PNPLA4

Summary

PNPLA4 (patatin like domain 4, phospholipase and triacylglycerol lipase , HGNC:24887) is a protein-coding gene on chromosome Xp22.31, encoding Patatin-like phospholipase domain-containing protein 4 (P41247). Has abundant triacylglycerol lipase activity.

This gene encodes a member of the patatin-like family of phospholipases. The encoded enzyme has both triacylglycerol lipase and transacylase activities and may be involved in adipocyte triglyceride homeostasis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome Y.

Source: NCBI Gene 8228 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Limited, GenCC)
• Clinical variants (ClinVar): 132 total — 45 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_004650

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24887
Approved symbol	PNPLA4
Name	patatin like domain 4, phospholipase and triacylglycerol lipase
Location	Xp22.31
Locus type	gene with protein product
Status	Approved
Aliases	DXS1283E, GS2, iPLA2eta
Ensembl gene	ENSG00000006757
Ensembl biotype	protein_coding
OMIM	300102
Entrez	8228

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 18 protein_coding

ENST00000381042, ENST00000442940, ENST00000444736, ENST00000537427, ENST00000889416, ENST00000889417, ENST00000889418, ENST00000889419, ENST00000889420, ENST00000889421, ENST00000889422, ENST00000889423, ENST00000889424, ENST00000889425, ENST00000889426, ENST00000889427, ENST00000931372, ENST00000931373

RefSeq mRNA: 3 — MANE Select: NM_004650 NM_001142389, NM_001172672, NM_004650

CCDS: CCDS14129, CCDS55368

Canonical transcript exons

ENST00000381042 — 7 exons

Exon	Start	End
ENSE00000648720	7921713	7921848
ENSE00000648722	7901989	7902141
ENSE00001487335	7925940	7926132
ENSE00001487340	7927286	7927413
ENSE00001687695	7912028	7912093
ENSE00001825325	7898247	7900817
ENSE00003576417	7922004	7922098

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 95.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4403 / max 79.0109, expressed in 1674 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198359	9.6724	1632
198361	1.8358	1048
198360	0.9320	627

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.32	gold quality
diaphragm	UBERON:0001103	92.57	silver quality
secondary oocyte	CL:0000655	92.20	gold quality
vastus lateralis	UBERON:0001379	91.67	gold quality
triceps brachii	UBERON:0001509	91.46	gold quality
islet of Langerhans	UBERON:0000006	90.86	gold quality
quadriceps femoris	UBERON:0001377	90.74	gold quality
left ventricle myocardium	UBERON:0006566	90.34	gold quality
biceps brachii	UBERON:0001507	90.26	gold quality
gingival epithelium	UBERON:0001949	90.26	gold quality
muscle organ	UBERON:0001630	89.86	gold quality
gastrocnemius	UBERON:0001388	89.76	gold quality
muscle of leg	UBERON:0001383	89.69	gold quality
gingiva	UBERON:0001828	89.40	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.40	gold quality
skeletal muscle tissue	UBERON:0001134	89.23	gold quality
heart left ventricle	UBERON:0002084	89.09	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.06	gold quality
cardiac ventricle	UBERON:0002082	89.06	gold quality
heart right ventricle	UBERON:0002080	88.93	gold quality
tongue squamous epithelium	UBERON:0006919	88.84	silver quality
choroid plexus epithelium	UBERON:0003911	88.44	gold quality
myocardium	UBERON:0002349	88.42	gold quality
muscle tissue	UBERON:0002385	88.41	gold quality
hair follicle	UBERON:0002073	87.94	silver quality
right atrium auricular region	UBERON:0006631	87.72	gold quality
heart	UBERON:0000948	87.60	gold quality
cardiac atrium	UBERON:0002081	87.51	gold quality
apex of heart	UBERON:0002098	87.29	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

90 targeting PNPLA4, 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-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540

Literature-anchored findings (GeneRIF, showing 7)

• iPLA2epsilon (adiponutrin), iPLA2zeta (TTS-2.2), and iPLA2eta (GS2) are three novel TAG lipases/acylglycerol transacylases that likely participate in TAG hydrolysis and the acyl-CoA independent transacylation of acylglycerols (PMID:15364929)
• The GS2 gene (PNPLA4) encodes a keratinocyte retinyl ester hydrolase. The protein also catalyzes fatty acyl CoA-dependent and -independent retinol esterification, using triolein as substrate and generates diacylglyceride and free fatty acid. (PMID:15955102)
• we report the identity of an inhibitor, TIP47, which prevents retinylester hydrolysis catalyzed by GS2 lipase and hormone-sensitive lipase (PMID:16741517)
• GS2 promotes RE accumulation and may do so either as a catalyst or as a regulatory protein that enhances retinylesters formation catalyzed by other acyl transferases. (PMID:19181555)
• No association between genetic variants in PNPLA4 genes and childhood and adolescent obesity (PMID:19390624)
• These results strongly suggest that PNPLA9, -6 and -4 play a key role in GPL turnover and homeostasis in human cells. A hypothetical model suggesting how these enzymes could recognize the relative concentration of the different GPLs is proposed (PMID:27317427)
• Association of copy number variation in X chromosome-linked PNPLA4 with heterotaxy and congenital heart disease. (PMID:38973237)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pnpla4	ENSDARG00000069834
rattus_norvegicus	Pnpla4	ENSRNOG00000026157
caenorhabditis_elegans		WBGENE00008370

Paralogs (4): PNPLA5 (ENSG00000100341), PNPLA3 (ENSG00000100344), PNPLA2 (ENSG00000177666), PNPLA1 (ENSG00000180316)

Protein

Protein identifiers

Patatin-like phospholipase domain-containing protein 4 — P41247 (reviewed: P41247)

Alternative names: Calcium-independent phospholipase A2-eta, Protein GS2

All UniProt accessions (2): P41247, C9IZF6

UniProt curated annotations — full annotation on UniProt →

Function. Has abundant triacylglycerol lipase activity. Transfers fatty acid from triglyceride to retinol, hydrolyzes retinylesters, and generates 1,3-diacylglycerol from triglycerides. Additionally possesses acylglycerol transacylase and phospholipase A2 activities.

Subcellular location. Mitochondrion.

Tissue specificity. Expressed in all tissues examined, including heart, brain, placenta, lung, liver, muscle, kidney, pancreas and spleen.

Disease relevance. Defects in PNPLA4 may play a role in mitochondrial disorders characterized by complex IV deficiency.

Activity regulation. The triglyceride lipase activity is inhibited by BEL ((E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one), a suicide substrate inhibitor.

Isoforms (2)

UniProt ID	Names	Canonical?
P41247-1	1	yes
P41247-2	2

RefSeq proteins (3): NP_001135861, NP_001166143, NP_004641* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002641	PNPLA_dom	Domain
IPR016035	Acyl_Trfase/lysoPLipase	Homologous_superfamily
IPR033562	PLPL	Family
IPR033902	PNPLA4	Family

Pfam: PF01734

Catalyzed reactions (Rhea), 12 shown:

• a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H(+) (RHEA:12044)
• all-trans-retinyl hexadecanoate + H2O = all-trans-retinol + hexadecanoate + H(+) (RHEA:13933)
• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-glycero-3-phosphocholine + a fatty acid + H(+) (RHEA:15801)
• a triacylglycerol + H2O = a 1,2-diacylglycerol + a fatty acid + H(+) (RHEA:35667)
• 2 1-(9Z-octadecenoyl)-glycerol = 1,2-di-(9Z-octadecenoyl)-glycerol + glycerol (RHEA:38323)
• 1-(9Z-octadecenoyl)-glycerol + 1,2-di-(9Z-octadecenoyl)-glycerol = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + glycerol (RHEA:38327)
• 1-(9Z-octadecenoyl)-glycerol + 1,3-di-(9Z-octadecenoyl)-glycerol = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + glycerol (RHEA:38331)
• 1,2-di-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) = 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O (RHEA:38379)
• 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O = 1,3-di-(9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:38387)
• a triacylglycerol + H2O = a 1,3-diacylglycerol + a fatty acid + H(+) (RHEA:38495)
• an all-trans-retinyl ester + H2O = all-trans-retinol + a fatty acid + H(+) (RHEA:38555)
• 1,2,3-tri-(9Z-octadecenoyl)-glycerol + all-trans-retinol = all-trans-retinyl 9Z-octadecenoate + di-(9Z)-octadecenoylglycerol (RHEA:39987)

UniProt features (11 total): sequence variant 4, short sequence motif 2, active site 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41247-F1	94.38	0.85

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): 43 (nucleophile); 163 (proton acceptor)

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-163560	Triglyceride catabolism

MSigDB gene sets: 111 (showing top): REACTOME_TRIGLYCERIDE_CATABOLISM, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, GOBP_LIPID_HOMEOSTASIS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_NEUTRAL_LIPID_CATABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOBP_TRIGLYCERIDE_CATABOLIC_PROCESS, GOBP_NEUTRAL_LIPID_METABOLIC_PROCESS, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, GOBP_GLYCEROLIPID_CATABOLIC_PROCESS, GOBP_LIPID_CATABOLIC_PROCESS

GO Biological Process (5): triglyceride catabolic process (GO:0019433), lipid homeostasis (GO:0055088), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042), retinol metabolic process (GO:0042572)

GO Molecular Function (9): A2-type glycerophospholipase activity (GO:0004623), triacylglycerol lipase activity (GO:0004806), acylglycerol O-acyltransferase activity (GO:0016411), all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity (GO:0047376), retinyl-palmitate esterase activity (GO:0050253), mono-olein transacylation activity (GO:0051264), diolein transacylation activity (GO:0051265), catalytic activity (GO:0003824), hydrolase activity (GO:0016787)

GO Cellular Component (5): cytoplasm (GO:0005737), mitochondrion (GO:0005739), lipid droplet (GO:0005811), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Triglyceride metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carboxylic ester hydrolase activity	3
cellular anatomical structure	3
acylglycerol O-acyltransferase activity	2
cytoplasm	2
triglyceride metabolic process	1
acylglycerol catabolic process	1
chemical homeostasis	1
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
retinoid metabolic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
glycerophospholipase activity	1
lipase activity	1
acyltransferase activity, transferring groups other than amino-acyl groups	1
retinyl-palmitate esterase activity	1
retinol metabolic process	1
molecular_function	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

734 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNPLA4	PUDP	Q08623	858
PNPLA4	LIPE	Q05469	782
PNPLA4	ABHD5	Q8WTS1	761
PNPLA4	PNPLA8	Q9NP80	722
PNPLA4	VCX3A	Q9NNX9	700
PNPLA4	PNPLA6	Q8IY17	681
PNPLA4	STS	P08842	671
PNPLA4	VCX2	Q9H322	641
PNPLA4	PLA2G6	O60733	598
PNPLA4	ARSD	P51689	595
PNPLA4	VCX3B	Q9H321	580
PNPLA4	GYG2	O15488	568
PNPLA4	TCEANC	Q8N8B7	567
PNPLA4	ANOS1	P23352	514
PNPLA4	EIF2S3	P41091	510

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PNPLA4	ATP2B3	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
PNPLA4	Mgu	psi-mi:“MI:0914”(association)	0.350
PNPLA4	PCCA	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): ATP2B3 (Affinity Capture-MS), PNPLA4 (Synthetic Growth Defect), PNPLA4 (Synthetic Lethality), ATP2B3 (Affinity Capture-MS), SNX11 (Affinity Capture-MS), C12orf5 (Affinity Capture-MS), UROS (Affinity Capture-MS), SNX11 (Affinity Capture-MS), C12orf5 (Affinity Capture-MS), ATP2B3 (Affinity Capture-MS), PPCS (Affinity Capture-MS), ATP2B1 (Affinity Capture-MS), LONP1 (Affinity Capture-MS), TMLHE (Affinity Capture-MS), PCCA (Affinity Capture-MS)

ESM2 similar proteins: A0A0F5HSE8, A0A0R6Y3I5, A0A2P6MHT4, A0RIC0, A1BI19, A4SD83, A6QB69, A7Z5B3, A8FCG5, B3EFW1, B7JLX3, C1EQZ2, C3LJP5, C3P7Q4, O06745, O07016, O24767, O31662, O34731, O34787, O85057, P0AFR0, P0AFR1, P23914, P38022, P39627, P39813, P41247, P42068, P53558, P54168, P54513, P54529, P58588, P96601, Q3ATV8, Q3B5Y2, Q49WR7, Q4L7T0, Q635G3

Diamond homologs: P0C548, P41247, Q11186, Q2KI18, Q32LZ8, Q3V1D5, Q7Z6Z6, Q8BJ56, Q8N8W4, Q91WW7, Q96AD5, Q9NST1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	5
Uncertain significance	43
Likely benign	9
Benign	3

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1172822	Single allele	Pathogenic
1180518	GRCh37/hg19 Xp22.31(chrX:6451623-8136851)x0	Pathogenic
1300212	GRCh37/hg19 Xp22.31(chrX:6575924-8173248)x0	Pathogenic
1300213	GRCh37/hg19 Xp22.31(chrX:6456940-8135053)x0	Pathogenic
1703531	GRCh37/hg19 Xp22.31(chrX:6954111-8058641)	Pathogenic
1707431	GRCh37/hg19 Xp22.31(chrX:6448751-8135644)x2	Pathogenic
1707438	GRCh37/hg19 Xp22.31(chrX:6980979-7891559)x1	Pathogenic
1708462	GRCh37/hg19 Xp22.31(chrX:6677961-8144721)x3	Pathogenic
202222	GRCh37/hg19 Xp22.31(chrX:6456837-8119329)x0	Pathogenic
2499159	GRCh37/hg19 Xp22.31(chrX:6451786-7894160)x0	Pathogenic
2506547	GRCh37/hg19 Xp22.31(chrX:6968337-8434424)	Pathogenic
253498	GRCh37/hg19 Xp22.31(chrX:6639808-7896607)x0	Pathogenic
253552	GRCh37/hg19 Xp22.31(chrX:6456036-8139238)x0	Pathogenic
2671626	Single allele	Pathogenic
2684396	GRCh37/hg19 Xp22.31(chrX:6568478-7898751)x0	Pathogenic
2685221	GRCh37/hg19 Xp22.31(chrX:6658871-8110243)x0	Pathogenic
2685691	GRCh37/hg19 Xp22.31(chrX:6455150-8135644)x1	Pathogenic
2685692	GRCh37/hg19 Xp22.31(chrX:6591135-9498909)x1	Pathogenic
3062476	GRCh37/hg19 Xp22.31(chrX:6938911-7902806)	Pathogenic
3148954	GRCh37/hg19 Xp22.31(chrX:6645873-8110204)x0	Pathogenic
3242304	GRCh37/hg19 Xp22.31(chrX:6451998-8136170)x1	Pathogenic
3391947	GRCh37/hg19 Xp22.31(chrX:7234606-8135644)x1	Pathogenic
374374	GRCh37/hg19 Xp22.31(chrX:6497085-7910475)	Pathogenic
395282	GRCh37/hg19 Xp22.31(chrX:6456036-8131751)x1	Pathogenic
395283	GRCh37/hg19 Xp22.31(chrX:6456036-8131751)x0	Pathogenic
4083500	GRCh37/hg19 Xp22.31(chrX:6968337-7894160)x0	Pathogenic
4279404	GRCh37/hg19 Xp22.31(chrX:6938912-7902806)x1	Pathogenic
441559	GRCh37/hg19 Xp22.31(chrX:6449752-8135644)x0	Pathogenic
442339	GRCh37/hg19 Xp22.31(chrX:6523326-8127576)x0	Pathogenic
442822	GRCh37/hg19 Xp22.31(chrX:6458939-8135053)x0	Pathogenic

SpliceAI

1003 predictions. Top by Δscore:

Variant	Effect	Δscore
X:7901985:TCA:T	donor_loss	1.0000
X:7901986:C:CG	donor_loss	1.0000
X:7901987:A:AC	donor_gain	1.0000
X:7901987:A:T	donor_loss	1.0000
X:7901987:AC:A	donor_gain	1.0000
X:7901988:C:CC	donor_gain	1.0000
X:7901988:CC:C	donor_gain	1.0000
X:7902137:CACTT:C	acceptor_gain	1.0000
X:7902139:CTT:C	acceptor_gain	1.0000
X:7902140:TT:T	acceptor_gain	1.0000
X:7902142:C:CA	acceptor_loss	1.0000
X:7902142:C:CC	acceptor_gain	1.0000
X:7921844:CACTT:C	acceptor_gain	1.0000
X:7921846:CTT:C	acceptor_gain	1.0000
X:7921849:C:CC	acceptor_gain	1.0000
X:7926133:C:CC	acceptor_gain	1.0000
X:7927306:T:TA	donor_gain	1.0000
X:7900815:CAA:C	acceptor_gain	0.9900
X:7901983:ACT:A	donor_loss	0.9900
X:7901988:CCA:C	donor_gain	0.9900
X:7901988:CCATG:C	donor_gain	0.9900
X:7902144:G:C	acceptor_gain	0.9900
X:7902144:G:GC	acceptor_gain	0.9900
X:7912022:GCTTA:G	donor_loss	0.9900
X:7912023:CTTA:C	donor_loss	0.9900
X:7912024:TTA:T	donor_loss	0.9900
X:7912025:TACC:T	donor_loss	0.9900
X:7912026:A:AG	donor_loss	0.9900
X:7912027:CCT:C	donor_loss	0.9900
X:7912091:GACC:G	acceptor_loss	0.9900

AlphaMissense

1644 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:7912079:G:C	S142R	0.986
X:7912079:G:T	S142R	0.986
X:7912081:T:G	S142R	0.986
X:7926081:A:C	F13L	0.984
X:7926081:A:T	F13L	0.984
X:7926083:A:G	F13L	0.984
X:7921737:A:C	F129L	0.978
X:7921737:A:T	F129L	0.978
X:7921739:A:G	F129L	0.978
X:7902067:G:C	F184L	0.974
X:7902067:G:T	F184L	0.974
X:7902069:A:G	F184L	0.974
X:7912076:A:C	S143R	0.974
X:7912076:A:T	S143R	0.974
X:7912078:T:G	S143R	0.974
X:7921720:A:G	L135P	0.969
X:7900713:A:C	F245L	0.966
X:7900713:A:T	F245L	0.966
X:7900715:A:G	F245L	0.966
X:7912073:A:C	F144L	0.962
X:7912073:A:T	F144L	0.962
X:7912075:A:G	F144L	0.962
X:7921786:A:T	V113E	0.961
X:7902138:A:G	W161R	0.958
X:7902138:A:T	W161R	0.958
X:7925974:G:T	A49D	0.958
X:7926062:C:A	G20W	0.956
X:7900711:A:G	L246S	0.952
X:7925992:G:T	S43Y	0.951
X:7912080:C:A	S142I	0.950

dbSNP variants (sampled 300 via entrez): RS1000010335 (X:7900315 C>T), RS1000082826 (X:7909346 T>A), RS1000212567 (X:7926187 T>C), RS1000556476 (X:7906740 A>G), RS1000708689 (X:7915696 T>C), RS1000817799 (X:7924068 G>A), RS1000876035 (X:7899204 G>A,C), RS1001011544 (X:7898865 G>C), RS1001083358 (X:7924606 C>T), RS1001183078 (X:7923600 T>G), RS1001653267 (X:7914251 G>C), RS1001703932 (X:7913784 T>G), RS1001952496 (X:7904611 A>C), RS1002085632 (X:7905212 A>G), RS1002553079 (X:7902952 T>G)

Disease associations

OMIM: gene MIM:300102 | disease phenotypes: MIM:308100, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial disease	Limited	X-linked

Mondo (10): cerebral palsy (MONDO:0006497), recessive X-linked ichthyosis (MONDO:0010622), microcephaly (MONDO:0001149), primary ovarian failure (MONDO:0005387), ichthyosis (MONDO:0019269), autism (MONDO:0005260), primary amenorrhea (MONDO:1060208), dystonic disorder (MONDO:0003441), intellectual disability (MONDO:0001071), mitochondrial disease (MONDO:0044970)

Orphanet (4): Recessive X-linked ichthyosis (Orphanet:461), Ichthyosis (Orphanet:79354), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0100021	Cerebral palsy
HP:0000252	Microcephaly
HP:0008064	Ichthyosis
HP:0000717	Autism
HP:0001332	Dystonia

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002547	Cerebral Palsy	C10.228.140.140.254
D020821	Dystonic Disorders	C10.228.662.300
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression	2
Valproic Acid	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
retinol palmitate	decreases reaction, increases hydrolysis	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
incobotulinumtoxinA	increases expression	1
NSC 689534	affects binding, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Copper	affects binding, decreases expression	1
Doxorubicin	increases expression	1
Methotrexate	decreases expression	1
Nicotine	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression, decreases reaction	1
Thiram	decreases expression	1
Vitamin E	decreases expression	1
Ionomycin	decreases expression, decreases reaction, affects cotreatment	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability