PNPLA8

Chr 7AR

patatin like domain 8, phospholipase A2

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

NCBI Gene: 50640 ENSG00000135241 UniProt: Q9NP80 OMIM: 612123

The protein is a calcium-independent phospholipase that cleaves fatty acids from membrane phospholipids and plays an essential role in maintaining mitochondrial membrane lipid composition and efficient mitochondrial bioenergetics. Mutations cause mitochondrial myopathy with lactic acidosis, which primarily affects muscle and metabolic function. Inheritance is autosomal recessive.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

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

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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

34 unique Pathogenic / Likely Pathogenic· 222 VUS of 420 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 OE?0.30 (0.18–0.51)

0≤0.351.4

Missense OE?0.99 (0.91–1.07)

0≤0.61.4

Synonymous OE?0.94

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

This gene — mechanism propensity

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

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

420 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21

Likely Pathogenic13

VUS222

Likely Benign135

Benign13

Conflicting7

Pathogenic

Likely Pathogenic

222

VUS

135

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	1	3	0	21
Likely Pathogenic	13	0	0	0	13
VUS	3	215	2	2	222
Likely Benign	0	7	36	92	135
Benign	0	0	6	7	13
Conflicting	—				7
Total	33	223	47	101	411

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap PNPLA8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →