PNPLA3

Summary

PNPLA3 (patatin like domain 3, 1-acylglycerol-3-phosphate O-acyltransferase , HGNC:18590) is a protein-coding gene on chromosome 22q13.31, encoding 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (Q9NST1). Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and glycerophospholipids.

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.

Source: NCBI Gene 80339 — RefSeq curated summary.

At a glance

• Gene–disease (curated): metabolic dysfunction-associated steatotic liver disease (Limited, GenCC)
• GWAS associations: 84
• Clinical variants (ClinVar): 159 total
• MANE Select transcript: NM_025225

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18590
Approved symbol	PNPLA3
Name	patatin like domain 3, 1-acylglycerol-3-phosphate O-acyltransferase
Location	22q13.31
Locus type	gene with protein product
Status	Approved
Aliases	dJ796I17.1, FLJ22012, adiponutrin, iPLA2epsilon
Ensembl gene	ENSG00000100344
Ensembl biotype	protein_coding
OMIM	609567
Entrez	80339

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000216180, ENST00000406117, ENST00000423180, ENST00000478713, ENST00000497129, ENST00000862819, ENST00000862820, ENST00000862821, ENST00000862822, ENST00000862823

RefSeq mRNA: 1 — MANE Select: NM_025225 NM_025225

CCDS: CCDS14054

Canonical transcript exons

ENST00000216180 — 9 exons

Exon	Start	End
ENSE00000656929	43946154	43947582
ENSE00001045917	43923805	43924098
ENSE00003487263	43934606	43934666
ENSE00003490788	43932878	43933087
ENSE00003557189	43944691	43944795
ENSE00003568902	43926935	43927167
ENSE00003576272	43937051	43937272
ENSE00003622031	43939993	43940125
ENSE00003688958	43928824	43928889

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 96.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.6637 / max 183.1693, expressed in 1220 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192621	5.2870	1175
192620	0.2385	91
192622	0.1381	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	96.79	gold quality
buccal mucosa cell	CL:0002336	91.50	gold quality
right lobe of liver	UBERON:0001114	90.84	gold quality
liver	UBERON:0002107	89.69	gold quality
secondary oocyte	CL:0000655	89.26	gold quality
tibia	UBERON:0000979	82.94	gold quality
skin of leg	UBERON:0001511	80.98	gold quality
mammalian vulva	UBERON:0000997	79.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.14	silver quality
cortical plate	UBERON:0005343	78.89	gold quality
zone of skin	UBERON:0000014	78.82	gold quality
skin of abdomen	UBERON:0001416	78.12	gold quality
middle temporal gyrus	UBERON:0002771	77.86	silver quality
Brodmann (1909) area 23	UBERON:0013554	77.07	silver quality
nipple	UBERON:0002030	76.44	gold quality
stromal cell of endometrium	CL:0002255	73.93	gold quality
ventricular zone	UBERON:0003053	72.72	gold quality
ganglionic eminence	UBERON:0004023	72.67	gold quality
visceral pleura	UBERON:0002401	72.52	gold quality
embryo	UBERON:0000922	71.90	gold quality
subcutaneous adipose tissue	UBERON:0002190	71.35	gold quality
pleura	UBERON:0000977	68.09	gold quality
adult mammalian kidney	UBERON:0000082	67.99	gold quality
adipose tissue	UBERON:0001013	67.44	gold quality
parietal pleura	UBERON:0002400	66.96	gold quality
connective tissue	UBERON:0002384	66.74	gold quality
gastrocnemius	UBERON:0001388	66.39	gold quality
caput epididymis	UBERON:0004358	66.32	gold quality
amniotic fluid	UBERON:0000173	66.12	silver quality
skin of hip	UBERON:0001554	65.73	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.39
E-GEOD-100618	no	3.78

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MLXIPL, NR1H3, SREBF1

miRNA regulators (miRDB)

39 targeting PNPLA3, 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-8075	99.97	67.20	962
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-622	98.99	66.48	1050
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302

Literature-anchored findings (GeneRIF, showing 40)

• iPLA2epsilon (adiponutrin), iPLA2zeta (TTS-2.2), and iPLA2eta (GS2) are three novel TAG lipases/acylglycerol transacylases that likely participate in TAG hydrolysis and the acyl-CoA independent transacylation of acylglycerols (PMID:15364929)
• Adiponutrin and Desnutrin/ATGL have distinct functions and GS2 may contribute significantly to lipolysis in adipose tissue (PMID:16150821)
• association between PNPLA3 and obesity; the rs738409 variant was associated with insulin secretion (PMID:18728122)
• Variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to nonalcoholic fatty liver disease. (PMID:18820647)
• A common variant in PNPLA3 increases the risk of hepatic steatosis in humans. (PMID:19224197)
• Polymorphic variations affect liver triglycerides and are associated with fatty liver. (PMID:19239840)
• PNPLA3 effect on insulin sensitivity (PMID:19390624)
• test whether knowledge of the recently discovered genetic variant in the PNPLA3 gene (rs738409) increases accuracy of the prediction of non-alcoholic fatty liver (PMID:19524579)
• A strong recessive association of the adiponutrin polymorphism was found with age and gender adjusted ALT and AST concentrations: being homozygous for the minor allele resulted in a highly significant increase of ALT concentration. (PMID:19542081)
• No association of a single nucleotide polymorphism in the adiponutrin gene and type 2 diabetes in a Chinese population. (PMID:19596471)
• PNPLA3 mRNA expression is upregulated by tri-iodothyronine in adipocytes in vitro, in humans and rats, and in vivo in rat white adipose tissue. (PMID:19619606)
• PNPLA3 may be an important key to understand the mechanisms discriminating fatty liver with and without metabolic consequences. (PMID:19651814)
• Adiponutrin is involved in the metabolism of apoB-containing lipoproteins. (PMID:19729411)
• Data suggest that the adiponutrin rs738409 G allele is associated not only with fat accumulation in the liver but also with liver injury, possibly triggered by lipotoxicity. (PMID:19738004)
• Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance. (PMID:19844213)
• Data show that that rs738409 in PNPLA3 is strongly associated with alcoholic liver disease and clinically evident alcoholic cirrhosis. (PMID:19946271)
• PNPLA3-I148M promotes triglyceride accumulation by limiting triglyceride hydrolysis (PMID:20034933)
• Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. (PMID:20373368)
• PNPLA3 gene I148M variant is associated with increased levels of ALT/AST in obese children and adolescents, suggesting that it confers genetic susceptibility to liver damage from a young age. (PMID:20546964)
• Genetic variation at PNPLA3 confers a markedly increased risk of increasingly severe histological features of nonalcoholic fatty liver disease, without a strong effect on metabolic syndrome component traits. (PMID:20648472)
• The PNPLA3 rs738409 polymorphism is associated with steatosis severity, hepatocellular ballooning, lobular inflammation, and perivenular fibrosis in pediatric nonalcoholic fatty liver disease. (PMID:20648474)
• There ias an association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. (PMID:20684021)
• A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance (PMID:20803499)
• Lack of relationship with visceral obesity andinverse correlation with crotid intima media thicknes suggests fatty liver association with the minor G allele of PNPLA3. (PMID:20826584)
• Effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol. (PMID:20852027)
• findings suggest that Hispanic children carrying the GG genotype are susceptible to increased hepatic fat when dietary carbohydrate intake is high (PMID:20962157)
• The aim of this study was to determine whether glucose and insulin increase adiponutrin mRNA transcription by directly regulating the promoter region of the human adiponutrin/PNPLA3 gene. (PMID:21036152)
• adiponutrin/PNPLA3 is regulated by two key factors of the glycolytic and lipogenic pathways, raising the question of its implication in the metabolism of carbohydrates and lipids (PMID:21145868)
• The variant PNPLA3 rs738409 genotypes increased the risk of NAFLD in our population of obese Taiwanese children. The effect of the G allele on pediatric NAFLD followed a dominant genetic model. (PMID:21168155)
• Carriers of distinct p.I148M adiponutrin genotypes display significant (p=0.017) differences in liver stiffness determined by elastography. In particular, individuals carrying the allele [G] are at higher risk of developing liver cirrhosis. (PMID:21168459)
• The G-allele of rs738409 polymorphism in PNPLA3 is associated with plasma ALT, AST, and triglycerides levels, and the fibrosis stage. (PMID:21176169)
• The rs738409 single nucleotide polymorphism in PNPLA3 is associated with an increased risk of steatosis in patients infected with Hepatitis C Virus genotypes non-3. (PMID:21236304)
• Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians. (PMID:21254164)
• We confirmed the association of a PNPLA3 variant with non-alcoholic fatty liver disease in Hispanic Americans and African Americans. (PMID:21281435)
• rs738409 PNPLA3 genotype influences steatosis development in chronic hepatitis C and is independently associated with cirrhosis and other steatosis-related clinical outcomes, lack of response to antiviral treatment and possibly hepatocellular carcinoma. (PMID:21319195)
• In European Caucasians, the rs738409 variant is associated with increased risk of alcoholic liver disease, liver damage, and cirrhosis. (PMID:21334404)
• The single nucleotide polymorphism of PNPLA3 does affect the genetic susceptibility of nonalcoholic fatty liver in different populations around the world. (PMID:21381068)
• The PNPLA3 (rs738409 C>G) polymorphism favors steatosis and fibrosis progression in chronic hepatitis C. (PMID:21488075)
• Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele (PMID:21525193)
• These findings provide evidence that the PNPLA3 SNP rs738409 contributes to risk for increased liver fat content in African Americans with type 2 diabetes. (PMID:21665509)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnpla3	ENSDARG00000102020
mus_musculus	Pnpla3	ENSMUSG00000041653
rattus_norvegicus	Pnpla3	ENSRNOG00000022268

Paralogs (4): PNPLA4 (ENSG00000006757), PNPLA5 (ENSG00000100341), PNPLA2 (ENSG00000177666), PNPLA1 (ENSG00000180316)

Protein

Protein identifiers

1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 — Q9NST1 (reviewed: Q9NST1)

Alternative names: Acylglycerol transacylase, Adiponutrin, Calcium-independent phospholipase A2-epsilon, Lysophosphatidic acid acyltransferase, Patatin-like phospholipase domain-containing protein 3

All UniProt accessions (2): Q9NST1, F8W8E5

UniProt curated annotations — full annotation on UniProt →

Function. Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and glycerophospholipids. Does not esterify other lysophospholipids. Acyl donors are long chain (at least C16) fatty acyl-CoAs: arachidonoyl-CoA, linoleoyl-CoA, oleoyl-CoA and at a lesser extent palmitoyl-CoA. Additionally possesses low triacylglycerol lipase and CoA-independent acylglycerol transacylase activities and thus may play a role in acyl-chain remodeling of triglycerides. In vitro may express hydrolytic activity against glycerolipids triacylglycerol, diacylglycerol and monoacylglycerol, with a strong preference for oleic acid as the acyl moiety. However, the triacylglycerol hydrolase activity is controversial and may be very low. Possesses phospholipase A2 activity.

Subcellular location. Membrane. Lipid droplet.

Disease relevance. Non-alcoholic fatty liver disease 1 (NAFLD1) [MIM:613282] A condition characterized by accumulation of triglycerides in the liver. It is associated with adverse metabolic consequences, including insulin resistance and dyslipidemia. In a subset of individuals, hepatic steatosis promotes an inflammatory response in the liver, referred to as steatohepatitis, which can progress to cirrhosis and liver cancer. NAFLD is the most common form of liver disease in Western countries. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. The triglyceride lipase activity is inhibited by BEL ((E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one), a suicide substrate inhibitor.

Induction. By changes in energy balance: down-regulated following very low-calorie diet, whereas refeeding elevates the mRNA level.

Pathway. Phospholipid metabolism. Glycerolipid metabolism.

Polymorphism. Polymorphic variation at position 148 influences insulin secretion levels and obesity. In obese subjects the body mass index and waist are higher in carriers of the Ile-148 allele. The Ile-148 carriers also display decreased insulin secretion in response to oral glucose tolerance test. Met-148 allele carriers are seemingly more insulin resistant at a lower body mass index.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NST1-1	1	yes
Q9NST1-2	2

RefSeq proteins (1): NP_079501* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002641	PNPLA_dom	Domain
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR033562	PLPL	Family
IPR039185	Pat_PNPLA3	Family

Pfam: PF01734

Catalyzed reactions (Rhea), 12 shown:

• a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H(+) (RHEA:12044)
• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)
• a 1-acyl-sn-glycero-3-phosphate + an acyl-CoA = a 1,2-diacyl-sn-glycero-3-phosphate + CoA (RHEA:19709)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + (9Z)-octadecenoyl-CoA = 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphate + CoA (RHEA:37131)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + hexadecanoyl-CoA = 1-(9Z)-octadecenoyl-2-hexadecanoyl-sn-glycero-3-phosphate + CoA (RHEA:37143)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + (9Z,12Z)-octadecadienoyl-CoA = 1-(9Z)-octadecenoyl-2-(9Z,12Z)-octadecadienoyl-sn-glycero-3-phosphate + CoA (RHEA:37159)
• 1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA = 1-(9Z)-octadecenoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphate + CoA (RHEA:37443)
• 2 1-(9Z-octadecenoyl)-glycerol = 1,2-di-(9Z-octadecenoyl)-glycerol + glycerol (RHEA:38323)
• 1-(9Z-octadecenoyl)-glycerol + 1,2-di-(9Z-octadecenoyl)-glycerol = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + glycerol (RHEA:38327)
• 1-(9Z-octadecenoyl)-glycerol + 1,3-di-(9Z-octadecenoyl)-glycerol = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + glycerol (RHEA:38331)
• 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O = 1,3-di-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:38387)
• 2 a 1-acylglycerol = a 1,2-diacylglycerol + glycerol (RHEA:44432)

UniProt features (26 total): sequence variant 9, mutagenesis site 4, short sequence motif 3, topological domain 2, glycosylation site 2, active site 2, chain 1, splice variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NST1-F1	71.70	0.30

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 (2): 47 (nucleophile); 166 (proton acceptor)

Glycosylation sites (2): 89, 280

Mutagenesis-validated functional residues (4):

Position	Phenotype
15	65% loss of 1-acylglycerol-3-phosphate o-acyltransferase catalytic activity.
47	no effect on 1-acylglycerol-3-phosphate o-acyltransferase catalytic activity. almost completely abolishes triacylglycero
206	no effect on 1-acylglycerol-3-phosphate o-acyltransferase catalytic activity.
311	67% loss of 1-acylglycerol-3-phosphate o-acyltransferase catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1482883	Acyl chain remodeling of DAG and TAG

MSigDB gene sets: 144 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_WHITE_FAT_CELL_DIFFERENTIATION, CREBP1_Q2, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, CREB_Q4

GO Biological Process (16): long-chain fatty acid metabolic process (GO:0001676), glycerophospholipid metabolic process (GO:0006650), phosphatidic acid biosynthetic process (GO:0006654), response to sucrose (GO:0009744), triglyceride biosynthetic process (GO:0019432), triglyceride catabolic process (GO:0019433), cellular response to insulin stimulus (GO:0032869), lipid droplet organization (GO:0034389), triglyceride acyl-chain remodeling (GO:0036153), acylglycerol acyl-chain remodeling (GO:0036155), white fat cell differentiation (GO:0050872), lipid homeostasis (GO:0055088), cellular response to 3,3’,5-triiodo-L-thyronine (GO:1905243), lipid metabolic process (GO:0006629), phospholipid biosynthetic process (GO:0008654), lipid catabolic process (GO:0016042)

GO Molecular Function (14): 1-acylglycerol-3-phosphate O-acyltransferase activity (GO:0003841), lipoprotein lipase activity (GO:0004465), A2-type glycerophospholipase activity (GO:0004623), triacylglycerol lipase activity (GO:0004806), acylglycerol O-acyltransferase activity (GO:0016411), lysophosphatidic acid binding (GO:0035727), long-chain fatty acyl-CoA binding (GO:0036042), lysophosphatidic acid acyltransferase activity (GO:0042171), mono-olein transacylation activity (GO:0051264), diolein transacylation activity (GO:0051265), catalytic activity (GO:0003824), transferase activity (GO:0016740), acyltransferase activity (GO:0016746), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
triglyceride metabolic process	3
acylglycerol O-acyltransferase activity	3
phospholipid metabolic process	2
carboxylic ester hydrolase activity	2
catalytic activity	2
cellular anatomical structure	2
fatty acid metabolic process	1
glycerolipid metabolic process	1
phosphatidic acid metabolic process	1
glycerophospholipid biosynthetic process	1
response to disaccharide	1
acylglycerol biosynthetic process	1
acylglycerol catabolic process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
organelle organization	1
acylglycerol acyl-chain remodeling	1
acylglycerol metabolic process	1
fat cell differentiation	1
chemical homeostasis	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to 3,3’,5-triiodo-L-thyronine	1
primary metabolic process	1
lipid biosynthetic process	1
organophosphate biosynthetic process	1
lipid metabolic process	1
catabolic process	1
lysophosphatidic acid acyltransferase activity	1
triacylglycerol lipase activity	1
glycerophospholipase activity	1
lipase activity	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
phospholipid binding	1
anion binding	1
carbohydrate derivative binding	1
fatty-acyl-CoA binding	1
lysophospholipid acyltransferase activity	1
molecular_function	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNPLA3	GPT	P24298	926
PNPLA3	TM6SF2	Q9BZW4	916
PNPLA3	SAMM50	Q9Y512	911
PNPLA3	MBOAT7	Q96N66	887
PNPLA3	HSD17B13	Q7Z5P4	879
PNPLA3	LIPE	Q05469	870
PNPLA3	ABHD5	Q8WTS1	860
PNPLA3	SREBF1	P36956	812
PNPLA3	LYPLAL1	Q5VWZ2	770
PNPLA3	NCAN	O14594	750
PNPLA3	PPP1R3B	Q86XI6	714
PNPLA3	TMC4	Q7Z404	696
PNPLA3	GCKR	Q14397	695
PNPLA3	FDFT1	P37268	624
PNPLA3	INS	P01308	620

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PNPLA3	AHNAK	psi-mi:“MI:0915”(physical association)	0.400
PNPLA3	SLC27A2	psi-mi:“MI:0915”(physical association)	0.400
PNPLA3	AKT2	psi-mi:“MI:0915”(physical association)	0.370
SNX27	PNPLA3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (16): PEX14 (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), PEX14 (Affinity Capture-MS), PNPLA3 (Protein-RNA), PNPLA3 (Proximity Label-MS), PNPLA3 (Affinity Capture-RNA), SLC27A2 (Affinity Capture-MS), PNPLA3 (Affinity Capture-MS), BFAR (Reconstituted Complex), PNPLA3 (Reconstituted Complex), PNPLA3 (Affinity Capture-Western), BFAR (Affinity Capture-Western), PNPLA3 (Biochemical Activity), SNX27 (Two-hybrid)

ESM2 similar proteins: A2ARP1, A7Z050, D3YWQ0, D3ZEY4, F1MAB7, F1S5L4, O08560, O75912, P0C548, P0C644, P16386, P49898, P54310, P97564, Q11186, Q13574, Q2KI18, Q2NKY8, Q32LZ8, Q3MJ16, Q3TRM4, Q3TZX8, Q3U1Y4, Q50L41, Q50L42, Q50L43, Q5GJ77, Q5RDF1, Q5XIL6, Q5ZI74, Q61586, Q68DD2, Q68J42, Q6IWH7, Q6NZR5, Q6P5E8, Q7Z6Z6, Q80UP3, Q80YU0, Q8BJ56

Diamond homologs: P0C548, P41247, Q11186, Q2KI18, Q32LZ8, Q3V1D5, Q7Z6Z6, Q8BJ56, Q8N8W4, Q91WW7, Q96AD5, Q9NST1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	27
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

2311 predictions. Top by Δscore:

Variant	Effect	Δscore
22:43927156:G:GT	donor_gain	1.0000
22:43927164:GGAT:G	donor_gain	1.0000
22:43927165:G:GT	donor_gain	1.0000
22:43927165:GAT:G	donor_gain	1.0000
22:43927168:G:GG	donor_gain	1.0000
22:43937046:CACA:C	acceptor_loss	1.0000
22:43937049:A:AG	acceptor_gain	1.0000
22:43937049:A:T	acceptor_loss	1.0000
22:43937049:AG:A	acceptor_gain	1.0000
22:43937050:G:GA	acceptor_gain	1.0000
22:43937050:GG:G	acceptor_gain	1.0000
22:43937050:GGC:G	acceptor_gain	1.0000
22:43937050:GGCA:G	acceptor_gain	1.0000
22:43937050:GGCAT:G	acceptor_gain	1.0000
22:43939454:G:GG	donor_gain	1.0000
22:43955595:CCGGG:C	donor_loss	1.0000
22:43955596:CGGGT:C	donor_loss	1.0000
22:43955597:GGGTA:G	donor_loss	1.0000
22:43963285:GA:G	acceptor_gain	1.0000
22:43963376:G:GT	donor_gain	1.0000
22:43963377:A:T	donor_gain	1.0000
22:43963392:AAGAT:A	donor_gain	1.0000
22:43963393:AGAT:A	donor_gain	1.0000
22:43963394:GAT:G	donor_gain	1.0000
22:43963394:GATG:G	donor_gain	1.0000
22:43963395:AT:A	donor_gain	1.0000
22:43963395:ATG:A	donor_loss	1.0000
22:43963396:TG:T	donor_loss	1.0000
22:43963397:G:GG	donor_gain	1.0000
22:43964447:TTTA:T	acceptor_loss	1.0000

AlphaMissense

3134 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:43923960:T:C	F17L	0.990
22:43923962:C:A	F17L	0.990
22:43923962:C:G	F17L	0.990
22:43928842:T:C	F147L	0.990
22:43928844:C:A	F147L	0.990
22:43928844:C:G	F147L	0.990
22:43933045:C:A	N218K	0.990
22:43933045:C:G	N218K	0.990
22:43927100:T:C	L118P	0.989
22:43932888:A:T	D166V	0.988
22:43928835:T:G	C144W	0.987
22:43932881:T:G	Y164D	0.987
22:43932899:A:C	S170R	0.987
22:43932901:T:A	S170R	0.987
22:43932901:T:G	S170R	0.987
22:43927100:T:A	L118H	0.986
22:43934631:G:A	G241E	0.985
22:43924056:G:T	G49W	0.984
22:43927103:C:T	T119I	0.984
22:43927141:T:C	F132L	0.984
22:43927142:T:C	F132S	0.984
22:43927143:T:A	F132L	0.984
22:43927143:T:G	F132L	0.984
22:43934630:G:A	G241R	0.984
22:43934630:G:C	G241R	0.984
22:43928879:T:C	F159S	0.983
22:43932944:T:C	S185P	0.983
22:43932957:G:A	G189E	0.983
22:43934651:T:C	F248L	0.982
22:43934653:C:A	F248L	0.982

dbSNP variants (sampled 300 via entrez): RS1000245760 (22:43937318 C>A,T), RS1000470643 (22:43932210 G>T), RS1000822967 (22:43932450 A>G), RS1000866662 (22:43923314 A>G), RS1001352698 (22:43934783 G>A,C,T), RS1001453817 (22:43940551 G>A), RS1001716490 (22:43924631 G>C,T), RS1001770313 (22:43924393 C>G), RS1001862478 (22:43940304 C>G,T), RS1001917455 (22:43936017 G>A), RS1002023175 (22:43926174 A>G), RS1002078633 (22:43925935 G>A), RS1002168502 (22:43947541 G>A), RS1002217924 (22:43947274 A>G), RS1002287308 (22:43946020 G>A)

Disease associations

OMIM: gene MIM:609567 | disease phenotypes: MIM:613282

GenCC curated gene-disease

Disease	Classification	Inheritance
metabolic dysfunction-associated steatotic liver disease	Limited	Autosomal dominant

Mondo (3): NAFLD1 (MONDO:0021105), fatty liver disease (MONDO:0004790), metabolic dysfunction-associated steatotic liver disease (MONDO:0013209)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

84 associations (top):

Study	Trait	p-value
GCST000248_9	Liver enzyme levels	8.000000e-16
GCST000583_15	Hematological and biochemical traits	2.000000e-12
GCST000583_18	Hematological and biochemical traits	2.000000e-12
GCST001008_1	Nonalcoholic fatty liver disease	4.000000e-34
GCST001233_4	Metabolite levels	2.000000e-39
GCST001233_5	Metabolite levels	2.000000e-18
GCST001275_2	Liver enzyme levels (alanine transaminase)	1.000000e-45
GCST001576_5	Nonalcoholic fatty liver disease	1.000000e-10
GCST001928_4	Pediatric non-alcoholic fatty liver disease activity score	2.000000e-20
GCST002632_2	Hepatic lipid content in extreme obesity	3.000000e-07
GCST003153_1	Cirrhosis (alcohol related)	2.000000e-48
GCST004250_26	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	3.000000e-08
GCST004250_45	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	2.000000e-07
GCST004603_153	Platelet count	9.000000e-15
GCST004604_6	Hematocrit	6.000000e-09
GCST004607_195	Plateletcrit	7.000000e-11
GCST004615_140	Hemoglobin concentration	3.000000e-12
GCST004621_210	Red cell distribution width	5.000000e-09
GCST004630_48	Mean corpuscular hemoglobin	1.000000e-10
GCST005190_1	Nonalcoholic fatty liver disease	2.000000e-15
GCST005308_5	Nonalcoholic fatty liver disease	2.000000e-31
GCST005309_1	Nonalcoholic steatohepatitis-derived hepatocellular carcinoma	2.000000e-08
GCST005991_51	Platelet count	3.000000e-22
GCST005993_26	Mean corpuscular hemoglobin	2.000000e-10
GCST005998_4	Alanine transaminase levels	3.000000e-62
GCST005999_27	Aspartate aminotransferase levels	4.000000e-74
GCST006011_34	Mean corpuscular volume	5.000000e-10
GCST006611_158	HDL cholesterol	3.000000e-08
GCST006614_91	Total cholesterol levels	4.000000e-08
GCST006804_5	Red cell distribution width	6.000000e-09

EFO canonical traits (20, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0006506	hepatic lipid content measurement
EFO:0007965	response to combination chemotherapy
EFO:0004309	platelet count
EFO:0004348	hematocrit
EFO:0007985	platelet crit
EFO:0004509	hemoglobin measurement
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004761	uric acid measurement
EFO:0008421	non-alcoholic fatty liver disease severity measurement
EFO:0004530	triglyceride measurement
EFO:0004531	urate measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0006845	liver disease biomarker
EFO:0010821	liver fat measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005234	Fatty Liver	C06.552.241
D065626	Non-alcoholic Fatty Liver Disease	C06.552.241.519

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs738409	Toxicity	3	ethanol	Alcohol abuse
rs738409	Toxicity	3	asparaginase;cyclophosphamide;daunorubicin;prednisolone;vincristine	Acute lymphoblastic leukemia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs738409	PNPLA3	3	5.00	2	ethanol;asparaginase;cyclophosphamide;daunorubicin;prednisolone;vincristine

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Hydrolases & Lipases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
PF-07853578	Binding	8.28	pEC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	4
Valproic Acid	affects expression, decreases expression, increases methylation, affects cotreatment, increases expression	4
Acetaminophen	decreases expression	3
Cyclosporine	decreases expression	3
Aflatoxin B1	affects expression, decreases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
entinostat	affects cotreatment, increases expression	2
Cadmium	increases abundance, increases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
dicrotophos	increases expression	1
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
trichostatin A	increases expression	1
dodecyldimethylamine oxide	increases expression	1
arsenite	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
enilconazole	decreases expression	1
perfluorooctanoic acid	decreases expression	1
cupric chloride	decreases expression	1
isosilybin	decreases reaction, increases expression, decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0VX	Ubigene Huh-7 PNPLA3 KO	Cancer cell line	Male
CVCL_VN14	HHUUKDi008-A	Induced pluripotent stem cell	Female
CVCL_VN15	HHUUKDi007-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00760513	PHASE4	COMPLETED	Treatment of Non Alcoholic Fatty Liver Disease With n-3 Fatty Acids
NCT00941642	PHASE4	UNKNOWN	Placebo Controlled Study Using Lovaza as Treatment for Non-Alcoholic Fatty Liver Disease
NCT00994682	PHASE4	COMPLETED	University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)
NCT01006889	PHASE4	COMPLETED	Adding Exenatide to Insulin Therapy for Patients With Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease
NCT01208649	PHASE4	COMPLETED	Effects of Exenatide (Byetta®) on Liver Function in Patients With Nonalcoholic Steatohepatitis (NASH)
NCT01355575	PHASE4	TERMINATED	Rifaximin in Fatty Liver Disease
NCT01956825	PHASE4	UNKNOWN	The Effect Of Dual Treatment With L-Carnitine And Magnesium On Fatty Liver
NCT02051842	PHASE4	UNKNOWN	Effect of Metadoxine on Oxidative Stress in Non-alcoholic Hepatic Steatosis
NCT02147925	PHASE4	COMPLETED	Efficacy Study of Liraglutide vs.Sitagliptin vs. Glargine on Liver Fat in T2DM Subjects
NCT02213224	PHASE4	UNKNOWN	Perindopril and Telmisartan for the Treatment of Nonalcoholic Fatty Liver Disease
NCT02263677	PHASE4	WITHDRAWN	Evaluation of the DPP-4 Inhibitor Sitagliptin in the Treatment of Non-Alcoholic Fatty Liver Disease Using MRI
NCT02285205	PHASE4	COMPLETED	A 24 Week, Multicenter, Prospective, Open-labeled, Single-arm, Exploratory Phase 4 Clinical Trial to Evaluate the Safety and Efficacy of Lobeglitazone in Decreasing Intrahepatic Fat Contents in Type 2 Diabetes With NAFLD
NCT02303730	PHASE4	COMPLETED	Exenatide Compared With Insulin Glargine to Change Liver Fat Content in Type 2 Diabetes
NCT02329405	PHASE4	COMPLETED	The Effects of PXR Activation on Hepatic Fat Content
NCT02500147	PHASE4	TERMINATED	Metformin for Ectopic Fat Deposition and Metabolic Markers in Polycystic Ovary Syndrome (PCOS)
NCT02637973	PHASE4	COMPLETED	Effects of Empagliflozin on Liver Fat Content, Energy Metabolism and Body Composition in Patients With Type 2 Diabetes
NCT02649465	PHASE4	COMPLETED	SGLT2 Inhibitor Versus Sulfonylurea on Type 2 Diabetes With NAFLD
NCT02964715	PHASE4	UNKNOWN	The Effect of Empagliflozin on NAFLD in Asian Patients With Type 2 Diabetes
NCT02973295	PHASE4	WITHDRAWN	Silymarin in NAFLD
NCT03068065	PHASE4	COMPLETED	Antidiabetic Effects on Intrahepatic Fat
NCT03222206	PHASE4	COMPLETED	The Comparison of Effect Between Salsalate and Placebo in Osteoarthritis With Nonalcoholic Fatty Liver Disease
NCT03434613	PHASE4	COMPLETED	Phase IV Study to Evaluate the Effects of Statin Monotherapy or Statin / Ezetimibe Combination Therapy on Hepatic Steatosis in Patients With Hyperlipidemia and Nonalcoholic Fatty Liver Disease
NCT03444233	PHASE4	COMPLETED	Impact of Short-term Fructose-enriched Diet on Serum Metabolome by Normal- and Over-weighed Women.
NCT03646292	PHASE4	COMPLETED	Antidiabetic Drugs for Steatotic Liver Disease
NCT03796975	PHASE4	COMPLETED	Efficacy of Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets on the Patients With Newly Diagnosed Type 2 Diabetes Mellitus Combined With Non-alcoholic Fatty Liver Disease
NCT03849729	PHASE4	COMPLETED	Effectiveness and Tolerability of Phentermine in Patients Under Bariatric Surgery
NCT03910361	PHASE4	COMPLETED	Efficacy and Safety of Evoglitin in Patients With Type 2 Diabetes and Non-alcoholic Fatty Liver Diseases
NCT04038853	PHASE4	COMPLETED	Vitamin D in Fatty Liver Disease
NCT04248335	PHASE4	COMPLETED	Effect of Obesity on Proton Pump Inhibitors
NCT04465032	PHASE4	UNKNOWN	The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD)
NCT04475276	PHASE4	COMPLETED	Effect of Alpha Lipoic Acid on Non-alcoholic Fatty Liver Diseases
NCT04639414	PHASE4	ACTIVE_NOT_RECRUITING	Combined Active Treatment in Type 2 Diabetes with NASH
NCT04642261	PHASE4	COMPLETED	Effect of Empagliflozin on Liver Fat in Non-diabetic Patients
NCT04910178	PHASE4	COMPLETED	Follow-up of NAFLD Patients With MRI-PDFF
NCT04976283	PHASE4	UNKNOWN	Effect of Oral Anti-diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non-alcoholic Fatty Liver
NCT05042245	PHASE4	COMPLETED	The Efficacy and Safety of Ornithine Aspartic Acid Granules in NAFLD Against Silymarin Capsules
NCT05147090	PHASE4	ACTIVE_NOT_RECRUITING	Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B Patients
NCT05195944	PHASE4	ENROLLING_BY_INVITATION	Semaglutide vs Sitagliptin
NCT05305287	PHASE4	RECRUITING	Quantifying Hepatic Mitochondrial Fluxes in Humans
NCT05459701	PHASE4	COMPLETED	Dapagliflozin in Type 2 Diabetes Mellitus Patients (T2DM) With Nonalcoholic Fatty Liver Disease (NAFLD)