LPIN2

Summary

LPIN2 (lipin 2, HGNC:14450) is a protein-coding gene on chromosome 18p11.31, encoding Phosphatidate phosphatase LPIN2 (Q92539). Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the endoplasmic reticulum membrane.

Mouse studies suggest that this gene functions during normal adipose tissue development and may play a role in human triglyceride metabolism. This gene represents a candidate gene for human lipodystrophy, characterized by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance.

Source: NCBI Gene 9663 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Majeed syndrome (Definitive, ClinGen)
• GWAS associations: 9
• Clinical variants (ClinVar): 1,033 total — 27 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 45
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001375808

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14450
Approved symbol	LPIN2
Name	lipin 2
Location	18p11.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0249
Ensembl gene	ENSG00000101577
Ensembl biotype	protein_coding
OMIM	605519
Entrez	9663

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000261596, ENST00000581568, ENST00000584915, ENST00000677752, ENST00000697039, ENST00000697040, ENST00000697041, ENST00000697042, ENST00000697043, ENST00000897964, ENST00000897967, ENST00000897968, ENST00000897969, ENST00000912763, ENST00000912764, ENST00000912765

RefSeq mRNA: 3 — MANE Select: NM_001375808 NM_001375808, NM_001375809, NM_014646

CCDS: CCDS11829

Canonical transcript exons

ENST00000677752 — 20 exons

Exon	Start	End
ENSE00000521805	2939480	2939603
ENSE00000664884	2923775	2923861
ENSE00000799521	2920778	2920881
ENSE00000799523	2921533	2921647
ENSE00000799525	2922047	2922199
ENSE00000799528	2924398	2924546
ENSE00000799529	2925224	2925368
ENSE00000799531	2926723	2926805
ENSE00000799533	2927722	2927811
ENSE00000799535	2928591	2928660
ENSE00000799536	2929065	2929158
ENSE00000799538	2931256	2931443
ENSE00000799541	2934351	2934450
ENSE00000799542	2937692	2938037
ENSE00000799546	2951055	2951356
ENSE00000799548	2954504	2954599
ENSE00002721353	3013087	3013144
ENSE00003548188	2960649	2960849
ENSE00003791482	2940605	2940712
ENSE00003907814	2916999	2920437

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 95.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8901 / max 678.4120, expressed in 1807 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170990	10.2384	1720
170992	4.3265	1504
170993	4.1542	1497
170986	2.6290	196
170991	0.5812	276
170987	0.3854	82
170988	0.2238	66
170994	0.2070	84
170982	0.1448	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.65	gold quality
liver	UBERON:0002107	94.93	gold quality
right lobe of liver	UBERON:0001114	93.87	gold quality
duodenum	UBERON:0002114	93.57	gold quality
secondary oocyte	CL:0000655	92.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.48	gold quality
substantia nigra pars compacta	UBERON:0001965	91.48	gold quality
blood	UBERON:0000178	91.18	gold quality
metanephros cortex	UBERON:0010533	91.01	gold quality
tibia	UBERON:0000979	90.73	gold quality
pons	UBERON:0000988	90.48	gold quality
gall bladder	UBERON:0002110	90.48	gold quality
lower lobe of lung	UBERON:0008949	90.41	gold quality
substantia nigra pars reticulata	UBERON:0001966	90.00	gold quality
superior vestibular nucleus	UBERON:0007227	89.82	gold quality
lateral globus pallidus	UBERON:0002476	89.20	gold quality
adrenal tissue	UBERON:0018303	89.19	gold quality
renal medulla	UBERON:0000362	88.94	gold quality
ventral tegmental area	UBERON:0002691	88.77	gold quality
nucleus accumbens	UBERON:0001882	88.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.56	gold quality
granulocyte	CL:0000094	88.45	gold quality
vena cava	UBERON:0004087	88.40	silver quality
trabecular bone tissue	UBERON:0002483	88.39	gold quality
jejunum	UBERON:0002115	88.34	gold quality
oocyte	CL:0000023	88.31	gold quality
cerebellar vermis	UBERON:0004720	88.23	gold quality
bone element	UBERON:0001474	88.06	gold quality
ileal mucosa	UBERON:0000331	88.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, PPARD

miRNA regulators (miRDB)

130 targeting LPIN2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-944	99.82	70.85	3042

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• LPIN2 gene was excluded as a candidate for myopia 2 (MYP2), but the SNPs detected in this study will aid in future mapping and association studies involving this gene. (PMID:15862761)
• We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology (PMID:15994876)
• A single nucleotide polymorphism of the LPIN2 gene is associated with type 2 diabetes and fat distribution. (PMID:17804763)
• distinct and non-redundant functions of lipin 1 and 2 regulate lipid production during the cell cycle and adipocyte differentiation (PMID:18694939)
• lipin 2 plays an important role as a hepatic PAP-1 enzyme. (PMID:19136718)
• A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2. (PMID:19717560)
• Data revealed that lipin 1 formed stable homo-oligomers with itself and hetero-oligomers with lipin 2/3. (PMID:20735359)
• role of lipin-2 in the proinflammatory action of saturated fatty acids in murine and human macrophages (PMID:22334674)
• LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscle manifestations. (PMID:22481384)
• We describe two brothers with Majeed syndrome, homozygous novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X) (PMID:23087183)
• Structural variants unique to the malignant cell line inactivated: LPIN2, a phosphatidic acid phosphatase and a co-factor of PGC1a that is important for lipid metabolism and for suppressing autoinflammation. (PMID:23792589)
• we proposed that four newly identified peripheral blood mononuclear cells-derived genes( DHRS3, TTC38, SAP30BP and LPIN2 )could be integrated with previously reported rheumatoid arthritis (RA)-associated genes to monitor and/or diagnose RA. (PMID:28371410)
• Data reveal that LPIN2 silencing interferes with HCV virion secretion at late stages of the infection, without significantly LPIN2-deficient cells display alterations in mitochondrial and Golgi apparatus morphology, suggesting that LPIN2 contributes to the maintenance of the overall organelle architecture. These data suggest a broader function of LPIN2 for replication of HCV and other RNA viruses. (PMID:31752156)
• Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis. (PMID:33314777)
• Identification of lipidomic profiles associated with drug-resistant prostate cancer cells. (PMID:33596934)
• LPIN2 -related Majeed syndrome: report of two Indian patients with novel variants in LPIN2 and review of literature. (PMID:37865862)
• Lipin-2 regulates the antiviral and anti-inflammatory responses to interferon. (PMID:37929625)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lpin2	ENSDARG00000061214
mus_musculus	Lpin2	ENSMUSG00000024052
rattus_norvegicus	Lpin2	ENSRNOG00000014876
drosophila_melanogaster	Lpin	FBGN0263593
caenorhabditis_elegans		WBGENE00010425

Paralogs (3): LPIN3 (ENSG00000132793), LPIN1 (ENSG00000134324), AP5Z1 (ENSG00000242802)

Protein

Protein identifiers

Phosphatidate phosphatase LPIN2 — Q92539 (reviewed: Q92539)

Alternative names: Lipin-2

All UniProt accessions (6): Q92539, A0A8V8TKL8, A0A8V8TKZ9, A0A8V8TLW1, A0A8V8TM42, J3QQN0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the endoplasmic reticulum membrane. Plays important roles in controlling the metabolism of fatty acids at different levels. Also acts as a nuclear transcriptional coactivator for PPARGC1A to modulate lipid metabolism.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in liver, lung, kidney, placenta, spleen, thymus, lymph node, prostate, testes, small intestine, and colon.

Disease relevance. Majeed syndrome (MJDS) [MIM:609628] An autosomal recessive syndrome characterized by chronic recurrent multifocal osteomyelitis that is of early onset with a lifelong course, congenital dyserythropoietic anemia that presents as hypochromic, microcytic anemia during the first year of life and ranges from mild to transfusion-dependent, and transient inflammatory dermatosis, often manifesting as Sweet syndrome (neutrophilic skin infiltration). The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by N-ethylmaleimide.

Domain organisation. Contains 1 Asp-Xaa-Asp-Xaa-Thr (DXDXT) motif, a catalytic motif known to be essential for phosphatidate phosphatase activity. Contains one Leu-Xaa-Xaa-Ile-Leu (LXXIL) motif, a motif known to be a transcriptional binding motif.

Similarity. Belongs to the lipin family.

RefSeq proteins (3): NP_001362737, NP_001362738, NP_055461 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007651	Lipin_N	Domain
IPR013209	LNS2	Domain
IPR026058	LIPIN	Family
IPR031315	LNS2/PITP	Domain
IPR031703	Lipin_mid	Domain
IPR036412	HAD-like_sf	Homologous_superfamily

Pfam: PF04571, PF08235, PF16876

Catalyzed reactions (Rhea), 1 shown:

• a 1,2-diacyl-sn-glycero-3-phosphate + H2O = a 1,2-diacyl-sn-glycerol + phosphate (RHEA:27429)

UniProt features (23 total): modified residue 7, region of interest 6, compositionally biased region 5, short sequence motif 3, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92539-F1	61.12	0.23

Functional residue map

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

Post-translational modifications (7): 106, 174, 186, 187, 243, 303, 566

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1483191	Synthesis of PC
R-HSA-1483213	Synthesis of PE
R-HSA-4419969	Depolymerization of the Nuclear Lamina
R-HSA-75109	Triglyceride biosynthesis
R-HSA-1430728	Metabolism
R-HSA-1483206	Glycerophospholipid biosynthesis
R-HSA-1483257	Phospholipid metabolism
R-HSA-1640170	Cell Cycle
R-HSA-2980766	Nuclear Envelope Breakdown
R-HSA-556833	Metabolism of lipids
R-HSA-68875	Mitotic Prophase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-8979227	Triglyceride metabolism

MSigDB gene sets: 376 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_FATTY_ACID_CATABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, UEDA_PERIFERAL_CLOCK, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN, DOANE_RESPONSE_TO_ANDROGEN_DN, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

GO Biological Process (6): lipid metabolic process (GO:0006629), fatty acid catabolic process (GO:0009062), triglyceride biosynthetic process (GO:0019432), cellular response to insulin stimulus (GO:0032869), positive regulation of transcription by RNA polymerase II (GO:0045944), fatty acid metabolic process (GO:0006631)

GO Molecular Function (3): transcription coactivator activity (GO:0003713), phosphatidate phosphatase activity (GO:0008195), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	2
Metabolism of lipids	2
Nuclear Envelope Breakdown	1
Triglyceride metabolism	1
Phospholipid metabolism	1
Mitotic Prophase	1
Metabolism	1
M Phase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of DNA-templated transcription	2
intracellular membrane-bounded organelle	2
cytoplasm	2
primary metabolic process	1
fatty acid metabolic process	1
lipid catabolic process	1
monocarboxylic acid catabolic process	1
triglyceride metabolic process	1
acylglycerol biosynthetic process	1
response to insulin	1
cellular response to peptide hormone stimulus	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
transcription coregulator activity	1
lipid phosphatase activity	1
catalytic activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular anatomical structure	1
endomembrane system	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LPIN2	PPARA	Q07869	779
LPIN2	PLPP2	O43688	752
LPIN2	PLPP3	O14495	741
LPIN2	PSTPIP1	O43586	712
LPIN2	PSTPIP2	Q9H939	653
LPIN2	CTDNEP1	O95476	593
LPIN2	GPAM	Q9HCL2	589
LPIN2	DGAT1	O75907	580
LPIN2	MVK	Q03426	575
LPIN2	DGAT2	Q96PD7	538
LPIN2	PPARD	Q03181	537
LPIN2	AGPAT2	O15120	532
LPIN2	GPAT4	Q86UL3	519
LPIN2	AGPAT1	Q99943	511
LPIN2	PPARGC1A	Q9UBK2	511

IntAct

16 interactions, top by confidence:

A	B	Type	Score
LPIN3	CSNK2A2	psi-mi:“MI:0914”(association)	0.640
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
PPP1CA	LPIN2	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
DYRK1B	POM121C	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
LPIN2	NRDC	psi-mi:“MI:0914”(association)	0.350
LPIN3	VASP	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
FBXW11	HNRNPDL	psi-mi:“MI:0914”(association)	0.350
LPIN2	gcvT	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): LPIN2 (Affinity Capture-MS), LPIN2 (Affinity Capture-MS), LPIN2 (Affinity Capture-MS), LPIN2 (Affinity Capture-RNA), LPIN2 (Affinity Capture-MS), DYRK1B (Affinity Capture-MS), PRKD1 (Affinity Capture-MS), LPIN2 (Affinity Capture-MS), BTRC (Affinity Capture-MS), NRD1 (Affinity Capture-MS), FBXW11 (Affinity Capture-MS), DYRK1A (Affinity Capture-MS), LPIN1 (Affinity Capture-MS), FNTB (Affinity Capture-MS), LPIN2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4I9Y1, A0A0R4IBK5, A2ARZ3, A5WUT8, A6NKT7, A7S7F2, E9Q3L2, E9Q555, F1QB81, F5H4B4, H2QII6, O08662, O14715, O15050, O43310, P0DJD0, P0DJD1, P13864, P42356, P49792, Q06190, Q0V9S3, Q0VF22, Q16533, Q1LVQ2, Q24K09, Q2T9I9, Q4R6W9, Q4V847, Q5U228, Q63HN8, Q65Z40, Q6NU22, Q6NU51, Q7TPV2, Q7Z3J3, Q80TA9, Q811D2, Q86Y13, Q921I6

Diamond homologs: P32567, Q14693, Q7TNN8, Q91ZP3, Q92539, Q99PI4, Q99PI5, Q9BQK8, Q9FMN2, Q9SF47, Q9UUJ6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cell Cycle	5	12.0×	4e-04
Signaling by Rho GTPases	5	11.4×	4e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	5	11.2×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1033 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	18
Uncertain significance	454
Likely benign	363
Benign	71

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012310	NM_001375808.2(LPIN2):c.1691_1694del (p.Arg564fs)	Pathogenic
1069224	NM_001375808.2(LPIN2):c.2342_2346del (p.Lys781fs)	Pathogenic
1075334	NM_001375808.2(LPIN2):c.1843G>T (p.Glu615Ter)	Pathogenic
1098839	NM_001375808.2(LPIN2):c.696del (p.Thr233fs)	Pathogenic
1416971	NM_001375808.2(LPIN2):c.1826dup (p.Ser610fs)	Pathogenic
1432195	NM_001375808.2(LPIN2):c.2495_2496dup (p.Asn833Ter)	Pathogenic
1452588	NM_001375808.2(LPIN2):c.1160_1163del (p.Lys387fs)	Pathogenic
2138125	NM_001375808.2(LPIN2):c.1684C>T (p.Arg562Ter)	Pathogenic
21519	NM_001375808.2(LPIN2):c.2327+1G>C	Pathogenic
2165430	NM_001375808.2(LPIN2):c.2125A>T (p.Lys709Ter)	Pathogenic
234327	NM_001375808.2(LPIN2):c.132_135dup (p.Ser46fs)	Pathogenic
2425962	NC_000018.9:g.(?2656075)(2960838_?)del	Pathogenic
2745437	NM_001375808.2(LPIN2):c.475A>T (p.Arg159Ter)	Pathogenic
2760513	NM_001375808.2(LPIN2):c.1673G>A (p.Trp558Ter)	Pathogenic
2769904	NM_001375808.2(LPIN2):c.689del (p.Pro230fs)	Pathogenic
4681401	NM_001375808.2(LPIN2):c.776_777del (p.Glu259fs)	Pathogenic
4696723	NC_000018.10:g.2921627_2921649del	Pathogenic
4699857	NM_001375808.2(LPIN2):c.1975_1979del (p.Val658_Val659insTer)	Pathogenic
4720899	NM_001375808.2(LPIN2):c.973_976del (p.Val325fs)	Pathogenic
4732570	NM_001375808.2(LPIN2):c.441del (p.Phe147fs)	Pathogenic
489197	NM_001375808.2(LPIN2):c.1594C>T (p.Gln532Ter)	Pathogenic
4909	NM_001375808.2(LPIN2):c.540_541del (p.Thr180_Cys181insTer)	Pathogenic
548484	NM_001375808.2(LPIN2):c.469C>T (p.Arg157Ter)	Pathogenic
831706	NC_000018.10:g.(?2926703)(2929178_?)del	Pathogenic
832615	NC_000018.10:g.(?2931236)(2951376_?)del	Pathogenic
856331	NM_001375808.2(LPIN2):c.1924_1928del (p.Ser642fs)	Pathogenic
969143	NM_001375808.2(LPIN2):c.1042_1045delinsGTA (p.Pro348fs)	Pathogenic
1066630	NC_000018.9:g.(?2921511)(2938055_?)del	Likely pathogenic
1066965	NM_001375808.2(LPIN2):c.288+2T>G	Likely pathogenic
1474796	NM_001375808.2(LPIN2):c.2443-2A>G	Likely pathogenic

SpliceAI

5207 predictions. Top by Δscore:

Variant	Effect	Δscore
18:2892483:GCAA:G	donor_gain	1.0000
18:2892487:G:GG	donor_gain	1.0000
18:2913062:CGCAG:C	acceptor_loss	1.0000
18:2913063:GCAG:G	acceptor_loss	1.0000
18:2913064:CAGGG:C	acceptor_loss	1.0000
18:2913065:A:AG	acceptor_gain	1.0000
18:2913065:A:AT	acceptor_loss	1.0000
18:2913065:AG:A	acceptor_gain	1.0000
18:2913065:AGG:A	acceptor_gain	1.0000
18:2913066:G:GT	acceptor_gain	1.0000
18:2913066:GG:G	acceptor_gain	1.0000
18:2913066:GGG:G	acceptor_gain	1.0000
18:2913066:GGGGT:G	acceptor_gain	1.0000
18:2920772:ACTT:A	donor_loss	1.0000
18:2920773:CT:C	donor_loss	1.0000
18:2920774:TTACG:T	donor_loss	1.0000
18:2920775:TACGA:T	donor_loss	1.0000
18:2920776:A:AC	donor_gain	1.0000
18:2920777:C:CC	donor_gain	1.0000
18:2920777:CG:C	donor_gain	1.0000
18:2920777:CGA:C	donor_gain	1.0000
18:2920777:CGAT:C	donor_gain	1.0000
18:2920777:CGATG:C	donor_gain	1.0000
18:2920878:CATC:C	acceptor_gain	1.0000
18:2920880:TC:T	acceptor_gain	1.0000
18:2920880:TCC:T	acceptor_loss	1.0000
18:2920881:CC:C	acceptor_gain	1.0000
18:2920881:CCTG:C	acceptor_loss	1.0000
18:2920882:C:CC	acceptor_gain	1.0000
18:2920883:T:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000013200 (18:2999148 G>T), RS1000039512 (18:3011447 G>A), RS1000043907 (18:2929777 C>T), RS1000122307 (18:3004621 G>A,C), RS1000134696 (18:2924763 C>A,G), RS1000155824 (18:3004479 G>A), RS1000166125 (18:2975771 A>C), RS1000184894 (18:2934020 A>G), RS1000214562 (18:2950486 A>G), RS1000220705 (18:2959476 T>C), RS1000231010 (18:2982555 T>A,C), RS1000280811 (18:2940942 T>A,C), RS1000292664 (18:2968144 C>T), RS1000335087 (18:3002014 T>C), RS1000347780 (18:2940351 A>G,T)

Disease associations

OMIM: gene MIM:605519 | disease phenotypes: MIM:609628, MIM:177900

GenCC curated gene-disease

Disease	Classification	Inheritance
Majeed syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Majeed syndrome	Definitive	AR

Mondo (3): Majeed syndrome (MONDO:0012316), autoinflammatory syndrome (MONDO:0019751), psoriasis (MONDO:0005083)

Orphanet (2): Majeed syndrome (Orphanet:77297), Autoinflammatory syndrome (Orphanet:93665)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000823	Delayed puberty
HP:0000969	Edema
HP:0000988	Skin rash
HP:0001061	Acne
HP:0001371	Flexion contracture
HP:0001386	Joint swelling
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001935	Microcytic anemia
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0001974	Increased total leukocyte count
HP:0002024	Malabsorption
HP:0002113	Pulmonary infiltrates
HP:0002240	Hepatomegaly
HP:0002315	Headache
HP:0002653	Bone pain
HP:0002659	Increased susceptibility to fractures
HP:0002750	Delayed skeletal maturation
HP:0002754	Osteomyelitis
HP:0002829	Arthralgia
HP:0002907	Microscopic hematuria
HP:0003025	Metaphyseal irregularity
HP:0003326	Myalgia
HP:0003565	Elevated erythrocyte sedimentation rate

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001033_3	Type 2 diabetes	9.000000e-06
GCST001945_1	Body mass index in asthmatics	8.000000e-09
GCST002337_145	Amyotrophic lateral sclerosis (sporadic)	4.000000e-06
GCST003254_1	Urinary albumin-to-creatinine ratio in non-diabetics	9.000000e-06
GCST003542_27	Night sleep phenotypes	9.000000e-06
GCST010241_59	Apolipoprotein A1 levels	2.000000e-14
GCST90002396_683	Mean reticulocyte volume	2.000000e-15
GCST90002404_190	Red cell distribution width	1.000000e-16
GCST90002406_508	Reticulocyte fraction of red cells	1.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007778	urinary albumin to creatinine ratio
EFO:0007827	nighttime rest measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D011565	Psoriasis	C17.800.859.675
C537839	Majeed syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Lipid phosphate phosphatases

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects expression, decreases expression, affects cotreatment, increases abundance	4
Cyclosporine	decreases expression, decreases methylation, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
potassium perchlorate	decreases expression	1
salinomycin	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
aflatoxin B2	increases methylation	1
coumarin	affects phosphorylation	1
K 7174	increases expression	1
GW 4064	affects cotreatment, decreases expression	1
obeticholic acid	decreases expression	1
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Lovastatin	decreases response to substance	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00096980	PHASE4	COMPLETED	A Study to Evaluate Raptiva in Combination With Topical Psoriasis Therapies
NCT00110981	PHASE4	COMPLETED	Utilization of Narrow Band Ultraviolet B (UVB) Light Therapy and Etanercept for the Treatment of Psoriasis
NCT00111124	PHASE4	COMPLETED	Enbrel® in Psoriatic Arthritis
NCT00150930	PHASE4	UNKNOWN	Home UVB Phototherapy for Psoriasis: Effectiveness, Quality of Life and Cost-Effectiveness
NCT00161655	PHASE4	COMPLETED	Study Evaluating Etanercept and Methotrexate in Plaque Psoriasis
NCT00195507	PHASE4	COMPLETED	Study Evaluating Etanercept in the Treatment of Subjects With Psoriasis
NCT00249808	PHASE4	COMPLETED	A Study of Efalizumab in Participants With Moderate to Severe Chronic Psoriasis Who Have Failed, Have a Contraindication to, or Are Intolerant of Other Systemic Therapies
NCT00287118	PHASE4	COMPLETED	A Multicentre, Open Label Phase IIIb/IV Study of Subcutaneously Administered Raptiva in the Treatment of Adult Subjects With Moderate to Severe Plaque Psoriasis
NCT00312026	PHASE4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Efalizumab in Adult Patients With Plaque Psoriasis Involving the Hands and/or Feet
NCT00332332	PHASE4	COMPLETED	Canadian Assessment of Patient Outcomes and Effectiveness of Etanercept (Enbrel) in Psoriasis
NCT00336973	PHASE4	COMPLETED	A Study to Evaluate Raptiva in Subjects With Chronic Moderate or Worse Plaque Psoriasis Who Have Had an Inadequate Response to an Anti-TNF Agent
NCT00436540	PHASE4	COMPLETED	A Comparison Between Clobetasol Propionate 0.05% (Clobex®) Spray and Clobetasol Propionate 0.05% (Olux®) Foam
NCT00437619	PHASE4	COMPLETED	A Study of Sequential Treatment With Daivobet (Betamethasone Dipropionate Plus Calcipotriol) and Daivonex (Calcipotriol) in Patients With Psoriasis.
NCT00462072	PHASE4	COMPLETED	Centocor Microarray Study of Patients
NCT00581165	PHASE4	COMPLETED	Study Evaluating Safety of Etanercept in Treatment of Patients With Moderate to Severe Psoriasiswith Etanercept
NCT00581555	PHASE4	COMPLETED	Evaluation of Etanercept in Patients With Plaque Psoriasis After Stopping Ciclosporin Therapy
NCT00655564	PHASE4	COMPLETED	Long-Term One Year Use of Alefacept (Amevive®) in Moderate to Severe Chronic Plaque Type Psoriasis
NCT00663052	PHASE4	COMPLETED	Study Evaluating Etanercept for the Treatment of Moderate to Severe Psoriasis
NCT00669123	PHASE4	COMPLETED	Chondroitin Sulphate Efficay/Safety in Patients With Knee Osteoarthritis and Psoriasis
NCT00669214	PHASE4	COMPLETED	A Study to Evaluate the Safety and Efficacy of Efalizumab in Adult Patients With Moderate to Severe Plaque Psoriasis With Involvement of the Scalp
NCT00686595	PHASE4	COMPLETED	A Study to Evaluate the Switch From Etanercept to Infliximab in Subjects With Moderate-to-Severe Psoriasis (Study P05133)
NCT00697034	PHASE4	TERMINATED	Effects of Capsaicin on the Structure, Distribution, and Function of Cutaneous Small Nerve Fibers in Psoriatic Skin
NCT00723437	PHASE4	COMPLETED	Evaluation of the Efficacy of Acitretin Therapy for Nail Psoriasis
NCT00735787	PHASE4	COMPLETED	Controlled Study of Humira in Subjects With Chronic Plaque Psoriasis of the Hands and/or Feet
NCT00748020	PHASE4	COMPLETED	Narrow-Band UVB-Therapy in Psoriasis
NCT00763529	PHASE4	COMPLETED	Elocon vs Fluticasone in Localized Psoriasis (P03197)
NCT00791765	PHASE4	COMPLETED	Moderate to Severe Plaque Psoriasis With Scalp Involvement
NCT00842153	PHASE4	COMPLETED	Evaluation of the Efficacy and Tolerability of Clobetasol Propionate Foam Compared to Vehicle Foam
NCT00932113	PHASE4	COMPLETED	Mechanism of Action Study for Psoriasis
NCT00940862	PHASE4	COMPLETED	Effect of Adalimumab on Vascular Inflammation in Patients With Moderate to Severe Plaque Psoriasis
NCT00967538	PHASE4	COMPLETED	Safety and Efficacy of Etanercept in Patients With Psoriasis Who Failed to Respond to Other Biologic Treatments
NCT00992394	PHASE4	COMPLETED	Study Comparing 2 Different Strategies For Management of Subjects With Plaque Psoriasis Who Have Responded to Etanercept
NCT01039142	PHASE4	COMPLETED	Dose Ranging Study to Assess the Efficacy and Safety of Acitretin in Severe Plaque Type Psoriasis
NCT01053819	PHASE4	COMPLETED	Can We Miss Pigmented Lesions in Psoriasis Patients?
NCT01059773	PHASE4	COMPLETED	A Safety and Efficacy Study of Ustekinumab in Patients With Plaque Psoriasis Who Have Had an Inadequate Response to Methotrexate
NCT01077882	PHASE4	COMPLETED	Analysis of the Quality of Life, the Clinical Effectiveness and Cost-effectiveness of a Novel Educational Programme in Patients With Psoriasis and Atopic Dermatitis
NCT01079988	PHASE4	COMPLETED	Study of Therapeutic Options for Subjects Discontinuing Efalizumab and Experiencing Disease Recurrence
NCT01088165	PHASE4	UNKNOWN	The Influence of Adalimumab on Cardiovascular and Metabolic Risk in Psoriasis
NCT01132235	PHASE4	UNKNOWN	An Open-label Study to Evaluate the Efficacy of Re-treatment for Patients With a History of Etanercept Use
NCT01137032	PHASE4	COMPLETED	Study to Evaluate Effect of Pandel Cream 0.1% on HPA Axis in Pediatric and Adult Population