PNPLA8

Chr 7AR

patatin like domain 8, phospholipase A2

Also known as: IPLA2-2, IPLA2G, MMLA, PNPLA-gamma, iPLA2gamma

NCBI Gene: 50640ENSG00000135241UniProt: Q9NP80OMIM: 612123

This gene encodes a member of the patatin-like phospholipase domain containing protein family. Members of this family are phospholipases which catalyze the cleavage of fatty acids from membrane phospholipids. The product of this gene is a calcium-independent phospholipase. Mutations in this gene have been associated with mitochondrial myopathy with lactic acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2015]

OMIMResearch
LOFmechanismARLOEUF 0.511 OMIM phenotype
Clinical Summary— PNPLA8
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Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.
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ClinVar Variants
54 unique Pathogenic / Likely Pathogenic· 227 VUS of 446 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.51LOEUF
pLI 0.011
Z-score 3.77
OE 0.30 (0.18–0.51)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.09Z-score
OE missense 0.99 (0.91–1.07)
395 obs / 400.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.30 (0.18–0.51)
0≤0.351.4
Missense OE0.99 (0.91–1.07)
0≤0.61.4
Synonymous OE0.94
0≤1.21.6
LoF obs/exp: 10 / 33.6Missense obs/exp: 395 / 400.3Syn Z: 0.57
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongPNPLA8-related progressive microcephaly with seizures and neurodegenerationLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6842th %ile
GOF
0.5954th %ile
LOF
0.3842th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

446 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic13
VUS227
Likely Benign136
Benign13
Conflicting7
41
Pathogenic
13
Likely Pathogenic
227
VUS
136
Likely Benign
13
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
1
23
0
41
Likely Pathogenic
13
0
0
0
13
VUS
3
215
7
2
227
Likely Benign
0
7
37
92
136
Benign
0
0
6
7
13
Conflicting
—7
Total3322373101437

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

View in ClinVar →

Protein Context — Lollipop Plot

PNPLA8 · 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
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 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