PNPLA8
protein-codingpatatin like phospholipase domain containing 8, the group of Patatin like phospholipase domain containing
Gene summary
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]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~99.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *PNPLA8* and *PNPLA8*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 24, 2025. The *PNPLA8* gene encodes the patatin-like phospholipase domain-containing protein 8, an enzyme that catalyzes the hydrolysis and release of oxidized aliphatic chains from cardiolipin. The *PNPLA8* gene was first reported in relation to autosomal recessive *PNPLA8*-related primary mitochondrial disease in 2015 (PMID: 25512002). *PNPLA8* has been associated with a single disease entity to date; mitochondrial myopathy with lactic acidosis [OMIM# 251950]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *PNPLA8*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine variants (two missense, three nonsense, four frameshift) identified in seven unrelated cases from five publications (PMIDs: 25512002, 29681094, 34177434, 37057294l, 37671596). The maximum score was reached for case level evidence, however additional cases have been reported (PMID: 39082157). Clinical features in affected individuals include myopathy, dystonia, ataxia, spasticity, developmental regression, seizures, microcephaly, and elevated lactate. The mechanism of disease is loss of function. This gene-disease relationship is also supported by functional alteration studies in patient cells (PMID: 39082157), a cell culture model (PMID: 39082157), and a mouse model (PMID: 25512002). In summary, there is definitive evidence to support the relationship between *PNPLA8* and autosomal recessive *PNPLA8*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 24, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0016825
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0016825
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0016825
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0016825
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PNPLA8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001256007.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 92 | 7 | 102 | ||
| missense | 1 | 219 | 13 | 233 | ||
| nonsense | 5 | 5 | 1 | 11 | ||
| start loss | 0 | |||||
| frameshift | 12 | 6 | 1 | 19 | ||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 3 | |||
| Total | 18 | 13 | 225 | 105 | 7 | 368 |
Highest pathogenic variant AF is 0.00002052581
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001242936.1 | 9 | MANE Select | |
| Ensembl | ENSP00000257694.8 | 9 | MANE Select | |
| RefSeq | NP_001242937.1 | 9 | Standard | |
| RefSeq | NP_001242938.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Eicosanoid Synthesis
- Metabolism of lipids
- Metabolism
- phospholipases
- Acyl chain remodelling of PC
Biological Process
- prostaglandin biosynthetic process
- fatty acid metabolic process
- cell death
- arachidonic acid metabolic process
- phosphatidylcholine catabolic process
Molecular Function
- lysophospholipase activity
- phospholipase A2 activity
- ATP binding
- calcium-independent phospholipase A2 activity
Cellular Component
- Golgi membrane
- peroxisome
- peroxisomal membrane
- endoplasmic reticulum membrane
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000422087
- Coding exons
- 9
- Length
- 99245
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 23
- Defined
- 125740
- p
- 0.0000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0949 | 395 | 400 | 0.987 | 0.0000199 | 5127 |
| Missense (PolyPhen) | 69 | 82.715 | 0.83419 | 1135 | ||
| Synonymous | 0.574 | 128 | 137 | 0.938 | 0.00000647 | 1461 |
| Loss of Function | 3.77 | 10 | 33.6 | 0.297 | 0.00000182 | 456 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00044 | 0.00043 | rare |
| Latino/Admixed American | 0.000061 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000063 | 0.000062 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Calcium-independent phospholipase A2, which catalyzes the hydrolysis of the sn-2 position of glycerophospholipids, PtdSer and to a lower extent PtdCho. Cleaves membrane phospholipids. {ECO:0000269|PubMed:10744668, ECO:0000269|PubMed:15695510}.;
Recessive Scores
- pRec
- 0.105
Intolerance Scores
- LoFtool
- 0.279
- RVIS EVS
- -0.42
- RVIS percentile EVS
- 25.79
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.632
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |