PNPLA4

Chr X

patatin like domain 4, phospholipase and triacylglycerol lipase

Also known as: DXS1283E, GS2, iPLA2eta

NCBI Gene: 8228ENSG00000006757UniProt: P41247

The protein functions as a triacylglycerol lipase with transacylase activity, transferring fatty acids from triglycerides to retinol and hydrolyzing retinyl esters. Mutations cause autosomal recessive spastic paraplegia with intellectual disability and thin corpus callosum. The gene shows low constraint to loss-of-function variants, consistent with the recessive inheritance pattern observed in affected individuals.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
5
Pubs (1 yr)
152
P/LP submissions
0%
P/LP missense
1.27
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— PNPLA4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
150 unique Pathogenic / Likely Pathogenic· 74 VUS of 300 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.27LOEUF
pLI 0.003
Z-score 1.05
OE 0.61 (0.32–1.27)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.15Z-score
OE missense 1.04 (0.89–1.23)
101 obs / 97.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.61 (0.32–1.27)
0≤0.351.4
Missense OE1.04 (0.89–1.23)
0≤0.61.4
Synonymous OE1.01
0≤1.21.6
LoF obs/exp: 5 / 8.2Missense obs/exp: 101 / 97.0Syn Z: -0.04
DN
0.78top 25%
GOF
0.75top 25%
LOF
0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic139
Likely Pathogenic11
VUS74
Likely Benign14
Benign5
139
Pathogenic
11
Likely Pathogenic
74
VUS
14
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
139
0
139
Likely Pathogenic
0
0
11
0
11
VUS
0
34
40
0
74
Likely Benign
0
2
9
3
14
Benign
0
2
2
1
5
Total0382014243

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

View in ClinVar →

Protein Context — Lollipop Plot

PNPLA4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Integrated analysis of lncRNAs and mRNAs by RNA-Seq in secondary hair follicle development and cycling (anagen, catagen and telogen) of Jiangnan cashmere goat (Capra hircus)
Wu C et al.·BMC Vet Res
2022
Incidental detection of a 1.61-Mb familial Xp22.31 microdeletion encompassing PUDP, STS, VCX and PNPLA4 in a male fetus with cleft lip and palate on prenatal ultrasound and a favorable postnatal outcome.
Chen CP·Taiwan J Obstet Gynecol
2025
Identification of Hub Genes and Small Molecule Drugs Associated with Acquired Resistance to Gefitinib in Non-Small Cell Lung Cancer
Li G et al.·J Cancer
2021
Integrative Analysis of Identifying Methylation-Driven Genes Signature Predicts Prognosis in Colorectal Carcinoma
Huang H et al.·Front Oncol
2021
Cardiac arrhythmia, developmental delay, epilepsy and ichthyosis due to Xp22.31 deletion: review of literature and case report.
Dantsev IS et al.·Transl Pediatr
2025Review
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients