PON1
protein-codingparaoxonase 1, the group of Paraoxonases
Gene summary
This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]
- PON
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~26.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
Clinical Genomic Database (CGD)
Manifestation: General
Intervention: Pharmacogenomic
Rationale: Among other associations, variants may be associated with susceptibility to stent thrombosis, possibly related to clopidogrel metabolism, and may thus have pharmacogenomic importance
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PON1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000446.7. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 1 | 4 | |||
| missense | 27 | 4 | 1 | 32 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 31 | 7 | 2 | 40 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000437.3 | 9 | MANE Select | |
| Ensembl | ENSP00000222381.3 | 9 | MANE Select | |
| Ensembl | ENSP00000407359.1 | 4 | Standard | |
| Ensembl | ENSP00000563095.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Clopidogrel Metabolism Pathway
- Clopidogrel Action Pathway
- Phase I biotransformations, non P450
- Metabolism of lipids
- Synthesis of 5-eicosatetraenoic acids
Biological Process
- cholesterol metabolic process
- response to toxic substance
- positive regulation of cholesterol efflux
- dephosphorylation
- lipoxygenase pathway
Molecular Function
- aryldialkylphosphatase activity
- arylesterase activity
- calcium ion binding
- phospholipid binding
- protein homodimerization activity
Cellular Component
- extracellular region
- extracellular space
- high-density lipoprotein particle
- spherical high-density lipoprotein particle
- intracellular membrane-bounded organelle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000222381
- Coding exons
- 9
- Length
- 98686
- Individuals with no LoFs
- 125592
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 156
- Defined
- 125748
- p
- 0.000620
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.725 | 151 | 178 | 0.847 | 0.00000863 | 2309 |
| Missense (PolyPhen) | 48 | 62.636 | 0.76633 | 818 | ||
| Synonymous | 0.259 | 67 | 69.7 | 0.961 | 0.00000363 | 684 |
| Loss of Function | 0.578 | 17 | 19.8 | 0.860 | 0.00000118 | 232 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0019 | 0.0019 | notable |
| Latino/Admixed American | 0.00035 | 0.00035 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00043 | 0.00044 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00042 | 0.00039 | rare |
| South Asian | 0.0018 | 0.0018 | notable |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides. Capable of hydrolyzing a broad spectrum of organophosphate substrates and lactones, and a number of aromatic carboxylic acid esters. Mediates an enzymatic protection of low density lipoproteins against oxidative modification and the consequent series of events leading to atheroma formation. {ECO:0000269|PubMed:10479665, ECO:0000269|PubMed:15772423}.;
- Disease
- DISEASE: Microvascular complications of diabetes 5 (MVCD5) [MIM:612633]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Homozygosity for the Leu-55 allele is strongly associated with the development of retinal disease in diabetic patients.;
Recessive Scores
- pRec
- 0.611
Intolerance Scores
- LoFtool
- 0.787
- RVIS EVS
- 0.75
- RVIS percentile EVS
- 86.65
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.725
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |