PNPLA3

Chr 22

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

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

NCBI Gene: 80339 ENSG00000100344 UniProt: Q9NST1 OMIM: 609567

The protein functions as a triacylglycerol lipase and CoA-dependent acyltransferase that catalyzes phosphatidic acid synthesis and mediates lipid metabolism in adipocytes. Mutations cause autosomal recessive early-onset familial hypertriglyceridemia and contribute to nonalcoholic fatty liver disease susceptibility. The gene shows high constraint against loss-of-function variants, indicating that complete loss of protein function is likely severely deleterious.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNon-alcoholic fatty liver disease 1

Active trials

298

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.10

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.47Z-score

OE missense 1.08 (0.98–1.19)

296 obs / 274.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.71 (0.47–1.10)

0≤0.351.4

Missense OE?1.08 (0.98–1.19)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 14 / 19.8Missense obs/exp: 296 / 274.0Syn Z: -0.40

Background carrier burden — how many people carry a rare variant somewhere in PNPLA3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 68

684 rare PASS variants

Rare truncating (LoF)

1 in 560

103 rare PASS variants

Rare synonymous (reference)

1 in 130

288 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PNPLA3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 550
South Asian	~43k	1 in 81	1 in 360
Remaining (unassigned)	~30k	1 in 47	1 in 480
European (Finnish)	~27k	1 in 480	1 in 2,900
Admixed American	~22k	1 in 73	1 in 430
African / African American	~21k	1 in 85	1 in 1,300
East Asian	~20k	1 in 86	1 in 560
Ashkenazi Jewish	~13k	1 in 240	1 in 710
Middle Eastern	~2,884	1 in 92	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 9 coding exons well covered in gnomAD exomes and genomes.? see exons ↓