PNPLA8

Summary

PNPLA8 (patatin like domain 8, phospholipase A2 , HGNC:28900) is a protein-coding gene on chromosome 7q31.1, encoding Calcium-independent phospholipase A2-gamma (Q9NP80). Calcium-independent and membrane-bound phospholipase, that catalyzes the esterolytic cleavage of fatty acids from glycerophospholipids to yield free fatty acids and lysophospholipids, hence regulating membrane physical properties and the release of lipid second messengers and gr….

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.

Source: NCBI Gene 50640 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 422 total — 21 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• MANE Select transcript: NM_001256007

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28900
Approved symbol	PNPLA8
Name	patatin like domain 8, phospholipase A2
Location	7q31.1
Locus type	gene with protein product
Status	Approved
Aliases	IPLA2G, IPLA2-2, iPLA2gamma
Ensembl gene	ENSG00000135241
Ensembl biotype	protein_coding
OMIM	612123
Entrez	50640

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000257694, ENST00000415498, ENST00000422087, ENST00000426128, ENST00000427008, ENST00000436062, ENST00000453085, ENST00000453144, ENST00000462466, ENST00000476592, ENST00000483879, ENST00000489738, ENST00000852536, ENST00000852537, ENST00000924158, ENST00000924159, ENST00000924160, ENST00000924161, ENST00000967878, ENST00000967879, ENST00000967880, ENST00000967881, ENST00000967882, ENST00000967883, ENST00000967884, ENST00000967885

RefSeq mRNA: 6 — MANE Select: NM_001256007 NM_001256007, NM_001256008, NM_001256009, NM_001256010, NM_001256011, NM_015723

CCDS: CCDS34733, CCDS59075, CCDS59508

Canonical transcript exons

ENST00000257694 — 11 exons

Exon	Start	End
ENSE00000580838	108496584	108496755
ENSE00000580840	108479184	108479379
ENSE00000716780	108487759	108487953
ENSE00000716781	108491410	108491467
ENSE00001410713	108470417	108472675
ENSE00001503772	108514436	108515574
ENSE00001558611	108521476	108521521
ENSE00003541509	108497483	108497577
ENSE00003551975	108502491	108502642
ENSE00003651285	108514144	108514293
ENSE00003842564	108526029	108526135

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.2156 / max 965.1311, expressed in 1792 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85689	37.3555	1792
85693	27.8349	1804
85688	0.8072	320
85690	0.0528	18

Top tissues by expression

260 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.65	gold quality
epithelial cell of pancreas	CL:0000083	97.15	gold quality
tibialis anterior	UBERON:0001385	97.00	gold quality
deltoid	UBERON:0001476	96.82	gold quality
entorhinal cortex	UBERON:0002728	96.60	gold quality
left ventricle myocardium	UBERON:0006566	96.48	gold quality
kidney epithelium	UBERON:0004819	96.32	gold quality
substantia nigra pars compacta	UBERON:0001965	96.25	gold quality
heart right ventricle	UBERON:0002080	96.24	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.19	gold quality
corpus callosum	UBERON:0002336	96.08	gold quality
secondary oocyte	CL:0000655	96.02	gold quality
lateral globus pallidus	UBERON:0002476	95.94	gold quality
myocardium	UBERON:0002349	95.92	gold quality
cauda epididymis	UBERON:0004360	95.83	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.83	gold quality
postcentral gyrus	UBERON:0002581	95.76	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.74	gold quality
biceps brachii	UBERON:0001507	95.61	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.36	gold quality
parietal lobe	UBERON:0001872	95.28	gold quality
adrenal tissue	UBERON:0018303	95.02	gold quality
superior frontal gyrus	UBERON:0002661	94.92	gold quality
pigmented layer of retina	UBERON:0001782	94.87	gold quality
retina	UBERON:0000966	94.84	gold quality
bone marrow	UBERON:0002371	94.81	gold quality
corpus epididymis	UBERON:0004359	94.81	gold quality
oral cavity	UBERON:0000167	94.65	gold quality
pons	UBERON:0000988	94.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-70580	no	553.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA2

miRNA regulators (miRDB)

139 targeting PNPLA8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 10)

• These results suggest distinct roles for iPLA2beta and iPLA2gamma in cellular homeostasis and signaling, a functional link between peroxisomal AA release and eicosanoid generation, and a potential contribution of iPLA2gamma to tumorigenesis. (PMID:15695510)
• iPLA2 activation is not sufficient for SOCE activation. iPLA2 may regulate basal phosphoinositide metabolism (PMID:18680539)
• Thus, complement-mediated activation of iPLA(2)gamma is mediated via ERK and p38 pathways, and phosphorylation of Ser-511 and/or Ser-515 plays a key role in the catalytic activity and signaling of iPLA(2)gamma. (PMID:23258543)
• iPLA2gamma plays a cardioprotective role during the acute stage of Chagas’ disease. (PMID:23429536)
• iPLA2gamma plays an important role in in vivo Thromboxane A2 production accompanied by thrombus formation. (PMID:25313821)
• Stable isotope kinetics revealed that in non-failing human hearts, cPLA2zeta metabolically channels arachidonic acid into EETs, whereas in failing hearts, increased iPLA2gamma activity channels AA into toxic HETEs. These results mechanistically identify the sequelae of pathological remodeling of human mitochondrial phospholipases in failing myocardium. (PMID:29158256)
• we report two unrelated individuals with variable but similar clinical features of microcephaly, severe global developmental delay, spasticity, lactic acidosis, and progressive cerebellar atrophy with biallelic loss-of-function variants in PNPLA8. (PMID:29681094)
• 12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2gamma knockout. (PMID:32161117)
• Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer. (PMID:38017485)
• Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia. (PMID:39082157)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnpla8	ENSDARG00000078745
mus_musculus	Pnpla8	ENSMUSG00000036257
rattus_norvegicus	Pnpla8	ENSRNOG00000039091
caenorhabditis_elegans		WBGENE00022233

Protein

Protein identifiers

Calcium-independent phospholipase A2-gamma — Q9NP80 (reviewed: Q9NP80)

Alternative names: Intracellular membrane-associated calcium-independent phospholipase A2 gamma, PNPLA-gamma, Patatin-like phospholipase domain-containing protein 8, iPLA2-2

All UniProt accessions (4): A0A0C4DG51, C9J9W9, C9JAX4, Q9NP80

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-independent and membrane-bound phospholipase, that catalyzes the esterolytic cleavage of fatty acids from glycerophospholipids to yield free fatty acids and lysophospholipids, hence regulating membrane physical properties and the release of lipid second messengers and growth factors. Hydrolyzes phosphatidylethanolamine, phosphatidylcholine and probably phosphatidylinositol with a possible preference for the former. Also has a broad substrate specificity in terms of fatty acid moieties, hydrolyzing saturated and mono-unsaturated fatty acids at nearly equal rates from either the sn-1 or sn-2 position in diacyl phosphatidylcholine. However, has a weak activity toward polyunsaturated fatty acids at the sn-2 position, and thereby favors the production of 2-arachidonoyl lysophosphatidylcholine, a key branch point metabolite in eicosanoid signaling. On the other hand, can produce arachidonic acid from the sn-1 position of diacyl phospholipid and from the sn-2 position of arachidonate-containing plasmalogen substrates. Therefore, plays an important role in the mobilization of arachidonic acid in response to cellular stimuli and the generation of lipid second messengers. Can also hydrolyze lysophosphatidylcholine. In the mitochondrial compartment, catalyzes the hydrolysis and release of oxidized aliphatic chains from cardiolipin and integrates mitochondrial bioenergetics and signaling. It is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.

Subcellular location. Endoplasmic reticulum membrane. Mitochondrion membrane. Peroxisome membrane.

Tissue specificity. Expressed in parenchymal tissues including heart, skeletal muscle, placenta, brain, liver and pancreas. Also expressed in bronchial epithelial cells and kidney. Highest expression is observed in skeletal muscle and heart.

Disease relevance. Mitochondrial myopathy with lactic acidosis (MMLA) [MIM:251950] An autosomal recessive disorder characterized by progressive muscle weakness, hypotonia, seizures, poor weight gain, lactic acidosis, and elevated serum pyruvate concentration. Some patients manifest growth failure and moderate neural deafness. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Calcium-independent phospholipase. Inhibited by (E)-6-bromomethylene-3-1-naphthalenyl-2H-tetrahydropyran-2-one (BEL). The activity toward 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine is stimulated by cardiolipin.

Pathway. Phospholipid metabolism.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NP80-1	1	yes
Q9NP80-2	2
Q9NP80-3	3

RefSeq proteins (6): NP_001242936, NP_001242937, NP_001242938, NP_001242939, NP_001242940, NP_056538 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002641	PNPLA_dom	Domain
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR045217	PNPLA8-like	Domain

Pfam: PF01734

Catalyzed reactions (Rhea), 12 shown:

• a 1-acyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + a fatty acid + H(+) (RHEA:15177)
• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)
• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 2-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:18689)
• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + (9Z)-octadecenoate + H(+) (RHEA:38779)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40427)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphoethanolamine + H2O = 1-hexadecanoyl-sn-glycero-3-phosphoethanolamine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40431)
• 1-hexadecanoyl-sn-glycero-3-phosphocholine + H2O = sn-glycerol 3-phosphocholine + hexadecanoate + H(+) (RHEA:40435)
• 1-hexadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphocholine + H2O = 2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphocholine + hexadecanoate + H(+) (RHEA:40571)
• 1-O-(1Z)-hexadecenyl-2 (5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphocholine + H2O = 1-(1Z-hexadecenyl)-sn-glycero-3-phosphocholine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40579)
• 1-acyl-2-(9Z,12Z)-octadecadienoyl-sn-glycero-3-phosphoethanolamine + H2O = a 1-acyl-sn-glycero-3-phosphoethanolamine + (9Z,12Z)-octadecadienoate + H(+) (RHEA:40639)
• 1-acyl-2-(9Z,12Z)-octadecadienoyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + (9Z,12Z)-octadecadienoate + H(+) (RHEA:40643)
• 1-acyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phosphoethanolamine + H2O = a 1-acyl-sn-glycero-3-phosphoethanolamine + (5Z,8Z,11Z,14Z)-eicosatetraenoate + H(+) (RHEA:40647)

UniProt features (20 total): sequence conflict 4, short sequence motif 3, active site 2, glycosylation site 2, splice variant 2, region of interest 2, chain 1, transmembrane region 1, modified residue 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NP80-F1	66.84	0.40

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 627 (proton acceptor); 483 (nucleophile)

Post-translational modifications (1): 736

Glycosylation sites (2): 4, 361

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1482788	Acyl chain remodelling of PC
R-HSA-1482839	Acyl chain remodelling of PE

MSigDB gene sets: 233 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLGLYCEROL_METABOLIC_PROCESS, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_TRANSPORT, BILD_HRAS_ONCOGENIC_SIGNATURE, GOBP_LIPID_HOMEOSTASIS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (14): prostaglandin biosynthetic process (GO:0001516), fatty acid metabolic process (GO:0006631), arachidonate metabolic process (GO:0019369), cardiolipin metabolic process (GO:0032048), phosphatidylcholine catabolic process (GO:0034638), intracellular signal transduction (GO:0035556), linoleic acid metabolic process (GO:0043651), phosphatidylethanolamine catabolic process (GO:0046338), arachidonate secretion (GO:0050482), lipid homeostasis (GO:0055088), triglyceride homeostasis (GO:0070328), regulation of cellular response to oxidative stress (GO:1900407), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042)

GO Molecular Function (8): phosphatidylcholine lysophospholipase A1 activity (GO:0004622), ATP binding (GO:0005524), glycerophospholipid phospholipase A1 activity (GO:0008970), obsolete calcium-independent phospholipase A2 activity (GO:0047499), catalytic activity (GO:0003824), glycerophospholipase activity (GO:0004620), A2-type glycerophospholipase activity (GO:0004623), hydrolase activity (GO:0016787)

GO Cellular Component (7): mitochondrion (GO:0005739), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), mitochondrial membrane (GO:0031966), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid metabolic process	2
long-chain fatty acid metabolic process	2
unsaturated fatty acid metabolic process	2
olefinic compound metabolic process	2
glycerophospholipid catabolic process	2
cytoplasm	2
intracellular membrane-bounded organelle	2
organelle membrane	2
prostaglandin metabolic process	1
prostanoid biosynthetic process	1
monocarboxylic acid metabolic process	1
icosanoid metabolic process	1
phosphatidylglycerol metabolic process	1
phosphatidylcholine metabolic process	1
intracellular anatomical structure	1
signal transduction	1
phosphatidylethanolamine metabolic process	1
icosanoid secretion	1
arachidonate transport	1
chemical homeostasis	1
acylglycerol homeostasis	1
cellular response to oxidative stress	1
regulation of cellular response to stress	1
regulation of response to oxidative stress	1
primary metabolic process	1
catabolic process	1
lysophospholipase A1 activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
A1-type glycerophospholipase activity	1
molecular_function	1
phospholipase activity	1
glycerophospholipase activity	1
carboxylic ester hydrolase activity	1
catalytic activity	1
microbody	1
peroxisome	1
microbody membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNPLA8	PNPLA6	Q8IY17	734
PNPLA8	PNPLA4	P41247	722
PNPLA8	PNPLA5	Q7Z6Z6	686
PNPLA8	PNPLA1	Q8N8W4	666
PNPLA8	PLA2G2A	P14555	622
PNPLA8	THAP5	Q7Z6K1	617
PNPLA8	PNPLA3	Q9NST1	602
PNPLA8	TAFAZZIN	Q16635	602
PNPLA8	PLA2G4A	P47712	587
PNPLA8	PNPLA2	Q96AD5	572
PNPLA8	PNPLA7	Q6ZV29	547
PNPLA8	PLA2G4C	Q9UP65	533
PNPLA8	PLA2G10	O15496	510
PNPLA8	PLA2G4F	Q68DD2	481
PNPLA8	PLA2G6	O60733	480

IntAct

20 interactions, top by confidence:

A	B	Type	Score
SIN3B	TNRC18	psi-mi:“MI:0914”(association)	0.530
PNPLA8	CCT5	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
	PTPRN2	psi-mi:“MI:0915”(physical association)	0.370
PNPLA8		psi-mi:“MI:0915”(physical association)	0.370
Pcbp2	USP11	psi-mi:“MI:0914”(association)	0.350
PLK4	SYNPO2	psi-mi:“MI:0914”(association)	0.350
KAT6A	ING5	psi-mi:“MI:0914”(association)	0.350
SGTB	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
HNRNPD	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
SYNCRIP	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
BAG6	CNOT1	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
H2AP	GNPAT	psi-mi:“MI:0914”(association)	0.350
MFSD5	ILVBL	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
CAT	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (75): PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Proximity Label-MS), PNPLA8 (Affinity Capture-MS), PNPLA8 (Proximity Label-MS), PNPLA8 (Proximity Label-MS), PNPLA8 (Proximity Label-MS), PNPLA8 (Proximity Label-MS)

ESM2 similar proteins: A0JMA8, A4IHS0, B5DF07, D3ZRC4, D6WMX4, E7EXT2, F7AEX0, F7BJB9, O15091, O93530, Q09287, Q14149, Q1L987, Q24558, Q28C44, Q2KI45, Q2TBE0, Q32NQ8, Q3MHI8, Q3UFY8, Q4KLI2, Q4R366, Q5RDI0, Q5U245, Q5U2R4, Q5VZ89, Q5XTS1, Q66JD1, Q66JJ4, Q6DDV1, Q6GLI9, Q7JUX9, Q7L0Y3, Q7Z401, Q86VD1, Q8C1Z8, Q8JZY4, Q8K1N1, Q8N6Q8, Q8TBZ6

Diamond homologs: D3ZRC4, F4HX15, Q5XTS1, Q8K1N1, Q9NP80, P0DTE9, P0DX85, Q20500, Q9KVG8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MKNK1	“up-regulates activity”	PNPLA8	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

422 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	11
Uncertain significance	223
Likely benign	134
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1332796	NM_001256007.3(PNPLA8):c.517G>T (p.Glu173Ter)	Pathogenic
190127	NM_001256007.3(PNPLA8):c.634_637del (p.Asn212fs)	Pathogenic
190128	NM_001256007.3(PNPLA8):c.2275_2276del (p.Leu759fs)	Pathogenic
1946508	NM_001256007.3(PNPLA8):c.1327C>T (p.Arg443Ter)	Pathogenic
1964967	NM_001256007.3(PNPLA8):c.86_87insA (p.Tyr30fs)	Pathogenic
2101064	NM_001256007.3(PNPLA8):c.2259_2263del (p.Ser753fs)	Pathogenic
2177027	NM_001256007.3(PNPLA8):c.2167C>T (p.Arg723Ter)	Pathogenic
2442058	NM_001256007.3(PNPLA8):c.524del (p.Ser175fs)	Pathogenic
2581318	NM_001256007.3(PNPLA8):c.870dup (p.Leu291fs)	Pathogenic
2850949	NM_001256007.3(PNPLA8):c.470del (p.Leu157fs)	Pathogenic
2978905	NM_001256007.3(PNPLA8):c.55del (p.Ser19fs)	Pathogenic
3245917	NC_000007.13:g.(?108142915)(108143106_?)del	Pathogenic
3245918	NC_000007.13:g.(?108154568)(108155935_?)del	Pathogenic
3623252	NM_001256007.3(PNPLA8):c.1337C>A (p.Ser446Ter)	Pathogenic
3777697	H625R	Pathogenic
3777698	NM_001256007.3(PNPLA8):c.2269del (p.Thr757fs)	Pathogenic
3777699	NM_001256007.3(PNPLA8):c.1231C>T (p.Arg411Ter)	Pathogenic
3777700	NM_001256007.3(PNPLA8):c.1559T>A (p.Val520Asp)	Pathogenic
4291772	NM_001256007.3(PNPLA8):c.620dup (p.Leu207fs)	Pathogenic
4697307	NM_001256007.3(PNPLA8):c.873_876del (p.Ser292fs)	Pathogenic
4733034	NM_001256007.3(PNPLA8):c.2219_2222del (p.Arg740fs)	Pathogenic
1050814	NM_001256007.3(PNPLA8):c.944_945del (p.Lys314_Tyr315insTer)	Likely pathogenic
1180693	NM_001256007.3(PNPLA8):c.65_66del (p.Gly22fs)	Likely pathogenic
1328387	NM_001256007.3(PNPLA8):c.1637del (p.Gly546fs)	Likely pathogenic
2584537	NM_001256007.3(PNPLA8):c.1614_1615insGG (p.Asn539fs)	Likely pathogenic
3065896	NM_001256007.3(PNPLA8):c.1748_1749del (p.Tyr583fs)	Likely pathogenic
3216124	NM_001256007.3(PNPLA8):c.2227C>T (p.Gln743Ter)	Likely pathogenic
3896954	NM_001256007.3(PNPLA8):c.1056+1G>A	Likely pathogenic
4077436	NM_001256007.3(PNPLA8):c.1045C>T (p.Gln349Ter)	Likely pathogenic
4728491	NM_001256007.3(PNPLA8):c.1684-1G>C	Likely pathogenic

SpliceAI

2639 predictions. Top by Δscore:

Variant	Effect	Δscore
7:108472673:CTT:C	acceptor_gain	1.0000
7:108472676:C:CC	acceptor_gain	1.0000
7:108526025:TTA:T	donor_loss	1.0000
7:108526027:A:AC	donor_gain	1.0000
7:108526027:A:T	donor_loss	1.0000
7:108526027:AC:A	donor_gain	1.0000
7:108526028:C:CA	donor_gain	1.0000
7:108526028:CC:C	donor_gain	1.0000
7:108526028:CCG:C	donor_gain	1.0000
7:108526028:CCGG:C	donor_gain	1.0000
7:108526028:CCGGG:C	donor_gain	1.0000
7:108565950:A:AC	donor_gain	1.0000
7:108565951:C:CC	donor_gain	1.0000
7:108569488:A:AC	donor_gain	1.0000
7:108569489:C:CC	donor_gain	1.0000
7:108472671:GACTT:G	acceptor_gain	0.9900
7:108472674:TT:T	acceptor_gain	0.9900
7:108472675:TCTG:T	acceptor_loss	0.9900
7:108472676:CT:C	acceptor_loss	0.9900
7:108472677:T:G	acceptor_loss	0.9900
7:108472685:C:CT	acceptor_gain	0.9900
7:108472686:A:T	acceptor_gain	0.9900
7:108479377:ATCCT:A	acceptor_loss	0.9900
7:108479378:TCCTG:T	acceptor_loss	0.9900
7:108479379:CCTGC:C	acceptor_loss	0.9900
7:108479381:T:A	acceptor_loss	0.9900
7:108479382:G:C	acceptor_loss	0.9900
7:108491467:CCTT:C	acceptor_gain	0.9900
7:108491473:T:TC	acceptor_gain	0.9900
7:108496582:A:AC	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000014467 (7:108488010 T>C), RS1000033866 (7:108471332 A>C), RS1000103100 (7:108500765 T>C), RS1000345211 (7:108526207 G>C,T), RS1000528380 (7:108495798 G>A), RS1000556847 (7:108489511 T>C), RS1000598691 (7:108494336 C>G,T), RS1000825554 (7:108510884 G>A), RS1000920269 (7:108527505 G>C), RS1001007672 (7:108516491 A>C,G), RS1001023547 (7:108495501 C>T), RS1001034222 (7:108472904 C>T), RS1001039221 (7:108476526 A>G), RS1001091291 (7:108503642 C>G), RS1001114393 (7:108482822 T>C)

Disease associations

OMIM: gene MIM:612123 | disease phenotypes: MIM:251950

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial myopathy-lactic acidosis-deafness syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (2): mitochondrial myopathy-lactic acidosis-deafness syndrome (MONDO:0016825), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Mitochondrial myopathy-lactic acidosis-deafness syndrome (Orphanet:2597), Non-specific syndromic intellectual disability (Orphanet:528084)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0002151	Increased circulating lactate concentration
HP:0002384	Focal impaired awareness seizure
HP:0003128	Lactic acidosis
HP:0003391	Gowers sign
HP:0003542	Increased circulating pyruvate concentration
HP:0003676	Progressive
HP:0003701	Proximal muscle weakness
HP:0003737	Mitochondrial myopathy
HP:0011463	Childhood onset
HP:0012378	Fatigue
HP:0012446	Decreased CSF 5-methyltetrahydrofolate concentration
HP:0030051	Tip-toe gait
HP:0031962	Elevated serum anion gap

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001286_4	Smoking behavior	2.000000e-06
GCST001286_5	Smoking behavior	3.000000e-07
GCST001286_6	Smoking behavior	9.000000e-07
GCST003264_815	Post bronchodilator FEV1/FVC ratio	8.000000e-07
GCST004032_6	JT interval (sulfonylurea treatment interaction)	5.000000e-07
GCST005956_26	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST005962_48	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0004713	FEV/FVC ratio
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537476	Mitochondrial myopathy with lactic acidosis (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2189126 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Cyclosporine	increases expression	3
(+)-JQ1 compound	increases expression	2
Acetaminophen	increases expression, affects response to substance	2
Estradiol	decreases expression	2
Plant Extracts	affects cotreatment, increases expression	2
Valproic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, decreases reaction, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2209080	Binding	Inhibition of PNPLA8 binding to FP-biotin in [12C][14N]-lysine, arginine and [13C6][15N2]-lysine, arginine labeled HEK293T cells at 20 uM after 1 hr by isotopic activity-based protein profiling-MudPIT assay	Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1. — J Med Chem

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder