PNPLA3

Chr 22

patatin like domain 3, 1-acylglycerol-3-phosphate O-acyltransferase

Also known as: ADPN, C22orf20, iPLA(2)epsilon

NCBI Gene: 80339ENSG00000100344UniProt: Q9NST1

The protein encoded by this gene is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes. The encoded protein, which appears to be membrane bound, may be involved in the balance of energy usage/storage in adipocytes. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

UniProtNon-alcoholic fatty liver disease 1
216
ClinVar variants
51
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical Summary— PNPLA3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 113 VUS of 216 total submissions
💊
Clinical Trials
12 active or recruiting trials — 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.
1.10LOEUF
pLI 0.000
Z-score 1.21
OE 0.71 (0.47–1.10)
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.
-0.47Z-score
OE missense 1.08 (0.98–1.19)
296 obs / 274.0 exp
Tolerant

Tolerant to missense variation

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.0.71 (0.47–1.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (0.98–1.19)
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.1.05
0≤1.21.6
LoF obs/exp: 14 / 19.8Missense obs/exp: 296 / 274.0Syn Z: -0.40

ClinVar Variant Classifications

216 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
Likely Pathogenic1
VUS113
Likely Benign29
Benign13
Conflicting2
50
Pathogenic
1
Likely Pathogenic
113
VUS
29
Likely Benign
13
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
50
0
50
Likely Pathogenic
0
0
1
0
1
VUS
1
80
28
4
113
Likely Benign
0
13
9
7
29
Benign
0
4
7
2
13
Conflicting
—2
Total1979513208

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

View in ClinVar →

Protein Context — Lollipop Plot

PNPLA3 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment.
Llovet JM et al.·Nat Rev Gastroenterol Hepatol
2023Review
PNPLA3 as a therapeutic target for fatty liver disease: the evidence to date.
Cherubini A et al.·Expert Opin Ther Targets
2021Review
Targeting PNPLA3 to Treat MASH and MASH Related Fibrosis and Cirrhosis.
Lindén D et al.·Liver Int
2025Review
Interaction between estrogen receptor-α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women.
Cherubini A et al.·Nat Med
2023
A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.
Abul-Husn NS et al.·N Engl J Med
2018
The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans.
Luukkonen PK et al.·Cell Metab
2023
TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD.
Sun B et al.·Clin Mol Hepatol
2024
IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease.
Park J et al.·J Hepatol
2023
PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis.
Chen VL et al.·Gastroenterology
2023Cohort
Integrative common and rare variant analyses provide insights into the genetic architecture of liver cirrhosis.
Ghouse J et al.·Nat Genet
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
HLA DRB1*01 and *04 Predisposition to Rheumatoid Arthritis and Polymorphisms of the SLCO1B1, MTHFR and PNPLA3 Genes Are Not Associated with Fatty Liver and Hepatotoxicity.
Zekić T et al.·J Clin Med
2026
The I148M PNPLA3 Variant Forces Progressive Portal MASLD by Spatially Perturbing Metabolic Pathways Across Liver Zones.
Paolini E et al.·Int J Mol Sci
2026🔓 Open Access
A PNPLA3-NACC1-RIPK3 pathway mediates macrophage necroptosis and inflammation in MASLD.
Wang X et al.·Hepatol Commun
2026🔓 Open Access
PNPLA3 Genotype and Clinical Factors Impact Hepatocellular Carcinoma Risk: Findings From a Prospective Cohort Study.
Huang DQ et al.·Aliment Pharmacol Ther
2026Cohort
Association between PNPLA3 rs738409 and susceptibility to etiology-specific liver cirrhosis: a systematic review and meta-analysis.
Yang S et al.·BMC Med Genomics
2026🔓 Open AccessReview
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
NAFLDLiver FibrosesCardiovascular Diseases

Liver Damage and Cardiometabolic Disorders in NAFLD

RECRUITING
NCT04036357University of Roma La SapienzaStarted 2011-11
MASLD/MASH (Metabolic Dysfunction-Associated Steatotic Liver Disease / Metabolic Dysfunction-Associated Steatohepatitis)

Study of PNPLA3 Genetic Polymorphisms in Patients With Non-Alcoholic Fatty Liver Disease in an Ultramarine Population (AdipoDROMExpo)

RECRUITING
NCT07330830Centre Hospitalier Universitaire de la GuadeloupeStarted 2025-11-26
NASHHCCGenetic Predisposition

Evaluation of Risk of hEpatocellular Carcinoma

RECRUITING
NCT06523179Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2018-01-01
quantify the impact of genetic risk factors
Fatty Liver Disease

The Role of Sugars in Fat Accumulation in the Liver

RECRUITING
NCT06751862Phase NAInstitute for Clinical and Experimental MedicineStarted 2024-06-20
150g of fat with glucose150g of fat with fructose150g of fat with sucrose
Obesity, ChildhoodChild Development

El Sendero: Pathways to Health Study

ENROLLING BY INVITATION
NCT05551650University of Southern CaliforniaStarted 2021-09-01
Healthy VolunteersMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

A Trial to Learn if ALN-PNP is Safe and Well Tolerated in Healthy Adults and Adult Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

RECRUITING
NCT05648214Phase PHASE1Regeneron PharmaceuticalsStarted 2022-12-27
ALN-PNPPlacebo (PB)
Metabolic Dysfunction-associated Steatotic Liver Disease

Fecal Microbiota Analysis of PNPLA3 Polymorphism in Hispanic Patients With MASLD

RECRUITING
NCT06495333Fundacion de Investigacion Science and EducationStarted 2024-07-05
Daily Step CountMASLDBMI

The Efficacy of Pedometer-motivated Physical Activity for the Management of Patients With MASLD.

ENROLLING BY INVITATION
NCT06334666Phase NAMahidol UniversityStarted 2024-08-01
Encourage using pedometer
NAFLD

Human Liver ORganoids as a Model to Study the Development of Non-Alcoholic SteatOhepatitis (NASH)

RECRUITING
NCT06856252Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2021-07-01
Liver resection to isolate cells
MASLD - Metabolic Dysfunction-Associated Steatotic Liver DiseaseCirrhosisAdvanced Fibrosis

MASLD in Type 2 Diabetes in Primary Care - a Follow-up Study

ENROLLING BY INVITATION
NCT07312136Linkoeping UniversityStarted 2025-12-16
B Acute Lymphoblastic LeukemiaB Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1B Acute Lymphoblastic Leukemia, BCR-ABL1-Like

Studying the Effect of Levocarnitine in Protecting the Liver From Chemotherapy for Leukemia or Lymphoma

RECRUITING
NCT05602194Phase PHASE3Children's Oncology GroupStarted 2023-08-24
Biospecimen CollectionCalaspargase PegolLevocarnitine
CirrhosisMASLD

DEFINITION OF THE GENOMIC LANDSCAPE OF MASLD

RECRUITING
NCT07249112Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2025-09-01
genetic and somatic variants involved in its progression toward advanced fibrosis and hepatocellular carcinoma

External Resources

Links to major genomics databases and tools