PON2

Summary

PON2 (paraoxonase 2, HGNC:9205) is a protein-coding gene on chromosome 7q21.3, encoding Serum paraoxonase/arylesterase 2 (Q15165). Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters.

This gene encodes a member of the paraoxonase gene family, which includes three known members located adjacent to each other on the long arm of chromosome 7. The encoded protein is ubiquitously expressed in human tissues, membrane-bound, and may act as a cellular antioxidant, protecting cells from oxidative stress. Hydrolytic activity against acylhomoserine lactones, important bacterial quorum-sensing mediators, suggests the encoded protein may also play a role in defense responses to pathogenic bacteria. Mutations in this gene may be associated with vascular disease and a number of quantitative phenotypes related to diabetes. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 5445 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Supportive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 15 total
• Phenotypes (HPO): 47
• Druggable target: yes
• MANE Select transcript: NM_000305

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9205
Approved symbol	PON2
Name	paraoxonase 2
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105854
Ensembl biotype	protein_coding
OMIM	602447
Entrez	5445

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 19 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000222572, ENST00000433091, ENST00000446142, ENST00000455123, ENST00000459842, ENST00000460873, ENST00000469716, ENST00000469926, ENST00000471883, ENST00000478801, ENST00000483292, ENST00000490778, ENST00000491069, ENST00000493290, ENST00000493469, ENST00000632034, ENST00000633192, ENST00000633531, ENST00000857126, ENST00000857127, ENST00000857128, ENST00000857129, ENST00000857130, ENST00000857131, ENST00000857132, ENST00000951226, ENST00000951227, ENST00000951228, ENST00000951229

RefSeq mRNA: 2 — MANE Select: NM_000305 NM_000305, NM_001018161

CCDS: CCDS47644, CCDS5640

Canonical transcript exons

ENST00000222572 — 9 exons

Exon	Start	End
ENSE00003502925	95424515	95424585
ENSE00003540693	95406987	95407068
ENSE00003572543	95406119	95406247
ENSE00003629674	95409901	95410101
ENSE00003655649	95416242	95416297
ENSE00003656262	95411653	95411779
ENSE00003678180	95412312	95412477
ENSE00003843144	95434878	95435028
ENSE00003845291	95404862	95405488

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.1709 / max 542.7415, expressed in 1793 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84956	59.0096	1793
84957	0.1613	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.26	gold quality
nucleus accumbens	UBERON:0001882	99.11	gold quality
right adrenal gland cortex	UBERON:0035827	99.08	gold quality
putamen	UBERON:0001874	99.05	gold quality
amygdala	UBERON:0001876	99.05	gold quality
lateral globus pallidus	UBERON:0002476	99.00	gold quality
jejunal mucosa	UBERON:0000399	98.98	gold quality
adrenal tissue	UBERON:0018303	98.98	gold quality
right adrenal gland	UBERON:0001233	98.97	gold quality
ventricular zone	UBERON:0003053	98.96	gold quality
adrenal cortex	UBERON:0001235	98.92	gold quality
left adrenal gland	UBERON:0001234	98.89	gold quality
caudate nucleus	UBERON:0001873	98.88	gold quality
left adrenal gland cortex	UBERON:0035825	98.87	gold quality
corpus callosum	UBERON:0002336	98.75	gold quality
upper lobe of left lung	UBERON:0008952	98.74	gold quality
upper lobe of lung	UBERON:0008948	98.73	gold quality
metanephros cortex	UBERON:0010533	98.64	gold quality
adrenal gland	UBERON:0002369	98.63	gold quality
hypothalamus	UBERON:0001898	98.59	gold quality
endothelial cell	CL:0000115	98.58	gold quality
temporal lobe	UBERON:0001871	98.48	gold quality
right frontal lobe	UBERON:0002810	98.43	gold quality
globus pallidus	UBERON:0001875	98.41	gold quality
Ammon’s horn	UBERON:0001954	98.40	gold quality
right lobe of liver	UBERON:0001114	98.37	gold quality
ventral tegmental area	UBERON:0002691	98.37	gold quality
peripheral nervous system	UBERON:0000010	98.33	gold quality
tibial nerve	UBERON:0001323	98.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.33	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	2236.39
E-MTAB-9154	yes	1825.54
E-MTAB-8495	yes	376.84
E-HCAD-1	yes	74.72
E-HCAD-5	yes	39.34
E-HCAD-25	yes	21.62
E-HCAD-10	yes	18.71
E-GEOD-93593	yes	18.46
E-MTAB-7303	no	1221.31
E-GEOD-110499	no	678.58
E-MTAB-7008	no	177.93
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JDP2, JUN, NFKBIA, PPARG, SREBF2

miRNA regulators (miRDB)

70 targeting PON2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
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-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-373-3P	99.84	70.68	1668

Literature-anchored findings (GeneRIF, showing 40)

• study suggested a gene-gene interaction between the PON1 and PON2 polymorphisms for CAD risk; may have linkage disequilibrium with a tightly linked PON3 locus or significant atherosclerotic alleles of nearby genes (PMID:11676977)
• association between left ventricular hypertrophy and the C825T allele of the G-protein beta3 subunit gene in Arabs. (G PROTEIN BETA3) (PMID:11768721)
• PON2*S and apoE4 alleles have interactive effect on the development of the two most common forms of dementias AD and VD, and further support the hypothesis that cardiovascular factors contribute to the development of AD. (PMID:11803456)
• diabetic microangiopathy is genetically heterogeneous; PON1 Leu/Leu increases the risk for retinopathy and PON2 Ser/Ser increases the risk for microalbuminuria (PMID:11918623)
• REVIEW: The paraoxonase gene family and coronary heart disease (PMID:12151850)
• Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study (PMID:12454802)
• Polymorphisms of paraoxonase 1 and 2 genes, alone or in combination is associated with with bone mineral density (PMID:12955589)
• These results suggested that the PON2 polymorphism might be a risk factor for LOAD independent of ApoE epsilon4 status in Chinese. (PMID:14741412)
• Genotyping for polymorphisms of PON1 Q192R, PON2 A148G, and PON2 S311C finds no association between mother’s PON1 and PON2 genotypes and preterm delivery, but finds infant’s PON1 RR and PON2 CC genotypes are associated with preterm delivery. (PMID:15232408)
• PON2 stimulation may represent a compensatory mechanism against the increase in cellular superoxide anion production and atherogenesis (PMID:15544923)
• PON1, PON2, and PON3 are lactonases with overlapping and distinct substrate specificities (PMID:15772423)
• PON1 55 LM genotype and M allele, PON2 148 GG/AG genotype and G allele are the risk factors for coronary artery disease, and the activity of plasma PON is also markedly reduced in individuals with above genotypes. (PMID:16767666)
• A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. (PMID:16822964)
• the C311S polymorphism was associated with sALS in dominant and additive models. (PMID:16822965)
• Plays a protective role against atherosclerosis in vivo. (PMID:16891303)
• PON2 variants have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes. (PMID:17096118)
• Gene polymorphisms of PON1 55 Met/Leu, PON2 148 Ala/Gly and MnSOD 9 Ala/Val seemed to involve in the morbidity of CHD by influencing the plasma activities of PON and MnSOD. (PMID:17299970)
• Here, we analyzed the ROS-reducing capability of paraoxonase-2 (PON2) in different vascular cells and its involvement in the endoplasmic reticulum stress pathway known as the unfolded protein response. (PMID:17404154)
• genotypes with the C allele of the PON2 gene C311S polymorphism is a risk factor for large vessel disease stroke in a Polish population (PMID:17406108)
• The rates of hydrolysis of estrogen esters by the paraoxonases is PON3 > PON1 > PON2, with the exception of 17beta estradiol, 3-acetate, 17-cyclopentylpropionate which is hydrolyzed at a slightly faster rate by PON2 compared to PON1. (PMID:17412306)
• In Ashkenazi Jewish population, carriage of PON1 R192 allele may confer protection against the development of IBD. (PMID:17436100)
• C311S polymorphism of PON2 has no significant correlation with stroke in Han people of Chinese Hunan area and allele C/S is not an independent risk factor for stroke,neither is G148A. (PMID:17557249)
• PON1/2/3 may have extracellular functions as part of the host response in inflammatory bowel diseases and celiac disease (PMID:17664137)
• These observations demonstrate that the human intestine is preferentially endowed with a marked PON2 expression compared with the rat intestine and this expression shows a developmental and intracellular pattern of distribution. (PMID:17916643)
• Cys(311)Ser variant of PON2 may contribute to albumin excretion rate (PMID:17940058)
• PON2 expression is upregulated in unesterified cholesterol enriched macrophages through activation of the PI(3)K signal pathway (PMID:18020951)
• There was no significant correlation between the C311S and G148A polymorphisms of PON2 and stroke in the Chinese population. (PMID:18063859)
• We demonstrate that PON2 mRNA and protein are decreased in plaques versus plaque-adjacent tissue, mammary arteries, and fetal carotids. Our data indicate that the protective effect of PON2 could fail during atherosclerosis exacerbation. (PMID:18258817)
• The hydrolytic effects of PON1, PON2, and PON3 on the key quorum sensing compound of P.aeruginosa are reported. (PMID:18347034)
• results indicate that PON2-311 polymorphism is an independent risk factor of AMI (PMID:18361900)
• Urokinase plasminogen activator upregulates paraoxonase 2 expression in macrophages via an NADPH oxidase-dependent mechanism. (PMID:18436804)
• Data suggest that independent mechanisms mediate the degradation of paraoxonase-2 mRNA and protein after disturbance of calcium homoeostasis. (PMID:18691157)
• major effect of the paraoxonase-2 polymorphism on coronary artery disease risk in patients (PMID:18759523)
• This study revealed a significant association between Ser311Cys variation in the paraoxonase 2 gene and type 2 diabetes in northern Chinese. (PMID:18776646)
• The anti-atherogenic biological activities were studied in vitro using serum or cell cultures, and also in vivo, using PON 1/2/3 knockout or transgenic mice, as well as humans - healthy volunteers and atherosclerotic patients. (PMID:19082953)
• Data suggest that PON2 attenuates macrophage triglyceride accumulation and foam cell formation via inhibition of microsomal DGAT1 activity, which appears to be sensitive to oxidative state. (PMID:19091699)
• Oxidative stress and proinflammatory agents selectively affect the expression of PONs. (PMID:19401157)
• Urokinase activates macrophage PON2 gene transcription via the PI3K/ROS/MEK/SREBP-2 signalling cascade mediated by the PDGFR-beta. (PMID:19497963)
• a possible role for PON2 C311S polymorphism in the pathogenesis of cardiac ischemic damage (PMID:19540141)
• the allele and genotype frequencies of PON polymorphisms were described in a south-western Korean population (PMID:19654933)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	pon2	ENSDARG00000016856
danio_rerio	pon1	ENSDARG00000032496
danio_rerio	pon3.1	ENSDARG00000040290
danio_rerio	pon3.2	ENSDARG00000097789
mus_musculus	Pon2	ENSMUSG00000032667
rattus_norvegicus	Pon2	ENSRNOG00000009112
caenorhabditis_elegans	mec-6	WBGENE00003170
caenorhabditis_elegans		WBGENE00010775
caenorhabditis_elegans	poml-2	WBGENE00017089
caenorhabditis_elegans		WBGENE00044697
caenorhabditis_elegans	poml-3	WBGENE00077701

Paralogs (2): PON1 (ENSG00000005421), PON3 (ENSG00000105852)

Protein

Protein identifiers

Serum paraoxonase/arylesterase 2 — Q15165 (reviewed: Q15165)

Alternative names: Aromatic esterase 2, Serum aryldialkylphosphatase 2

All UniProt accessions (10): Q15165, A0A0J9YVW3, A0A0J9YXF2, A0A0J9YXM1, A0A0J9YXU7, A0A0J9YYF0, A0A0J9YYF3, A0A0J9YYJ1, A0A2Q2SAK4, G3XAK4

UniProt curated annotations — full annotation on UniProt →

Function. Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters. Has antioxidant activity. Is not associated with high density lipoprotein. Prevents LDL lipid peroxidation, reverses the oxidation of mildly oxidized LDL, and inhibits the ability of MM-LDL to induce monocyte chemotaxis.

Subunit / interactions. Homotrimer.

Subcellular location. Membrane.

Tissue specificity. Widely expressed with highest expression in liver, lung, placenta, testis and heart.

Post-translational modifications. The signal sequence is not cleaved.

Cofactor. Binds 2 calcium ions per subunit.

Polymorphism. Ser-311 is associated with an increased risk of cornary heart disease.

Similarity. Belongs to the paraoxonase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15165-2	2	yes
Q15165-1	1
Q15165-3	3

RefSeq proteins (2): NP_000296, NP_001018171 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002640	Arylesterase	Family
IPR008364	Paraoxonase2	Family
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR051288	Serum_paraoxonase/arylesterase	Family

Pfam: PF01731

Enzyme classification (BRENDA):

• EC 3.1.1.2 — arylesterase (BRENDA: 43 organisms, 245 substrates, 136 inhibitors, 172 Km, 116 kcat entries)
• EC 3.1.1.25 — 1,4-lactonase (BRENDA: 18 organisms, 263 substrates, 56 inhibitors, 186 Km, 153 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PHENYL ACETATE	0.01–16	60
4-NITROPHENYL ACETATE	—	19
ZEARALENONE	0.011–0.083	17
DELTA-VALEROLACTONE	0.4–8.5	12
GAMMA-BUTYROLACTONE	0.16–36.8	9
2-NAPHTHYL ACETATE	0.0079–0.65	8
DIHYDROCOUMARIN	0.013–1.376	7
GAMMA-CAPROLACTONE	0.9–3.8	7
GAMMA-UNDECANOLACTONE	0.013–2.099	7
DELTA-UNDECANOLACTONE	0.057–0.219	6
4-NITROPHENYL BUTYRATE	0.072–1.5	5
4-NITROPHENYL PROPIONATE	0.15–1.6	5
GAMMA-NONALACTONE	0.047–2.943	5
N-(3-OXODECANOYL)-L-HOMOSERINE LACTONE	0.143–1.605	5
N-(3-OXODODECANOYL)-L-HOMOSERINE LACTONE	0.0178–0.456	5

Catalyzed reactions (Rhea), 2 shown:

• a phenyl acetate + H2O = a phenol + acetate + H(+) (RHEA:17309)
• an N-acyl-L-homoserine lactone + H2O = an N-acyl-L-homoserine + H(+) (RHEA:22576)

UniProt features (25 total): binding site 8, sequence conflict 5, glycosylation site 3, sequence variant 3, splice variant 2, chain 1, signal peptide 1, disulfide bond 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15165-F1	96.94	0.98

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 (1): 114 (proton acceptor)

Ligand- & substrate-binding residues (8): 269; 53; 54; 116; 167; 168; 223; 268

Disulfide bonds (1): 42–352

Glycosylation sites (3): 254, 269, 323

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2142688	Synthesis of 5-eicosatetraenoic acids

MSigDB gene sets: 335 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, MODULE_52, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, SWEET_KRAS_ONCOGENIC_SIGNATURE, SMITH_TERT_TARGETS_DN, MISSIAGLIA_REGULATED_BY_METHYLATION_UP, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, BOYAULT_LIVER_CANCER_SUBCLASS_G123_UP, KIM_GERMINAL_CENTER_T_HELPER_UP, TIEN_INTESTINE_PROBIOTICS_24HR_UP, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, JAATINEN_HEMATOPOIETIC_STEM_CELL_UP, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, CUI_TCF21_TARGETS_2_DN, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS

GO Biological Process (2): response to toxic substance (GO:0009636), lactone catabolic process (GO:1901335)

GO Molecular Function (6): arylesterase activity (GO:0004064), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), acyl-L-homoserine-lactone lactonohydrolase activity (GO:0102007), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Arachidonate metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
response to chemical	1
catabolic process	1
lactone metabolic process	1
carboxylic ester hydrolase activity	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
lactonohydrolase activity	1
binding	1
catalytic activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

646 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PON2	DHX40	Q8IX18	765
PON2	ALB	P02768	606
PON2	APOE	P02649	582
PON2	CLU	P10909	565
PON2	PARK7	Q99497	536
PON2	APOC3	P02656	519
PON2	TP53	P04637	480
PON2	CCN2	P29279	439
PON2	CHST10	O43529	432
PON2	CHST12	Q9NRB3	430
PON2	SERPINF1	P36955	428
PON2	ARSK	Q6UWY0	420
PON2	APOF	Q13790	403
PON2	PON3	Q15166	385
PON2	PPP1R9A	Q9ULJ8	369

IntAct

138 interactions, top by confidence:

A	B	Type	Score
ERBB3	PIK3R2	psi-mi:“MI:0914”(association)	0.700
B3GNT3	PGRMC1	psi-mi:“MI:0914”(association)	0.670
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
ITGA6	ITGB1	psi-mi:“MI:0914”(association)	0.560
UST	GOLIM4	psi-mi:“MI:0914”(association)	0.530
SLC39A11	GAPDHS	psi-mi:“MI:0914”(association)	0.530
POGLUT1	CLGN	psi-mi:“MI:0914”(association)	0.530
CHST10	B4GAT1	psi-mi:“MI:0914”(association)	0.530
LRIG1	LRIG2	psi-mi:“MI:0914”(association)	0.530
DNASE2B	ARSA	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
PON2	NPC1	psi-mi:“MI:0914”(association)	0.530
HYAL2	PON2	psi-mi:“MI:0915”(physical association)	0.500
env	PSMD11	psi-mi:“MI:0914”(association)	0.460
env	APP	psi-mi:“MI:0914”(association)	0.460
HTR2A	PON2	psi-mi:“MI:0915”(physical association)	0.370
GRB2	PON2	psi-mi:“MI:0915”(physical association)	0.370
Nup98	POM121C	psi-mi:“MI:0914”(association)	0.350
Kcnk1	TRAPPC13	psi-mi:“MI:0914”(association)	0.350
ATP6AP2	TMUB1	psi-mi:“MI:0914”(association)	0.350
Atp2a2	ESYT2	psi-mi:“MI:0914”(association)	0.350
STRN3	STK24	psi-mi:“MI:0914”(association)	0.350
MAGEA10	XPO1	psi-mi:“MI:0914”(association)	0.350
GPATCH8	FDX1	psi-mi:“MI:0914”(association)	0.350
Ktn1	ESYT2	psi-mi:“MI:0914”(association)	0.350
Tubg1	ZC3H18	psi-mi:“MI:0914”(association)	0.350
PCNT	IMP4	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (347): PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), PON2 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), SLC39A11 (Affinity Capture-MS), CACNA2D2 (Affinity Capture-MS), INSR (Affinity Capture-MS), SIL1 (Affinity Capture-MS), LRP11 (Affinity Capture-MS), NETO2 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QP51, A4IG53, B5X3B2, F1N2K1, F4ZGF2, O95497, P27169, P27170, P52430, P54832, P55159, P70665, P82450, P98192, Q08C93, Q15165, Q15166, Q1LWG4, Q2TAA5, Q3T0E5, Q3TZM9, Q4V3D9, Q58CQ9, Q58DS7, Q5I047, Q5R748, Q5R7Z6, Q5RFU0, Q5ZIF1, Q5ZK82, Q62086, Q62087, Q68FP2, Q6AXM8, Q6P9A2, Q7TP48, Q803F5, Q8K1B9, Q90678, Q90952

Diamond homologs: P27169, P27170, P52430, P54832, P55159, Q15165, Q15166, Q58DS7, Q62086, Q62087, Q68FP2, Q6AXM8, Q90952, Q91090, Q9BGN0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SREBF2	“up-regulates quantity by expression”	PON2	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 199 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratan sulfate/keratin metabolism	6	22.6×	8e-05
Keratan sulfate biosynthesis	7	20.2×	3e-05
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	6	17.9×	2e-04
Sialic acid metabolism	5	12.4×	4e-03
Glycosphingolipid metabolism	5	11.4×	5e-03
Synthesis of substrates in N-glycan biosythesis	5	11.1×	5e-03
Glycosaminoglycan metabolism	6	10.0×	2e-03
O-linked glycosylation	9	9.9×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
keratan sulfate proteoglycan biosynthetic process	5	29.3×	3e-04
positive regulation of T cell mediated cytotoxicity	5	15.1×	4e-03
glycoprotein biosynthetic process	6	12.0×	3e-03
protein O-linked glycosylation	8	10.6×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1738 predictions. Top by Δscore:

Variant	Effect	Δscore
7:95409899:A:AC	donor_gain	1.0000
7:95409900:C:CC	donor_gain	1.0000
7:95409903:A:AC	donor_gain	1.0000
7:95409903:AT:A	donor_gain	1.0000
7:95409903:ATCAT:A	donor_gain	1.0000
7:95409904:T:C	donor_gain	1.0000
7:95410098:CACA:C	acceptor_gain	1.0000
7:95410100:CA:C	acceptor_gain	1.0000
7:95410102:C:CC	acceptor_gain	1.0000
7:95411648:AGTAC:A	donor_loss	1.0000
7:95411649:GTAC:G	donor_loss	1.0000
7:95411650:TACC:T	donor_loss	1.0000
7:95411651:A:AT	donor_loss	1.0000
7:95411652:C:CG	donor_loss	1.0000
7:95411753:T:C	acceptor_gain	1.0000
7:95411753:T:TC	acceptor_gain	1.0000
7:95411777:CAT:C	acceptor_gain	1.0000
7:95411780:C:CC	acceptor_gain	1.0000
7:95434874:CTAC:C	donor_loss	1.0000
7:95434876:A:AC	donor_gain	1.0000
7:95434877:C:CC	donor_gain	1.0000
7:95434877:C:CG	donor_loss	1.0000
7:95410097:TCACA:T	acceptor_gain	0.9900
7:95410098:CACAC:C	acceptor_gain	0.9900
7:95410099:ACA:A	acceptor_gain	0.9900
7:95410100:CAC:C	acceptor_gain	0.9900
7:95410101:ACTGA:A	acceptor_loss	0.9900
7:95410102:C:CG	acceptor_loss	0.9900
7:95411776:TCAT:T	acceptor_gain	0.9900
7:95411777:CATC:C	acceptor_gain	0.9900

AlphaMissense

2320 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:95416245:A:C	S66R	0.995
7:95416245:A:T	S66R	0.995
7:95416247:T:G	S66R	0.995
7:95411758:A:T	V130D	0.993
7:95411764:A:G	L128P	0.992
7:95405405:A:C	S330R	0.989
7:95405405:A:T	S330R	0.989
7:95405407:T:G	S330R	0.989
7:95410060:G:T	A179D	0.988
7:95410066:A:G	F177S	0.983
7:95411692:A:G	L152P	0.983
7:95411719:A:G	F143S	0.983
7:95416255:G:T	A63D	0.982
7:95405376:A:G	L340P	0.981
7:95410061:C:G	A179P	0.981
7:95410065:G:C	F177L	0.981
7:95410065:G:T	F177L	0.981
7:95410067:A:G	F177L	0.981
7:95405367:C:T	G343D	0.980
7:95412425:A:T	I85K	0.980
7:95409985:A:T	V204D	0.979
7:95434921:C:G	G11R	0.979
7:95434921:C:T	G11R	0.979
7:95405397:G:T	A333D	0.978
7:95411751:G:C	N132K	0.978
7:95411751:G:T	N132K	0.978
7:95410064:A:C	Y178D	0.977
7:95412328:G:C	S117R	0.977
7:95412328:G:T	S117R	0.977
7:95412330:T:G	S117R	0.977

dbSNP variants (sampled 300 via entrez): RS1000112785 (7:95409987 A>G,T), RS1000140145 (7:95428227 T>A), RS1000188253 (7:95415924 C>T), RS1000200100 (7:95421293 G>A), RS1000204044 (7:95411021 A>C), RS1000425223 (7:95408722 T>A), RS1000561785 (7:95413763 C>G), RS1000561841 (7:95406536 A>G,T), RS1000592481 (7:95421443 C>T), RS1000659194 (7:95423237 G>A), RS1000720553 (7:95427866 T>C), RS1000751870 (7:95427539 G>A), RS1000803979 (7:95422537 T>C), RS1000859028 (7:95414480 C>T), RS1001055229 (7:95433853 A>C)

Disease associations

OMIM: gene MIM:602447 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

Mondo (1): amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (0):

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign
HP:0003693	Distal amyotrophy
HP:0004326	Cachexia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003026_2	Yu-Zhi constitution type in type 2 diabetes	5.000000e-06
GCST010241_276	Apolipoprotein A1 levels	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007638	Yu-Zhi constitution type
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295823 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2299267	Efficacy	3	antidepressants	Major Depressive Disorder

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2299267	PON2	3	0.00	1	antidepressants

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Paraoxonase (PON) family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, decreases expression, decreases methylation	5
sodium arsenite	decreases expression, increases abundance, increases expression	3
Chlorpyrifos	affects expression, affects response to substance, decreases expression, increases activity, increases expression (+1 more)	3
Hydrogen Peroxide	affects expression, increases expression, decreases response to substance	3
Tretinoin	affects cotreatment, increases expression, decreases expression	3
Cyclosporine	decreases expression	3
(+)-JQ1 compound	decreases expression	2
Arsenic	affects response to substance, increases abundance, increases expression	2
Calcium	decreases activity, decreases reaction, affects abundance	2
Cholesterol, HDL	affects abundance	2
Cholesterol, LDL	affects abundance	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
thyme oil	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	decreases activity, decreases reaction, increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid	decreases reaction, increases expression	1
cobaltous chloride	decreases expression	1
phenylacetic acid	increases hydrolysis, decreases hydrolysis	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
5-hydroxyeicosatetraenoic acid lactone	affects metabolic processing	1
iron(II)-ascorbic acid complex	decreases reaction, increases expression	1
Am 580	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
N-(3-oxododecanoyl)homoserine lactone	increases response to substance	1
6-formylindolo(3,2-b)carbazole	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4187635	Binding	Inhibition of PON2 (unknown origin) expressed in baculovirus system using CMNA substrate by fluorescence based assay	Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2BJ	Abcam HeLa PON2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS