PNPLA8

Chr 7AR

patatin like domain 8, phospholipase A2

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

NCBI Gene: 50640ENSG00000135241UniProt: Q9NP80

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]

Primary Disease Associations & Inheritance

Mitochondrial myopathy with lactic acidosisMIM #251950
AR
436
ClinVar variants
53
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— PNPLA8
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.
📋
ClinVar Variants
53 Pathogenic / Likely Pathogenic· 227 VUS of 436 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
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?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.
0.09Z-score
OE missense 0.99 (0.91–1.07)
395 obs / 400.3 exp
Tolerant

Mild missense constraint

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.0.30 (0.18–0.51)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.91–1.07)
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.0.94
0≤1.21.6
LoF obs/exp: 10 / 33.6Missense obs/exp: 395 / 400.3Syn Z: 0.57

ClinVar Variant Classifications

436 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic41
Likely Pathogenic12
VUS227
Likely Benign136
Benign13
Conflicting7
41
Pathogenic
12
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
12
1
28
0
41
Likely Pathogenic
7
0
5
0
12
VUS
2
213
10
2
227
Likely Benign
0
7
37
92
136
Benign
0
0
6
7
13
Conflicting
—7
Total2122186101436

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.

Gene2Phenotype Curations

PNPLA8-related progressive microcephaly with seizures and neurodegeneration

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗
frameshift variantstop gainedmissense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial myopathy with lactic acidosis

MIM #251950

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.
Nakamura Y et al.·Brain
2024
Novel PNPLA8 variants associated with primary ovarian insufficiency, tremors, cerebellar ataxia and limb weakness: a case report and literature review.
Chen B et al.·J Neurol
2024Review
Fetal and neonatal outcomes of posterior fossa anomalies: a retrospective cohort study.
Alsehli H et al.·Sci Rep
2024Cohort
Delineating the phenotype of PNPLA8-related mitochondriopathies.
Abdel-Hamid MS et al.·Clin Genet
2024
A PNPLA8 frameshift variant in Australian shepherd dogs with hereditary ataxia.
Abitbol M et al.·Anim Genet
2022
Fine mapping for Weaver syndrome in Brown Swiss cattle and the identification of 41 concordant mutations across NRCAM, PNPLA8 and CTTNBP2.
McClure M et al.·PLoS One
2013
Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 γ recapitulate the mitochondriopathy of the homologous null mouse.
Saunders CJ et al.·Hum Mutat
2015Functional
Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing.
Masih S et al.·Eur J Med Genet
2022
A neurodegenerative mitochondrial disease phenotype due to biallelic loss-of-function variants in PNPLA8 encoding calcium-independent phospholipase A2γ.
Shukla A et al.·Am J Med Genet A
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools