PON1

Chr 7

paraoxonase 1

Also known as: ESA, MVCD5, PON

NCBI Gene: 5444ENSG00000005421UniProt: P27169

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]

Primary Disease Associations & Inheritance

UniProtMicrovascular complications of diabetes 5
86
ClinVar variants
17
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— PON1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
17 Pathogenic / Likely Pathogenic· 28 VUS of 86 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.29LOEUF
pLI 0.000
Z-score 0.58
OE 0.86 (0.59–1.29)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.72Z-score
OE missense 0.85 (0.74–0.97)
151 obs / 178.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.86 (0.59–1.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.74–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 17 / 19.8Missense obs/exp: 151 / 178.2Syn Z: 0.26

ClinVar Variant Classifications

86 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
VUS28
Likely Benign8
Benign33
17
Pathogenic
28
VUS
8
Likely Benign
33
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
0
0
0
VUS
0
26
2
0
28
Likely Benign
0
4
1
3
8
Benign
0
3
29
1
33
Total03349486

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PON1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
PARAOXONASE 1; PON1
MIM #168820 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Metals and Paraoxonases.
Costa LG et al.·Adv Neurobiol
2017Review
Paraoxonases and infectious diseases.
Camps J et al.·Clin Biochem
2017Review
Pleiotropic functions and clinical importance of circulating HDL-PON1 complex.
Mahrooz A·Adv Clin Chem
2024Review
Paraoxonase 1 and HDL maturation.
Gugliucci A et al.·Clin Chim Acta
2015Review
Paraoxonase genes and disease.
Hegele RA·Ann Med
1999Review
Paraoxonase 1 in neurological disorders.
Menini T et al.·Redox Rep
2014Review
Liver-specific paraoxonase-1 alleviates regulatory T cell-driven immunosuppression via metabolic reprogramming in hepatocellular carcinoma.
Lu Z et al.·Nat Commun
2025
Paraoxonase and atherosclerosis.
Durrington PN et al.·Arterioscler Thromb Vasc Biol
2001Review
Why Should Psychiatrists and Neuroscientists Worry about Paraoxonase 1?
Moreira EG et al.·Curr Neuropharmacol
2019Review
Effects of curcumin on HDL functionality.
Ganjali S et al.·Pharmacol Res
2017Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Noncatalytic Functions Are Required for MPO and PON1 in Modulating the Involvement of Monocytes and Endothelial Cells in Atherosclerosis.
Li Y et al.·Biochem Res Int
2026🔓 Open Access
Research on the therapeutic effects of recombinant protein PON1Q/R192 intervention on mice poisoned by different categories of organophosphorus compounds.
Zhou S et al.·Toxicol Lett
2026
Oxidative Stress-Related HDL Dysfunction in Hemodialysis: The Clinical Utility of MPO/PON1 and MPO/HDL-C Ratios in Cardiovascular Risk Assessment.
Delibaş EAÖ et al.·Ther Apher Dial
2026
Multi-omics dissection of RAD21-PON1 axis reveals metabolic-immune crosstalk and prognostic significance in hepatocellular carcinoma.
Liu Z et al.·Mamm Genome
2025
Ex vivo expanded human regulatory T cells promote cholesterol efflux and PON1 expression in oxLDL-exposed macrophages via gap junction-mediated cAMP transfer.
Albany CJ et al.·Front Immunol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
HealthyNormal WeightOverweight

Olive Oil Polyphenols and Cardiovascular Health Biomarkers

ACTIVE NOT RECRUITING
NCT04149288Phase NAUniversity of California, DavisStarted 2021-10-06
High-polyphenol olive oilLow-polyphenol olive oil

External Resources

Links to major genomics databases and tools