PON3

Summary

PON3 (paraoxonase 3, HGNC:9206) is a protein-coding gene on chromosome 7q21.3, encoding Serum paraoxonase/lactonase 3 (Q15166). Has low activity towards the organophosphate paraxon and aromatic carboxylic acid esters.

This gene is a member of the paraoxonase family and lies in a cluster on chromosome 7 with the other two family members. The encoded protein is secreted into the bloodstream and associates with high-density lipoprotein (HDL). The protein also rapidly hydrolyzes lactones and can inhibit the oxidation of low-density lipoprotein (LDL), a function that is believed to slow the initiation and progression of atherosclerosis. Alternatively spliced variants which encode different protein isoforms have been described; however, only one has been fully characterized.

Source: NCBI Gene 5446 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Supportive, GenCC)
• Clinical variants (ClinVar): 80 total
• Phenotypes (HPO): 47
• Druggable target: yes
• MANE Select transcript: NM_000940

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9206
Approved symbol	PON3
Name	paraoxonase 3
Location	7q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000105852
Ensembl biotype	protein_coding
OMIM	602720
Entrez	5446

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 20 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000265627, ENST00000418617, ENST00000427422, ENST00000442770, ENST00000451904, ENST00000456855, ENST00000460248, ENST00000475439, ENST00000482624, ENST00000492800, ENST00000902748, ENST00000902749, ENST00000902750, ENST00000902751, ENST00000902752, ENST00000902753, ENST00000902754, ENST00000902755, ENST00000902756, ENST00000902757, ENST00000902758, ENST00000902759, ENST00000902760, ENST00000902761, ENST00000902762, ENST00000902763, ENST00000902764

RefSeq mRNA: 1 — MANE Select: NM_000940 NM_000940

CCDS: CCDS5639

Canonical transcript exons

ENST00000265627 — 9 exons

Exon	Start	End
ENSE00003464577	95362362	95362490
ENSE00003494582	95367362	95367488
ENSE00003533524	95359872	95360131
ENSE00003545144	95372173	95372338
ENSE00003601863	95394644	95394714
ENSE00003613102	95362760	95362841
ENSE00003671984	95390154	95390209
ENSE00003693483	95363863	95364063
ENSE00003849691	95396277	95396375

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 98.78.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.8536 / max 432.2175, expressed in 171 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84949	1.7406	158
84950	0.0764	23
84951	0.0366	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.78	gold quality
liver	UBERON:0002107	98.61	gold quality
parotid gland	UBERON:0001831	92.20	gold quality
pituitary gland	UBERON:0000007	90.99	gold quality
left ovary	UBERON:0002119	90.42	gold quality
adenohypophysis	UBERON:0002196	90.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.97	gold quality
palpebral conjunctiva	UBERON:0001812	87.96	gold quality
right ovary	UBERON:0002118	87.65	gold quality
islet of Langerhans	UBERON:0000006	87.41	gold quality
upper leg skin	UBERON:0004262	86.61	gold quality
ovary	UBERON:0000992	86.56	gold quality
lower lobe of lung	UBERON:0008949	84.43	gold quality
jejunal mucosa	UBERON:0000399	84.37	gold quality
right lung	UBERON:0002167	83.79	gold quality
body of pancreas	UBERON:0001150	83.17	gold quality
pancreas	UBERON:0001264	82.72	gold quality
upper lobe of lung	UBERON:0008948	82.36	gold quality
upper lobe of left lung	UBERON:0008952	82.32	gold quality
lung	UBERON:0002048	82.27	gold quality
left testis	UBERON:0004533	81.64	gold quality
right testis	UBERON:0004534	81.64	gold quality
testis	UBERON:0000473	81.54	gold quality
skin of abdomen	UBERON:0001416	80.56	gold quality
skin of leg	UBERON:0001511	80.17	gold quality
zone of skin	UBERON:0000014	80.15	gold quality
mammalian vulva	UBERON:0000997	80.10	gold quality
oocyte	CL:0000023	79.83	gold quality
duodenum	UBERON:0002114	79.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.60
E-MTAB-5061	yes	8.65
E-GEOD-81547	yes	4.58
E-HCAD-31	yes	4.32
E-GEOD-83139	no	3.29

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting PON3, 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-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-3668	98.52	68.76	951
HSA-MIR-217-3P	95.67	68.42	1000

Literature-anchored findings (GeneRIF, showing 40)

• Decreased coronary heart disease risk associated with polymorphisms of paraoxonase 1. (PMID:12151850)
• insights into the evolutionary relationships between different family members (PMID:14695884)
• Organophosphates are hydrolyzed almost exclusively by PON1, lovastatin and spironolactone are hydrolyzed only by PON3. All three proteins hydrolyze and thereby inactivate N-acyl-homoserine lactones, which are quorum-sensing signals of pathogenic bacteria. (PMID:15772423)
• The refolded recombinant PON3 exhibited similar antioxidant activity to that of PON3 purified from the soluble fraction of cell lysate and could effectively protect LDL from Cu2+ induced oxidation. (PMID:16139510)
• A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. (PMID:16822964)
• Elevated human paraoxanase 3 protein expression significantly decreases atherosclerotic lesion formation and adiposity in male transgenic mice. (PMID:17379834)
• The rates of hydrolysis of estrogen esters by the paraoxonases is PON3 > PON1 > PON2; diesters are better substrates for the PONs and are very efficiently hydrolyzed, particularly by PON3. (PMID:17412306)
• PON1/2/3 may have extracellular functions as part of the host response in inflammatory bowel diseases and celiac disease (PMID:17664137)
• Two of seven SNPs in PON1 and PON3 were associated with SALS in the Irish population (PMID:17702780)
• Genetic variation in the PON3 gene is associated with serum PON1 activity. (PMID:17900266)
• The hydrolytic effects of PON1, PON2, and PON3 on the key quorum sensing compound of P.aeruginosa are reported. (PMID:18347034)
• 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)
• Report protective effects of transgene expressed human PON3 against CCl4-induced subacute liver injury in mice. (PMID:19345057)
• Oxidative stress and proinflammatory agents selectively affect the expression of PONs. (PMID:19401157)
• The directed evolution and characterization of recombinant variants of serum paraoxonase PON3, is described. (PMID:19492856)
• Paraoxonase-3, a putative circulating antioxidant, is systemically up-regulated in late gestation in the fetal rat, sheep, and human (PMID:20463093)
• We now report that in genomic DNA from individuals with familial and sporadic amyotrophic lateral sclerosis, we have identified at least 7 gene mutations that are predicted to alter PON1, PON2, and PON3 function. (PMID:20582942)
• These functional effects of PON1, PON2, PON3 variation should be considered in protecting vulnerable subpopulations from organophosphate pesticides and other inducers of oxidative stress. (PMID:20839225)
• paraoxonase components PON1, PON2, and PON3 are regulated by diverse nutritional molecules and pharmacological agents and pathophysiological events, such as oxidative stress and inflammation [review] (PMID:20934178)
• Our results suggest that low serum paraoxonase activity is a risk factor for Alzheimer disease. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic. (PMID:20980077)
• in hemodialysis patients, frequency distribution of PON ratio showed 3 PON phenotypes: 74% oshowed PON1, 21% PON2, and 5% PON3. Compared to hemodialysis patients with PON1, patients with PON2 or 3 showed higher conversion rates for 4-nitrophenylacetate (PMID:21118365)
• Serum PON3 concentrations showed a moderate influence (about 10% variation) by PON3 promoter polymorphisms. (PMID:21335322)
• investigation of whether gene silencing of Pon3 causes oxidative stress in cell line: Data suggest that PON3 knockdown reduces cell proliferation and total antioxidant capacity at ambient oxygen levels. (PMID:21952037)
• This study reports for the first time an important increase in serum PON3 concentrations in HIV-infected patients that is associated with their oxidative status and their treatment with NNRTI. (PMID:22003209)
• Increased serum paraoxonase-3 concentration is associated with insulin sensitivity in peripheral artery disease and with inflammation in coronary artery disease. (PMID:22153698)
• PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death. (PMID:22441669)
• PON2 and PON3 (i) are associated with mitochondria and mitochondria-associated membranes, (ii) modulate mitochondria-dependent superoxide production, and (iii) prevent apoptosis. (PMID:25038992)
• PON3 in HDL may be an important protein in preventing atherosclerosis. (PMID:25723336)
• Data suggest cigarette smoke leads to inhibition of hydrolytic activity of paraoxonase isoenzymes (PON1, PON2, PON3) by modification of thiol groups, by interactions with free radicals/heavy metals, or by decreasing HDL level in blood. [REVIEW] (PMID:25953737)
• Interaction of PON-3 and PON-1 and HDL are associated with the presence and severity of coronary artery disease in type 2 diabetes mellitus patients. (PMID:25964115)
• PON3 SNP rs13226149 was associated with intracerebral hemorrhage in log-additive and dominant models. The A allele of rs13226149 contributed to the decreased risk of ICH. SNP rs1053275 was not associated with ICH. (PMID:26227792)
• Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumor (PMID:26929985)
• Low PON3 expression is associated with hepatocellular carcinoma progression. (PMID:27553024)
• Data show that the mRNA levels of both paraoxonases PON2 and PON3 were significantly upregulated whereas PON1’s mRNA was absent in transgenic mouse hearts. (PMID:27578362)
• PON3 suppressed cell proliferation in vivo and in vitro, which was attributed to its cell-cycle arrest effect. (PMID:27661119)
• Studies indicate that three paraoxonases PON1, PON2, and PON3 genes are clustered on chromosome 7, and that PONs possess numerous atheroprotective properties. (PMID:27771368)
• This study showed that the PI3K/Akt pathway is up-regulated by the expression of PON3 in oral squamous cell carcinoma by AP-1. (PMID:27923688)
• Data suggest that paraoxonases (PON1, PON2, PON3) play roles in innate immunity, inflammatory response, and protection against oxidative stress; these factors are associated with the body’s response to infectious diseases; low serum PON1 activities are associated with poor survival in patients with severe sepsis. [REVIEW] (PMID:28433610)
• No significant differences were observed between PON2 and PON3 gene expression in psoriatic lesional and non lesional skin compared with healthy controls (PMID:28509526)
• Our study showed that although lipoic acid up-regulates PON3 but down-regulates PON1 mRNA expression, it increases both PON1 and PON3 protein levels and arylesterase activity in HepG2 cells. We can report that lipoic acid may be useful for preventing atherosclerosis at therapeutic doses. (PMID:28653653)

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	Pon3	ENSMUSG00000029759
rattus_norvegicus	Pon3	ENSRNOG00000009096
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), PON2 (ENSG00000105854)

Protein

Protein identifiers

Serum paraoxonase/lactonase 3 — Q15166 (reviewed: Q15166)

All UniProt accessions (5): Q15166, C9JZ99, F2Z2L3, F8WBV4, F8WD41

UniProt curated annotations — full annotation on UniProt →

Function. Has low activity towards the organophosphate paraxon and aromatic carboxylic acid esters. Rapidly hydrolyzes lactones such as statin prodrugs (e.g. lovastatin). Hydrolyzes aromatic lactones and 5- or 6-member ring lactones with aliphatic substituents but not simple lactones or those with polar substituents.

Subunit / interactions. Homodimer.

Subcellular location. Secreted. Extracellular space.

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

Cofactor. Binds 2 calcium ions per subunit.

Similarity. Belongs to the paraoxonase family.

RefSeq proteins (1): NP_000931* (*=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)
• EC 3.1.8.1 — aryldialkylphosphatase (BRENDA: 49 organisms, 600 substrates, 192 inhibitors, 422 Km, 434 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PARAOXON	0.005–24.25	109
PHENYL ACETATE	0.01–16	60
MALATHION	0.001–1.9	27
S-(2-[DI(PROPAN-2-YL)AMINO]ETHYL) O,O-DIETHYL PH	0.22–20	25
DIETHYL-PARAOXON	0.0017–1.586	23
S-(2-[DI(PROPAN-2-YL)AMINO]ETHYL) O,O-DIMETHYL P	0.3–7	20
4-NITROPHENYL ACETATE	—	19
ZEARALENONE	0.011–0.083	17
4-ACETYLPHENYL (S)-2-METHYLPROPYL METHYLPHOSPHON	0.03–4.5	15
4-ACETYLPHENYL (R)-2-METHYLPROPYL METHYLPHOSPHON	0.15–4	14
(S)-[2-[DI(PROPAN-2-YL)AMINO]ETHYL] O,O-DIETHYL	0.35–3.2	13
DELTA-VALEROLACTONE	0.4–8.5	12
METHYL PARAOXON	0.05–2.79	12
GAMMA-BUTYROLACTONE	0.16–36.8	9
2-NAPHTHYL ACETATE	0.0079–0.65	8

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 (24 total): binding site 8, sequence conflict 6, glycosylation site 3, sequence variant 2, chain 1, signal peptide 1, modified residue 1, disulfide bond 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15166-F1	96.36	0.95

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

Post-translational modifications (1): 165

Disulfide bonds (1): 42–352

Glycosylation sites (3): 29, 269, 323

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2142688	Synthesis of 5-eicosatetraenoic acids
R-HSA-9754706	Atorvastatin ADME

MSigDB gene sets: 259 (showing top): GNF2_GSTM1, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GNF2_HPN, GOBP_REGULATION_OF_SUPEROXIDE_ANION_GENERATION, GOBP_SUPEROXIDE_METABOLIC_PROCESS, RIZKI_TUMOR_INVASIVENESS_3D_DN, MARTINEZ_RB1_TARGETS_UP, MODULE_195, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GNF2_LCAT, HSIAO_LIVER_SPECIFIC_GENES, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, GATA1_04

GO Biological Process (7): renal sodium ion transport (GO:0003096), response to toxic substance (GO:0009636), negative regulation of superoxide anion generation (GO:0032929), carboxylic acid catabolic process (GO:0046395), establishment of localization in cell (GO:0051649), lactone catabolic process (GO:1901335), regulation of cellular response to drug (GO:2001038)

GO Molecular Function (6): aryldialkylphosphatase activity (GO:0004063), arylesterase activity (GO:0004064), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), acyl-L-homoserine-lactone lactonohydrolase activity (GO:0102007), hydrolase activity (GO:0016787)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum membrane (GO:0005789), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Arachidonate metabolism	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
renal system process	1
sodium ion transport	1
response to chemical	1
regulation of superoxide anion generation	1
superoxide anion generation	1
negative regulation of reactive oxygen species metabolic process	1
carboxylic acid metabolic process	1
small molecule catabolic process	1
establishment of localization	1
cellular localization	1
catabolic process	1
lactone metabolic process	1
regulation of cellular process	1
cellular response to xenobiotic stimulus	1
regulation of response to drug	1
phosphoric triester hydrolase activity	1
carboxylic ester hydrolase activity	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
lactonohydrolase activity	1
catalytic activity	1
cellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
extracellular vesicle	1

Protein interactions and networks

STRING

384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PON3	CLU	P10909	731
PON3	CCL2	P13500	598
PON3	DHX40	Q8IX18	589
PON3	APOF	Q13790	575
PON3	APOL1	O14791	574
PON3	PCYOX1	Q9UHG3	561
PON3	APOA4	P06727	539
PON3	PLTP	P55058	513
PON3	APOE	P02649	504
PON3	APOM	O95445	496
PON3	APOA1	P02647	474
PON3	CETP	P11597	466
PON3	ALB	P02768	447
PON3	TTR	P02766	442
PON3	APOD	P05090	436

IntAct

12 interactions, top by confidence:

A	B	Type	Score
PON1	PON3	psi-mi:“MI:0914”(association)	0.530
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
PON3		psi-mi:“MI:0915”(physical association)	0.370
PON1	NDUFB6	psi-mi:“MI:0914”(association)	0.350
NFYC	NFKB1	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
ASIC4	TMEM131L	psi-mi:“MI:0914”(association)	0.350
HS2ST1	DENND11	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (6): PON3 (Affinity Capture-MS), PON3 (Affinity Capture-MS), PON3 (Affinity Capture-MS), PON3 (Affinity Capture-MS), PON3 (Affinity Capture-MS), PON3 (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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	6
Benign	19

Top pathogenic / likely-pathogenic (0)

SpliceAI

1613 predictions. Top by Δscore:

Variant	Effect	Δscore
7:95362355:AACTT:A	donor_loss	1.0000
7:95362356:ACTTA:A	donor_loss	1.0000
7:95362357:CTT:C	donor_loss	1.0000
7:95362358:TTA:T	donor_loss	1.0000
7:95362359:TA:T	donor_loss	1.0000
7:95362360:A:AC	donor_gain	1.0000
7:95362361:C:CC	donor_gain	1.0000
7:95362361:CTT:C	donor_gain	1.0000
7:95362488:CACCT:C	acceptor_gain	1.0000
7:95362490:CCT:C	acceptor_gain	1.0000
7:95362492:T:C	acceptor_gain	1.0000
7:95362492:T:TC	acceptor_gain	1.0000
7:95363861:A:AC	donor_gain	1.0000
7:95363862:C:CC	donor_gain	1.0000
7:95363862:CTT:C	donor_gain	1.0000
7:95363864:T:TA	donor_gain	1.0000
7:95363927:C:A	donor_gain	1.0000
7:95364059:TCACA:T	acceptor_gain	1.0000
7:95364060:CACA:C	acceptor_gain	1.0000
7:95364060:CACAC:C	acceptor_gain	1.0000
7:95364062:CA:C	acceptor_gain	1.0000
7:95364064:C:CC	acceptor_gain	1.0000
7:95372170:TACCT:T	donor_loss	1.0000
7:95372171:ACC:A	donor_loss	1.0000
7:95372338:CCTTT:C	acceptor_gain	1.0000
7:95390153:CA:C	donor_gain	1.0000
7:95360131:CCT:C	acceptor_loss	0.9900
7:95360132:C:CC	acceptor_gain	0.9900
7:95360132:C:T	acceptor_loss	0.9900
7:95360133:T:A	acceptor_loss	0.9900

AlphaMissense

2339 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:95363888:C:A	G224W	0.975
7:95390164:A:G	F64S	0.974
7:95367473:A:G	L128P	0.971
7:95372197:C:A	G115W	0.970
7:95364022:G:T	A179D	0.968
7:95367467:A:T	V130D	0.962
7:95360010:C:T	G343D	0.961
7:95390167:G:T	A63D	0.961
7:95364023:C:G	A179P	0.957
7:95362423:C:T	G282E	0.955
7:95364028:A:G	F177S	0.954
7:95363887:C:A	G224V	0.952
7:95362465:T:A	D268V	0.949
7:95363887:C:T	G224E	0.948
7:95362464:A:C	D268E	0.947
7:95362464:A:T	D268E	0.947
7:95360000:A:C	F346L	0.946
7:95360000:A:T	F346L	0.946
7:95360002:A:G	F346L	0.946
7:95367428:A:G	F143S	0.946
7:95360016:A:G	L341P	0.945
7:95364027:G:C	F177L	0.945
7:95364027:G:T	F177L	0.945
7:95364029:A:G	F177L	0.945
7:95390158:G:T	S66Y	0.945
7:95362424:C:G	G282R	0.944
7:95362424:C:T	G282R	0.944
7:95367460:A:C	N132K	0.943
7:95367460:A:T	N132K	0.943
7:95390158:G:A	S66F	0.943

dbSNP variants (sampled 300 via entrez): RS1000308314 (7:95377881 A>G), RS1000361627 (7:95377645 T>C,G), RS1000452747 (7:95388405 GT>G), RS1000471986 (7:95384677 G>A), RS1000535084 (7:95365153 G>T), RS1000536587 (7:95371039 T>A), RS1000595628 (7:95365732 G>A), RS1000601761 (7:95372447 C>A,T), RS1000692904 (7:95376823 T>C), RS1000755620 (7:95383871 A>G), RS1000934322 (7:95389208 C>T), RS1000948382 (7:95365515 C>T), RS1000949809 (7:95370552 G>C), RS1000966821 (7:95388765 G>A), RS1001056749 (7:95387132 C>G,T)

Disease associations

OMIM: gene MIM:602720 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

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

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

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

0 associations (top):

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): CHEMBL4295824 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Paraoxonase (PON) family

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, decreases expression, increases abundance, affects methylation	3
Cyclosporine	decreases expression, increases expression	3
phenylacetic acid	increases hydrolysis	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	affects cotreatment, decreases expression, increases abundance, affects methylation	2
Coumarins	increases hydrolysis	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
ethyl-p-hydroxybenzoate	increases expression	1
arsenite	increases methylation	1
cobaltous chloride	decreases expression	1
ceric oxide	affects cotreatment, decreases expression, increases abundance	1
5-hydroxyeicosatetraenoic acid lactone	affects metabolic processing	1
K 7174	decreases expression	1
phenyl acetate	affects hydrolysis	1
Benztropine	affects cotreatment, decreases expression	1
Carbon Tetrachloride	decreases abundance, decreases reaction, increases abundance, increases secretion, decreases response to substance	1
Clozapine	increases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Docosahexaenoic Acids	affects metabolic processing	1
Glutathione	decreases abundance, decreases reaction	1
Lovastatin	increases hydrolysis	1
Malondialdehyde	decreases reaction, increases abundance	1
Oxygen	increases expression	1
Ozone	affects methylation, increases abundance	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
CHEMBL4187636	Binding	Inhibition of PON3 (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

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