-stimulated insulin secretion. (PMID:14749286)
• The GVIB iPLA2 is widely expressed in human tissues but is enriched in heart, placenta, and skeletal muscle. (PMID:15052324)
• Here we show that the C-terminal region of human iPLA(2)gamma is responsible for the enzymatic activity. (PMID:15249229)
• iPLA2 may be dispensable for the apoptotic process to occur (PMID:15252038)
• iPLA2epsilon (adiponutrin), iPLA2zeta (TTS-2.2), and iPLA2eta (GS2) are three novel TAG lipases/acylglycerol transacylases that likely participate in TAG hydrolysis and the acyl-CoA independent transacylation of acylglycerols (PMID:15364929)
• truncated iPLA(2) proteins associate with active iPLA(2) and down-regulate its activity during G(1) (PMID:15385540)
• Detailed characterization of group VIA phospholipase A2 beta suggests that the pancreatic islet beta-cells express multiple isoforms of iPLA2beta; the hypothesis in this review is that these isozymes participate in different cellular functions. (PMID:15573142)
• This study reviews the evidence and discusses the potential roles of phospholipase A2 Group 6A for schizophrenia with particular emphasis on published association studies. (PMID:16585943)
• mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a group VI phospholipase A2, in NBIA, INAD and Karak syndrome (PMID:16783378)
• Increase in iPLA(2) and accumulation of membrane phospholipid-derived metabolites in HCAEC exposed to hypoxia or thrombin have important implications in inflammation and arrhythmogenesis in atherosclerosis/thrombosis and myocardial ischemia. (PMID:16943248)
• iPLA2-VIA is a novel regulator of endothelial cell S phase progression, cell cycle residence, and angiogenesis (PMID:16966332)
• The role of calcium influx factor and PLA2G6 in the activation of CRAC channels and calcium entry in rat tumor cell lines is reported. (PMID:17003039)
• The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1. (PMID:17033970)
• Transient receptor potential subfamily M member 8 (TRPM8) channel is stimulated by the Ca2+-independent phospholipase A2 (iPLA2) signaling pathway with its end products, lysophospholipids, acting as its endogenous ligands. (PMID:17082190)
• human coronary artery endothelial cells exposed to thrombin or tryptase stimulation demonstrated an increase in iPLA2 activity and arachidonic acid release (PMID:17188740)
• Cerebellar atrophy without cerebellar cortex hyperintensity in infantile neuroaxonal dystrophy (INAD) due to PLA2G6 mutation. (PMID:17254819)
• Secretion and activity of sPLA(2) were found to be similar in granulocyte-like PLB cells expressing or lacking cPLA(2)alpha, indicating that they are not under cPLA(2)alpha regulation. (PMID:17275398)
• oxytocin stimulation of uterine PGF2alpha production is mediated, at least in part, by up-regulation of PLA2G6 expression and activity (PMID:17459165)
• iPLA(2)beta and cPLA(2)alpha regulate monocyte migration from different intracellular locations, with iPLA(2)beta acting as a critical regulator of the cellular compass. (PMID:18208975)
• PLA2G6 mutations are associated with infantile neuroaxonal dystrophy and have been reported previously to cause early cerebellar signs, and the syndrome was classified as neurodegeneration with brain iron accumulation (type 2). (PMID:18570303)
• This review discusses the role of iPLA2 in cell growth with special emphasis placed on its role in cell signaling; the putative lipid signals involved are also discussed. (PMID:18775417)
• Tryptase stimulation of human small airway epithelial cells increased membrane-associated, calcium-independent phospholipase A(2)gamma (iPLA(2)gamma) activity, resulting in increased arachidonic acid and PGE(2) release. (PMID:18790994)
• PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy. (PMID:18799783)
• H2O2-mediated hyperoxidation of Prdx6 induces cell cycle arrest at the G2/M transition through up-regulation of iPLA2 activity. (PMID:18826942)
• iPLA2 activity is responsible for membrane phospholipid hydrolysis in response to tryptase or thrombin stimulation in pulmonary vascular endothelial cells (PMID:19059366)
• Different and even identical PLA2G6 mutations may cause neurodegenerative diseases with heterogeneous clinical manifestations, including dystonia-parkinsonism. (PMID:19087156)
• The nine novel mutations identified in this study suggest the uniqueness of the PLA2G6 mutation spectrum in Chinese patients (PMID:19138334)
• Chromofungin or Catestatin , penetrate into PMNs, inducing extracellular calcium entry by a CaM-regulated iPLA2 pathway. (PMID:19225567)
• The region with the greatest change upon lipid binding in phospholipase A2 group VI was region 708-730. (PMID:19556238)
• iPLA2 expression is increased in neutrophils from people with diabetes and mediates superoxide generation, presenting an alternate pathway independent of protein kinase C and phosphatidic acid phosphohydrolase-1 hydrolase signaling. (PMID:20053941)
• These data demonstrate the novel findings that iPLA2 inhibition activates p38 by inducing reactive species, and further suggest that this signaling kinase is involved in p53 activation, cell cycle arrest and cytostasis. (PMID:20171194)
• Our data suggest that PLA2G6 mutations are unlikely to be an important cause of the common garden variety of Parkinson’s disease patients with dystonia or a positive family history (PMID:20186954)
• Results characterize a pathway leading to NOX2 activation in which iPLA(2)-regulated p38 MAPK activity is a key regulator of S100A8/A9 translocation via S100A9 phosphorylation. (PMID:20219570)
• Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one patient with infantile neuroaxonal dystrophy while the other is carrying two novel splice-site mutations (PMID:20584031)
• This report further defines the clinical features and neuropathology of PLA2G6 related childhood and adult onset dystonia-parkinsonism . (PMID:20619503)
• Genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations (PMID:20629144)
• We identified genetic deficits in PLA2G6 that were associated with Levodopa responsive parkinsonism with pyramidal signs. (PMID:20669327)
• This study demonistrated that pLA2G6 has a dynamic expression pattern both in terms of the location of expression and the differentiation state of expressing cells. (PMID:20813170)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pla2g6	ENSDARG00000060921
mus_musculus	Pla2g6	ENSMUSG00000042632
rattus_norvegicus	Pla2g6	ENSRNOG00000012295
drosophila_melanogaster	iPLA2-VIA	FBGN0036053
drosophila_melanogaster	mask	FBGN0043884
caenorhabditis_elegans		WBGENE00011240
caenorhabditis_elegans		WBGENE00011423

Paralogs (4): NFKBIA (ENSG00000100906), NFKBIB (ENSG00000104825), ANKRD22 (ENSG00000152766), TONSL (ENSG00000160949)

Protein

Protein identifiers

85/88 kDa calcium-independent phospholipase A2 — O60733 (reviewed: O60733)

Alternative names: 2-lysophosphatidylcholine acylhydrolase, Group VI phospholipase A2, Intracellular membrane-associated calcium-independent phospholipase A2 beta, Palmitoyl-CoA hydrolase, Patatin-like phospholipase domain-containing protein 9

All UniProt accessions (15): A0A590UJC7, A0A590UJH4, A0A590UJZ2, A0A590UK51, A0A590UK67, B0QYE9, E7EX67, O60733, F8WEN3, F8WEQ9, H0Y6T3, H0Y7G5, H7C3P5, M0R1Q9, M0R3D9

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction. Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 or sn-2 position of phospholipids (phospholipase A1 and A2 activity respectively), producing lysophospholipids that are used in deacylation-reacylation cycles. Hydrolyzes both saturated and unsaturated long fatty acyl chains in various glycerophospholipid classes such as phosphatidylcholines, phosphatidylethanolamines and phosphatidates, with a preference for hydrolysis at sn-2 position. Can further hydrolyze lysophospholipids carrying saturated fatty acyl chains (lysophospholipase activity). Upon oxidative stress, contributes to remodeling of mitochondrial phospholipids in pancreatic beta cells, in a repair mechanism to reduce oxidized lipid content. Preferentially hydrolyzes oxidized polyunsaturated fatty acyl chains from cardiolipins, yielding monolysocardiolipins that can be reacylated with unoxidized fatty acyls to regenerate native cardiolipin species. Hydrolyzes oxidized glycerophosphoethanolamines present in pancreatic islets, releasing oxidized polyunsaturated fatty acids such as hydroxyeicosatetraenoates (HETEs). Has thioesterase activity toward fatty-acyl CoA releasing CoA-SH known to facilitate fatty acid transport and beta-oxidation in mitochondria particularly in skeletal muscle. Plays a role in regulation of membrane dynamics and homeostasis. Selectively hydrolyzes sn-2 arachidonoyl group in plasmalogen phospholipids, structural components of lipid rafts and myelin. Regulates F-actin polymerization at the pseudopods, which is required for both speed and directionality of MCP1/CCL2-induced monocyte chemotaxis. Targets membrane phospholipids to produce potent lipid signaling messengers. Generates lysophosphatidate (LPA, 1-acyl-glycerol-3-phosphate), which acts via G-protein receptors in various cell types. Has phospholipase A2 activity toward platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), likely playing a role in inactivation of this potent pro-inflammatory signaling lipid. In response to glucose, amplifies calcium influx in pancreatic beta cells to promote INS secretion. Lacks the catalytic domain and may act as a negative regulator of the catalytically active isoforms. Lacks the catalytic domain and may act as a negative regulator of the catalytically active isoforms.

Subunit / interactions. Homodimer formed by catalytic domains tightly interacting through a large hydrophobic interface. The contact area involves 3 alpha helices, several loops and a part of the beta sheet from each monomer. Both active sites of the dimer are in close proximity adopting an open conformation that provide sufficient space for phospholipid access and favoring cooperativity in deacylation-reacylation reactions. Each monomer has 9 ankyrin repeats stacked side-by-side in an elongated structure oriented outwards from the catalytic core.

Subcellular location. Cytoplasm. Cell membrane. Mitochondrion. Cell projection. Pseudopodium.

Tissue specificity. Four different transcripts were found to be expressed in a distinct tissue distribution.

Disease relevance. Neurodegeneration with brain iron accumulation 2B (NBIA2B) [MIM:610217] A neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. It is characterized by progressive extrapyramidal dysfunction leading to rigidity, dystonia, dysarthria and sensorimotor impairment. The disease is caused by variants affecting the gene represented in this entry. Neurodegeneration with brain iron accumulation 2A (NBIA2A) [MIM:256600] A neurodegenerative disease characterized by pathologic axonal swelling and spheroid bodies in the central nervous system. Onset is within the first 2 years of life with death by age 10 years. The disease is caused by variants affecting the gene represented in this entry. Parkinson disease 14 (PARK14) [MIM:612953] An adult-onset progressive neurodegenerative disorder characterized by parkinsonism, dystonia, severe cognitive decline, cerebral and cerebellar atrophy and absent iron in the basal ganglia on magnetic resonance imaging. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by ATP. Inhibited by calcium-activated calmodulin. Inhibited by bromoenol lactone (BEL).

Domain organisation. Has two putative calmodulin binding domains, the 1-9-14 and IQ motifs. One calmodulin molecule interacts with PLA2G6 dimer, likely through 1-9-14 motif on each monomer. Binds calmodulin in a calcium-dependent way.

Isoforms (4)

UniProt ID	Names	Canonical?
O60733-1	LH-iPLA2	yes
O60733-2	SH-iPLA2
O60733-3	Ankyrin-iPLA2-1
O60733-4	Ankyrin-iPLA2-2

RefSeq proteins (9): NP_001004426, NP_001186491, NP_001336793, NP_001336794, NP_001336795, NP_001336796, NP_001336797, NP_001336798, NP_003551* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR002641	PNPLA_dom	Domain
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR047148	PLPL9	Family

Pfam: PF00023, PF01734, PF12796

Enzyme classification (BRENDA):

• EC 3.1.1.4 — phospholipase A2 (BRENDA: 129 organisms, 452 substrates, 710 inhibitors, 90 Km, 14 kcat entries)

Substrate kinetics (BRENDA)

58 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDYLCHOLINE	0.05–17	12
1,2-DIHEXANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.94–13.85	7
PHOSPHATIDYLETHANOLAMINE	0.02–10.5	5
1,2-DIHEPTANOYL-SN-GLYCERO-3-PHOPHORYLCHOLINE	1.12–5.13	3
1,2-DIHEPTANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	3–3.92	3
1,2-DIOCTANOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.12–3.2	3
1-HEXADECYL-2-ACETYL-SN-GLYCEROL-3-PHOSPHOCHOLIN	0.0137–0.0142	2
1-PALMITOYL-2-ARACHIDONYLPHOSPHATIDYLCHOLINE	0.0016–0.0033	2
LECITHIN	8.3–8.5	2
(3E)-3-[(3AS,7AS)-3-METHYL-2-OXO-6-(PROPAN-2-YLI	0.742	1
(3R,3AS,5AS,8BR)-3,5A,5B-TRIMETHYL-3A,4,5,5A,5B,	0.746	1
(3R,3AS,5AS,9BR)-3,5A,9-TRIMETHYL-3A,4,5,5A-TETR	0.734	1
(3R,3AS,6R,8S,9BS)-6,8-DIHYDROXY-3,6,9-TRIMETHYL	0.744	1
(3R,3AS,6R,8S,9BS)-8-HYDROXY-3,6,9-TRIMETHYL-2-O	0.738	1
(3R,3AS,6R,9BS)-3,6,9-TRIMETHYL-2,8-DIOXO-2,3,3A	0.742	1

Catalyzed reactions (Rhea), 12 shown:

• a 1-acyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + a fatty acid + H(+) (RHEA:15177)
• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)
• hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+) (RHEA:16645)
• a 1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine + H2O = a 1-O-alkyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:36231)
• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + (9Z)-octadecenoate + H(+) (RHEA:38779)
• 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-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + hexadecanoate + H(+) (RHEA:40435)
• 1’,3’-bis[1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + H2O = 1’-[1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho]-3’-[1-(9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + (9Z)-octadecenoate + H(+) (RHEA:40463)
• 1’-[1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho]-3’-[1-(9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + H2O = 1’,3’-bis-[1-(9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + (9Z)-octadecenoate + H(+) (RHEA:40467)
• 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine + H2O = 1-O-hexadecyl-sn-glycero-3-phosphocholine + acetate + H(+) (RHEA:40479)
• 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 1-octadecanoyl-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40519)

UniProt features (53 total): sequence variant 21, repeat 9, splice variant 6, sequence conflict 5, short sequence motif 3, transmembrane region 2, region of interest 2, active site 2, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60733-F1	86.16	0.69

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): 519 (nucleophile); 652 (proton acceptor)

Mutagenesis-validated functional residues (1):

Position	Phenotype
519	abolishes phospholipase and lysophospholipase activities.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1482788	Acyl chain remodelling of PC
R-HSA-1482798	Acyl chain remodeling of CL
R-HSA-1482839	Acyl chain remodelling of PE
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic

MSigDB gene sets: 539 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, MYAATNNNNNNNGGC_UNKNOWN, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, CHIBA_RESPONSE_TO_TSA_UP, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (12): chemotaxis (GO:0006935), antibacterial humoral response (GO:0019731), phosphatidylcholine catabolic process (GO:0034638), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), cardiolipin acyl-chain remodeling (GO:0035965), Fc-gamma receptor signaling pathway involved in phagocytosis (GO:0038096), phosphatidylethanolamine catabolic process (GO:0046338), platelet activating factor metabolic process (GO:0046469), phosphatidic acid metabolic process (GO:0046473), positive regulation of ceramide biosynthetic process (GO:2000304), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042)

GO Molecular Function (11): 1-alkyl-2-acetylglycerophosphocholine esterase activity (GO:0003847), phosphatidylcholine lysophospholipase A1 activity (GO:0004622), A2-type glycerophospholipase activity (GO:0004623), calmodulin binding (GO:0005516), hydrolase activity (GO:0016787), serine hydrolase activity (GO:0017171), identical protein binding (GO:0042802), obsolete calcium-independent phospholipase A2 activity (GO:0047499), long-chain fatty acyl-CoA hydrolase activity (GO:0052816), catalytic activity (GO:0003824), protein binding (GO:0005515)

GO Cellular Component (10): obsolete extracellular space (GO:0005615), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), microtubule cytoskeleton (GO:0015630), nuclear speck (GO:0016607), pseudopodium (GO:0031143), cytoplasm (GO:0005737), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	3
Fcgamma receptor (FCGR) dependent phagocytosis	1
Golgi-to-ER retrograde transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
glycerophospholipid catabolic process	2
glycerophospholipid metabolic process	2
carboxylic ester hydrolase activity	2
protein binding	2
cytoplasm	2
response to chemical	1
taxis	1
antimicrobial humoral response	1
defense response to bacterium	1
phosphatidylcholine metabolic process	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
cardiolipin metabolic process	1
Fc receptor mediated stimulatory signaling pathway	1
phagocytosis	1
Fc-gamma receptor signaling pathway	1
phosphatidylethanolamine metabolic process	1
ether lipid metabolic process	1
ceramide biosynthetic process	1
positive regulation of sphingolipid biosynthetic process	1
regulation of ceramide biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
lysophospholipase A1 activity	1
glycerophospholipase activity	1
catalytic activity	1
hydrolase activity	1
fatty acyl-CoA hydrolase activity	1
molecular_function	1
binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cytoskeleton	1
nuclear ribonucleoprotein granule	1
plasma membrane bounded cell projection	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1700 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLA2G6	PANK2	Q9BZ23	958
PLA2G6	FTL	P02792	907
PLA2G6	FBXO7	Q9Y3I1	898
PLA2G6	ATP13A2	Q9NQ11	841
PLA2G6	PLA2G2A	P14555	823
PLA2G6	PARK7	Q99497	812
PLA2G6	C19orf12	Q9NSK7	810
PLA2G6	GIGYF2	Q6Y7W6	802
PLA2G6	PINK1	Q9BXM7	801
PLA2G6	CALML6	Q8TD86	780
PLA2G6	CALML3	P27482	780
PLA2G6	CALML4	Q96GE6	780
PLA2G6	CALML5	Q9NZT1	780
PLA2G6	MTAP	Q13126	771
PLA2G6	GBA1	P04062	752

IntAct

41 interactions, top by confidence:

A	B	Type	Score
PLA2G6	CEP76	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	NUP93	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	SERTAD2	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	PLA2G6	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	USP54	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	MAT2B	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	RCBTB2	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	TRIM50	psi-mi:“MI:0915”(physical association)	0.560
	PLA2G6	psi-mi:“MI:0915”(physical association)	0.560
PLA2G6	RUSC1	psi-mi:“MI:0915”(physical association)	0.560
ZBTB42	PLA2G6	psi-mi:“MI:0915”(physical association)	0.560
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
PLA2G6	CHEK1	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
CIAO2A		psi-mi:“MI:0914”(association)	0.350
DHFR	FANCA	psi-mi:“MI:0914”(association)	0.350
NXT2	MYO1G	psi-mi:“MI:0914”(association)	0.350
PLA2G6	CEP76	psi-mi:“MI:0915”(physical association)	0.000
PLA2G6	NUP93	psi-mi:“MI:0915”(physical association)	0.000
PLA2G6	SERTAD2	psi-mi:“MI:0915”(physical association)	0.000
PLA2G6	RCBTB2	psi-mi:“MI:0915”(physical association)	0.000
PLA2G6	PLA2G6	psi-mi:“MI:0915”(physical association)	0.000
PLA2G6	USP54	psi-mi:“MI:0915”(physical association)	0.000
MAT2B	PLA2G6	psi-mi:“MI:0915”(physical association)	0.000
PLA2G6	TRIM50	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (28): Arf1 (Affinity Capture-Western), PLA2G6 (Reconstituted Complex), PLA2G6 (Affinity Capture-RNA), PLA2G6 (Affinity Capture-MS), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid), PLA2G6 (Two-hybrid)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A2AGL3, A7MB89, B0LPN4, E9Q401, O60733, P30957, P42694, P49754, P97570, P97819, Q15413, Q29RM5, Q2KIX2, Q2T9K6, Q32PW3, Q3SX45, Q4V890, Q59H18, Q5F361, Q5GIG6, Q5KU39, Q5RF15, Q5U2S6, Q5ZKK2, Q66H07, Q66H63, Q6B858, Q6DFV5, Q6NYU2, Q7T3P8, Q7TQP6, Q8C0T1, Q8CEF1, Q8K0L0, Q8K114, Q8TC84, Q91W86, Q92736

Diamond homologs: A0A3L7I2I8, O60733, O89019, P97570, P97819, Q20500, Q9KVG8, P07207, P46530, Q9TZM3, A6QR20, B2RXR6, G0LXV8, L7XDS4, O15084, O75762, O90760, P0DJE3, P19838, P23631, P53356, Q3SX00, Q4FE45, Q4JHE0, Q505D1, Q54HW1, Q55FM5, Q5F478, Q5R8C8, Q63369, Q68FF6, Q6JAN1, Q6RI86, Q7Z020, Q86W74, Q8BLA8, Q8BTI7, Q8N8A2, Q8NB46, Q94B55

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1223 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	91
Likely pathogenic	54
Uncertain significance	360
Likely benign	489
Benign	56

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012263	NM_003560.4(PLA2G6):c.668C>A (p.Pro223Gln)	Pathogenic
1012698	NM_003560.4(PLA2G6):c.2251G>T (p.Glu751Ter)	Pathogenic
1028628	NM_003560.4(PLA2G6):c.1933C>T (p.Arg645Ter)	Pathogenic
1076982	NC_000022.10:g.(?38528818)(38539315_?)dup	Pathogenic
1252075	NM_003560.4(PLA2G6):c.1125del (p.Val376fs)	Pathogenic
1323464	NM_003560.4(PLA2G6):c.857_858del (p.Tyr286fs)	Pathogenic
1343814	NM_003560.4(PLA2G6):c.1690del (p.Phe563_Leu564insTer)	Pathogenic
1453196	NC_000022.10:g.(?38565205)(38565433_?)del	Pathogenic
1459347	NC_000022.10:g.(?38528818)(38536196_?)del	Pathogenic
159730	NC_000022.10:g.38522454delG	Pathogenic
159734	NM_003560.4(PLA2G6):c.1509del (p.Ser504fs)	Pathogenic
159749	NM_003560.4(PLA2G6):c.1903C>T (p.Arg635Ter)	Pathogenic
159764	NM_003560.4(PLA2G6):c.2327_2328del (p.Thr776fs)	Pathogenic
159773	NM_003560.4(PLA2G6):c.517C>T (p.Gln173Ter)	Pathogenic
159780	NM_003560.4(PLA2G6):c.821T>G (p.Met274Arg)	Pathogenic
1686076	NM_003560.4(PLA2G6):c.1969G>A (p.Ala657Thr)	Pathogenic
1686077	NM_003560.4(PLA2G6):c.1474_1478del (p.Ile492fs)	Pathogenic
1712833	NM_003560.4(PLA2G6):c.1648del (p.Arg550fs)	Pathogenic
2121380	NM_003560.4(PLA2G6):c.1460del (p.Gly487fs)	Pathogenic
2170057	NM_003560.4(PLA2G6):c.1974C>G (p.Asn658Lys)	Pathogenic
2412648	NM_003560.4(PLA2G6):c.1427+2T>C	Pathogenic
2412654	NM_003560.4(PLA2G6):c.127C>T (p.Gln43Ter)	Pathogenic
2424703	NC_000022.10:g.(?38535969)(38536196_?)del	Pathogenic
2501533	NM_003560.4(PLA2G6):c.1915del (p.Ala639fs)	Pathogenic
265449	NM_003560.4(PLA2G6):c.208C>T (p.Arg70Ter)	Pathogenic
2709169	NM_003560.4(PLA2G6):c.2276+1G>C	Pathogenic
2711293	NM_003560.4(PLA2G6):c.1833dup (p.Arg612fs)	Pathogenic
2724426	NM_003560.4(PLA2G6):c.1982C>T (p.Thr661Met)	Pathogenic
2737044	NM_003560.4(PLA2G6):c.1524dup (p.Lys509fs)	Pathogenic
2739108	NM_003560.4(PLA2G6):c.2144G>A (p.Trp715Ter)	Pathogenic

SpliceAI

4871 predictions. Top by Δscore:

Variant	Effect	Δscore
22:38112305:TC:T	acceptor_loss	1.0000
22:38112306:C:CA	acceptor_loss	1.0000
22:38112306:C:CC	acceptor_gain	1.0000
22:38112498:CCTCA:C	donor_loss	1.0000
22:38112499:CTCAC:C	donor_loss	1.0000
22:38112500:TCA:T	donor_loss	1.0000
22:38112501:CA:C	donor_loss	1.0000
22:38112502:ACCTG:A	donor_loss	1.0000
22:38112503:CCT:C	donor_loss	1.0000
22:38112574:TGCA:T	acceptor_gain	1.0000
22:38112575:GCA:G	acceptor_gain	1.0000
22:38112576:CA:C	acceptor_gain	1.0000
22:38112576:CAC:C	acceptor_gain	1.0000
22:38112578:C:CC	acceptor_gain	1.0000
22:38113480:CA:C	donor_gain	1.0000
22:38113485:A:AC	donor_gain	1.0000
22:38113485:A:AT	donor_loss	1.0000
22:38113486:C:CC	donor_gain	1.0000
22:38113486:C:CG	donor_loss	1.0000
22:38113486:CA:C	donor_gain	1.0000
22:38113495:C:CT	donor_gain	1.0000
22:38113505:G:A	donor_gain	1.0000
22:38113512:T:A	donor_gain	1.0000
22:38113652:ACCC:A	acceptor_loss	1.0000
22:38113653:CC:C	acceptor_gain	1.0000
22:38113653:CCCTG:C	acceptor_loss	1.0000
22:38113654:CC:C	acceptor_gain	1.0000
22:38113654:CCTG:C	acceptor_loss	1.0000
22:38113655:C:CA	acceptor_loss	1.0000
22:38113656:T:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000008648 (22:38164892 G>A,C), RS1000030845 (22:38154085 A>C), RS1000049180 (22:38134973 T>A,C,G), RS1000054648 (22:38123088 C>T), RS1000120429 (22:38159328 A>G,T), RS1000140578 (22:38112635 G>A,C,T), RS1000162160 (22:38143879 A>G), RS1000192393 (22:38157880 T>C), RS1000268169 (22:38118639 A>T), RS1000303487 (22:38115649 C>A,T), RS1000400563 (22:38134788 G>T), RS1000419201 (22:38175586 C>T), RS1000474397 (22:38127890 A>G), RS1000493952 (22:38130856 C>A), RS1000500182 (22:38174807 G>A)

Disease associations

OMIM: gene MIM:603604 | disease phenotypes: MIM:256600, MIM:610217, MIM:612953, MIM:234200, MIM:168600, MIM:600329, MIM:108600, MIM:209850, MIM:213000, MIM:611584

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration with brain iron accumulation 2A	Definitive	Autosomal recessive
neurodegeneration with brain iron accumulation 2B	Definitive	Autosomal recessive
autosomal recessive Parkinson disease 14	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
PLA2G6-associated neurodegeneration	Definitive	AR

Mondo (16): neurodegeneration with brain iron accumulation 2A (MONDO:0024457), PLA2G6-associated neurodegeneration (MONDO:0017998), neurodegeneration with brain iron accumulation 2B (MONDO:0012444), autosomal recessive Parkinson disease 14 (MONDO:0013060), neurodegeneration with brain iron accumulation (MONDO:0018307), congenital nervous system disorder (MONDO:0002320), Parkinson disease (MONDO:0005180), parkinsonian disorder (MONDO:0021095), vascular parkinsonism (MONDO:0956980), infantile osteopetrosis with neuroaxonal dysplasia (MONDO:0010866), spastic ataxia (MONDO:0017845), autism (MONDO:0005260), cerebellar ataxia (MONDO:0000437), microcephaly (MONDO:0001149), isolated cerebellar hypoplasia/agenesis (MONDO:0008939)

Orphanet (11): Infantile neuroaxonal dystrophy (Orphanet:35069), PLA2G6-associated neurodegeneration (Orphanet:329303), Adult-onset dystonia-parkinsonism (Orphanet:199351), Neurodegeneration with brain iron accumulation (Orphanet:385), Infantile osteopetrosis with neuroaxonal dysplasia (Orphanet:85179), Spastic ataxia (Orphanet:316226), Rare ataxia (Orphanet:102002), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Waardenburg syndrome (Orphanet:3440), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

133 total (30 of 133 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000017	Nocturia
HP:0000338	Hypomimic face
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000486	Strabismus
HP:0000511	Vertical supranuclear gaze palsy
HP:0000571	Hypometric saccades
HP:0000572	Visual loss
HP:0000605	Supranuclear gaze palsy
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000658	Eyelid apraxia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000746	Delusion
HP:0000750	Delayed speech and language development
HP:0000751	Personality changes
HP:0000752	Hyperactivity
HP:0000762	Decreased nerve conduction velocity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia

GWAS associations

31 associations (top):

Study	Trait	p-value
GCST000438_2	Cutaneous nevi	3.000000e-08
GCST000758_25	Triglycerides	4.000000e-08
GCST001034_3	Cutaneous nevi	1.000000e-06
GCST001267_10	Melanoma	2.000000e-06
GCST002216_3	Triglycerides	3.000000e-08
GCST002667_11	Mammographic density (dense area)	3.000000e-08
GCST002669_5	Percent mammographic density	5.000000e-09
GCST003435_15	Body fat percentage	3.000000e-09
GCST003435_29	Body fat percentage	1.000000e-06
GCST003435_37	Body fat percentage	9.000000e-08
GCST003435_9	Body fat percentage	2.000000e-07
GCST003681_5	C-reactive protein levels or triglyceride levels (pleiotropy)	9.000000e-10
GCST004142_13	Melanoma	2.000000e-09
GCST004237_7	Triglyceride levels	3.000000e-12
GCST004238_10	Triglyceride levels	4.000000e-10
GCST004988_670	Breast cancer	1.000000e-13
GCST007504_10	Nevus count	3.000000e-18
GCST007505_8	Nevus count or cutaneous melanoma	2.000000e-28
GCST010002_82	Refractive error	2.000000e-13
GCST010173_28	Triglyceride levels	8.000000e-18
GCST010241_132	Apolipoprotein A1 levels	7.000000e-24
GCST010242_289	HDL cholesterol levels	2.000000e-26
GCST010244_243	Triglyceride levels	2.000000e-26
GCST010303_6	Nevus count or cutaneous melanoma	4.000000e-41
GCST010703_11	Brain morphology (MOSTest)	9.000000e-10
GCST012480_17	C-reactive protein levels	5.000000e-09
GCST012480_5	C-reactive protein levels	8.000000e-08
GCST90000025_709	Appendicular lean mass	1.000000e-11
GCST90002385_582	High light scatter reticulocyte count	1.000000e-09
GCST90002401_277	Platelet distribution width	3.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0000625	nevus
EFO:0004530	triglyceride measurement
EFO:0005941	mammographic density measurement
EFO:0006503	dense area measurement
EFO:0006502	mammographic density percentage
EFO:0007800	body fat percentage
EFO:0004458	C-reactive protein measurement
EFO:0004632	nevus count
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0007984	platelet component distribution width

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
C562568	Cerebellar Hypoplasia (supp.)
C567844	Dystonia-Parkinsonism, Adult-Onset (supp.)
C536071	Hunter Carpenter Macdonald syndrome (supp.)
C538421	Neurodegeneration with brain iron accumulation (NBIA) (supp.)
C536055	Osteopetrosis and infantile neuroaxonal dystrophy (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3213 (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

ChEMBL bioactivities

33 potent at pChembl≥5 of 34 total, top 31 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL4476476
7.52	IC50	30	nM	CHEMBL6223
7.34	IC50	46	nM	CHEMBL89506
7.32	IC50	48	nM	CHEMBL89506
7.31	IC50	49	nM	CHEMBL89506
7.30	IC50	50	nM	CHEMBL89506
7.27	IC50	54	nM	CHEMBL89506
7.26	IC50	55	nM	CHEMBL89506
7.25	IC50	56	nM	VARESPLADIB
7.20	IC50	63	nM	CHEMBL89506
7.17	IC50	67	nM	CHEMBL89506
7.08	IC50	83	nM	CHEMBL89506
7.05	IC50	90	nM	CHEMBL4438490
7.02	IC50	95	nM	CHEMBL269758
6.98	IC50	104	nM	VARESPLADIB
6.88	IC50	131	nM	VARESPLADIB
6.85	IC50	140	nM	BROMOENOL LACTONE
6.80	IC50	160	nM	CHEMBL89506
6.72	IC50	190	nM	CHEMBL6228
6.60	IC50	250	nM	VARESPLADIB
6.48	IC50	330	nM	VARESPLADIB
6.23	IC50	590	nM	VARESPLADIB
6.22	IC50	600	nM	VARESPLADIB
5.91	IC50	1230	nM	CHEMBL4438490
5.89	IC50	1300	nM	CHEMBL4438490
5.86	IC50	1390	nM	CHEMBL4438490
5.85	IC50	1410	nM	CHEMBL4438490
5.82	IC50	1520	nM	CHEMBL4438490
5.74	IC50	1830	nM	CHEMBL4438490
5.73	IC50	1880	nM	CHEMBL4438490
5.46	IC50	3500	nM	CHEMBL4439384

PubChem BioAssay actives

33 with measured affinity, of 359 total; 9 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
(3R,4R)-3-(4-phenylbutyl)-4-propyloxetan-2-one	1602894: Inhibition of human recombinant G6A iPLA2 using arachidonyl-1-14C PAPC and PAPC incubated for 30 mins by HPLC-MS analysis based radioactivity-based group specific mixed micelle assay	ic50	0.0010	uM
(6E)-6-(iodomethylidene)-3-naphthalen-1-yloxan-2-one	158790: Compounds were evaluated for the inhibitory activity against canine myocardial cytosolic calcium dependent phospholipase A2.	ic50	0.0300	uM
1,1,1-trifluoro-3-octylsulfanylpropan-2-one	1614031: Inhibition of human recombinant calcium-independent PLA2 using PAPS as substrate assessed as reduction in 16:0 LPC formation after 30 mins in presence of equal molar mixture of PAPA/PAPC/PAPE/PAPG/PAPS/PLPC by HPLC-MS analysis	ic50	0.0460	uM
2-(1-benzyl-2-ethyl-3-oxamoylindol-4-yl)oxyacetic acid	1614029: Inhibition of human recombinant calcium-independent PLA2 using PAPC as substrate assessed as reduction in free [14C]-AA formation after 30 mins by scintillation counting	ic50	0.0560	uM
N-[[(2S,4R)-1-[2-(2,4-difluorobenzoyl)benzoyl]-4-tritylsulfanylpyrrolidin-2-yl]methyl]-4-[(E)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide	1614035: Inhibition of human recombinant calcium-independent PLA2 using PAPA as substrate assessed as reduction in 16:0 LPC formation after 30 mins by HPLC-MS analysis	ic50	0.0900	uM
(6E)-3-naphthalen-1-yl-6-prop-2-ynylideneoxan-2-one	158790: Compounds were evaluated for the inhibitory activity against canine myocardial cytosolic calcium dependent phospholipase A2.	ic50	0.0950	uM
(6E)-6-(bromomethylidene)-3-naphthalen-1-yloxan-2-one	158790: Compounds were evaluated for the inhibitory activity against canine myocardial cytosolic calcium dependent phospholipase A2.	ic50	0.1400	uM
(6Z)-6-(iodomethylidene)-3-naphthalen-1-yloxan-2-one	158790: Compounds were evaluated for the inhibitory activity against canine myocardial cytosolic calcium dependent phospholipase A2.	ic50	0.1900	uM
(3R,4S)-3-(4-phenylbutyl)-4-propyloxetan-2-one	1602894: Inhibition of human recombinant G6A iPLA2 using arachidonyl-1-14C PAPC and PAPC incubated for 30 mins by HPLC-MS analysis based radioactivity-based group specific mixed micelle assay	ic50	3.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases methylation	2
Aflatoxin B1	decreases methylation, increases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
3’-O-(4-benzoyl)benzoyladenosine 5’-triphosphate	decreases reaction, increases reaction, increases secretion	1
pentanal	decreases expression	1
6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one	decreases activity	1
perfluorooctane sulfonic acid	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects methylation	1
Aspirin	increases expression	1
Benzo(a)pyrene	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
NAD	decreases reaction, increases reaction, increases secretion	1
Sarin	increases expression	1
Smoke	increases expression	1
Valproic Acid	increases methylation	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

47 unique, capped per target: 47 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1011801	Binding	Inhibition of human group 6A iPLA2 at 0.091 mol fraction by mixed micelle-based assay	Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes. — J Med Chem

Cellosaurus cell lines

16 cell lines: 9 induced pluripotent stem cell, 4 cancer cell line, 2 embryonic stem cell, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8HL	RCPFi004-A	Induced pluripotent stem cell	Male
CVCL_A8HM	RCPFi005-A	Induced pluripotent stem cell	Female
CVCL_A8HN	RCPFi006-A	Induced pluripotent stem cell	Male
CVCL_C1UV	NCBSi003-A	Induced pluripotent stem cell	Male
CVCL_C1UW	NCBSi004-A	Induced pluripotent stem cell	Female
CVCL_D0HN	LNDWCHi001-A	Induced pluripotent stem cell	Female
CVCL_D0KC	ONHi001-A	Induced pluripotent stem cell	Male
CVCL_D1TY	Abcam U-87MG PLA2G6 KO	Cancer cell line	Male
CVCL_E2W4	WIBR3_PLA2G6_D331Y_A4_C2	Embryonic stem cell	Female
CVCL_E2W5	WIBR3_PLA2G6_D331Y_A9_A4	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03726996	PHASE4	TERMINATED	Desipramine in Infantile Neuroaxonal Dystrophy (INAD).
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off