LIPH

Summary

LIPH (lipase H, HGNC:18483) is a protein-coding gene on chromosome 3q27.2, encoding Lipase member H (Q8WWY8). Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid.

This gene encodes a membrane-bound member of the mammalian triglyceride lipase family. It catalyzes the production of 2-acyl lysophosphatidic acid (LPA), which is a lipid mediator with diverse biological properties that include platelet aggregation, smooth muscle contraction, and stimulation of cell proliferation and motility.

Source: NCBI Gene 200879 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotrichosis 7 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 140 total — 7 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 25
• MANE Select transcript: NM_139248

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18483
Approved symbol	LIPH
Name	lipase H
Location	3q27.2
Locus type	gene with protein product
Status	Approved
Aliases	mPA-PLA1, PLA1B, mPA-PLA1alpha, LPDLR
Ensembl gene	ENSG00000163898
Ensembl biotype	protein_coding
OMIM	607365
Entrez	200879

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 nonsense_mediated_decay

ENST00000296252, ENST00000424591, ENST00000429510, ENST00000435679, ENST00000452897, ENST00000897634, ENST00000897635, ENST00000897636, ENST00000897637, ENST00000897638, ENST00000953488, ENST00000953489, ENST00000953490, ENST00000953491

RefSeq mRNA: 1 — MANE Select: NM_139248 NM_139248

CCDS: CCDS3272

Canonical transcript exons

ENST00000296252 — 10 exons

Exon	Start	End
ENSE00001079484	185514410	185514521
ENSE00001079496	185517067	185517162
ENSE00001152282	185511524	185511697
ENSE00001152304	185519142	185519309
ENSE00001152311	185524071	185524160
ENSE00001152318	185527484	185527585
ENSE00001152323	185533571	185533679
ENSE00001944700	185552423	185552588
ENSE00001957202	185506262	185508877
ENSE00003510196	185534765	185535132

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 94.30.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5238 / max 117.0665, expressed in 533 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45926	1.6707	466
45927	0.4483	205
45925	0.1826	93
45923	0.1181	60
45924	0.1042	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	94.30	gold quality
rectum	UBERON:0001052	92.99	gold quality
pancreatic ductal cell	CL:0002079	92.19	gold quality
mucosa of transverse colon	UBERON:0004991	91.28	gold quality
lower esophagus mucosa	UBERON:0035834	90.10	gold quality
islet of Langerhans	UBERON:0000006	89.32	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.14	gold quality
nasal cavity epithelium	UBERON:0005384	88.31	gold quality
epithelium of nasopharynx	UBERON:0001951	87.62	gold quality
nasopharynx	UBERON:0001728	87.61	gold quality
colonic mucosa	UBERON:0000317	87.28	gold quality
oviduct epithelium	UBERON:0004804	87.23	gold quality
ileal mucosa	UBERON:0000331	87.04	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.81	gold quality
esophagus squamous epithelium	UBERON:0006920	86.45	gold quality
amniotic fluid	UBERON:0000173	85.49	gold quality
palpebral conjunctiva	UBERON:0001812	83.89	gold quality
gall bladder	UBERON:0002110	83.89	gold quality
esophagus mucosa	UBERON:0002469	82.07	gold quality
adrenal tissue	UBERON:0018303	82.04	gold quality
minor salivary gland	UBERON:0001830	80.90	gold quality
right lung	UBERON:0002167	80.54	gold quality
body of stomach	UBERON:0001161	80.48	gold quality
transverse colon	UBERON:0001157	80.44	gold quality
stomach	UBERON:0000945	80.08	gold quality
colonic epithelium	UBERON:0000397	80.07	gold quality
upper lobe of left lung	UBERON:0008952	79.43	gold quality
upper lobe of lung	UBERON:0008948	79.28	gold quality
duodenum	UBERON:0002114	79.02	gold quality
epithelial cell of pancreas	CL:0000083	78.82	silver quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	44.51
E-GEOD-81547	yes	22.39
E-GEOD-83139	yes	10.81
E-ENAD-27	yes	4.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA4, IRF6, SP1, SP3

miRNA regulators (miRDB)

52 targeting LIPH, 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-4500	99.99	72.72	2367
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-6734-3P	99.15	66.27	1627

Literature-anchored findings (GeneRIF, showing 40)

• PA-selective PLA(1) has a role in LPA production. (PMID:12063250)
• mRNA expressed in intestine, lung, and pancreas. Lipase H protein was also detected in human intestine. (PMID:12213196)
• individuals with an inherited form of hair loss and a hair growth defect were homozygous for a deletion in the LIPH gene on chromosome 3q27; results suggest that lipase H participates in hair growth and development (PMID:17095700)
• identification of a novel deletion mutation in exon 2 of LIPH gene in a Pakistani family with autosomal recessive hypotrichosis (PMID:17333281)
• a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon causes autosomal recessive hypotrichosis (LAH2) (PMID:18445047)
• The deletion mutation (c.682delT) reported lies between beta9 and lid loops and changes the reading frame after 31 amino acids, thereby eliminating the lid peptide sequence required for substrate recognition in combination with beta9 loop. (PMID:18795930)
• gene duplication mutation in exon 2 was found to segregate with hypotrichosis in consanguineous and distantly related Izraeli families (PMID:18820939)
• LIPH is a second causative gene for ARWH/hypotrichosis, giving rise to a phenotype clinically indistinguishable from P2RY5 mutations (PMID:18830268)
• The mutations reported here are the first missense mutations identified in the LIPH gene, which extend the body of evidences implicating the LIPH gene in the pathogenesis of human hereditary hair loss. (PMID:19167195)
• crucial role of LIPH gene in hair growth. (PMID:19262606)
• Our study increases the spectrum of known LIPH mutations and provides biochemical evidence for the important role of lipase H and its product LPA in human hair growth (PMID:19536142)
• Mutations in LIPH result in variable degrees of hypotrichosis simplex, woolly hair is an essential component of the clinical spectrum;hot spot in the LIPH gene may be c.280_369dup in exon 2 (PMID:19766349)
• these findings not only expand the spectrum of LIPH mutations, but also provide a better understanding of the crucial role of the LIPH/LPA/P2Y5 signaling in hair growth in humans. (PMID:19892526)
• Studied five consanguineous Pakistani families with autosomal recessive hypotrichosis and identified a novel splice site and two previously reported mutations in the LIPH gene. (PMID:20107739)
• The results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA1a that are encoded by LIPH is involved in the pathogenesis of ARH. (PMID:20213768)
• 736T>A transition is highly specific and common in autosomal recessive woolly hair/hypotrichosis of Japanese origin. (PMID:21352330)
• Mutations identified in the present study extend the body of evidence implicating LPAR6 and LIPH genes in pathogenesis of human hereditary hair loss. (PMID:21426374)
• A phosphatidic acid-phospholipase A1alpha-lysophosphatidic acid-P2Y5 axis regulates differentiation of hair follicles via a tumour necrosis factor alpha converting enzyme-transforming growth factor alpha-epidermal growth factor receptor pathway. (PMID:21857648)
• the c.659_660delTA mutation in the LIPH gene caused autosomal recessive wooly hair/hypotrichosis phenotype in the studied family. (PMID:22125978)
• study extends the spectrum of mutations in LPAR6/P2RY5 gene and underscores those mutations in LPAR6/P2RY5 and LIPH result in similar phenotypes (PMID:22385360)
• Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood (PMID:22449147)
• The beta9 loop domain of PA-PLA1alpha has a crucial role in autosomal recessive woolly hair/hypotrichosis [case report] (PMID:22475755)
• analysis of the LIPH gene revealed homozygosity for a novel truncating mutation, as well as three previously identified mutations in affected individuals with autosomal recessive hypotrichosis and woolly hair. (PMID:23066499)
• Among South Indian subjects without diabetes, the rs1800588 C/T (C-480T) and rs6074 C/A (Thr479Thr) variants of the HL gene are associated with hypertriglyceridemia and low HDL-C, respectively. The TGC haplotype was significantly associated with low HDL-C (PMID:23550552)
• A case of Japanese siblings with autosomal recessive woolly hair associated with LIPH gene homozygous mutation of c.736T > A is presented. (PMID:23590372)
• Immunohistochemistry detected LIPH expression in most of the adenocarcinomas and bronchioloalveolar carcinomas obtained from lung cancer patients. LIPH expression was also observed less frequently in the squamous lung cancer tissue samples. (PMID:24380866)
• Mutation patterns of LIPH might be associated with hypotrichosis severity in autosomal recessive woolly hair/hypotrichosis. (PMID:24586639)
• sequencing LIPH identi fi ed a novel non-sense mutation (c.328C>T; p.Arg110*) in one and a previously reported 2-bp deletion mutation (c.659_660delTA, p.Ile220ArgfsX29) in three other families. (PMID:24628704)
• High LIPH expression is associated with metastasis in breast cancer. (PMID:25123262)
• c.460_461AG>GA (p.Ser154Asp) in exon 3 and c.742C>A (p.His248Asn) in exon 6 associated with autosomal recessive woolly hair (PMID:25201209)
• A heterozygous missense mutation c.736T>A (p.Cys246Ser) in exon 6 of the LIPH gene of both the affected individuals was identified. In addition, we also found that both patients carried heterozygous sequences in exon 5 of the LIPH gene. (PMID:25899282)
• Our data suggest that LIPH may have prognostic value for esophageal cancer. (PMID:26341494)
• The study further extends the body of evidence that sequence variants in the LIPH gene result in hypotrichosis and woolly hair phenotype. (PMID:26645693)
• The authors report no apparent decrease in total hair count but remarkable miniaturization and increased telogen/anagen hair ratio in patients homozygous mutations in LIPH. (PMID:27375176)
• The present study shows 93% of Japanese patients with ARWH had at least one of the two founder mutations in exon 6 of LIPH. Highly prevalent founder mutations in LIPH. (PMID:27641630)
• This meta-analysis demonstrates that the T allele in the LIPC rs493258 polymorphism was significantly associated with the risk of any and late age related macular degeneration (PMID:27763569)
• Novel sequence variants in the LIPH and LPAR6 genes underlies autosomal recessive woolly hair/hypotrichosis in three consanguineous Pakistani families. (PMID:28425126)
• Two mutants of LIPH lead to secretion defects of LIPH, which are involved in the pathogenesis of Autosomal recessive woolly hair/hypotrichosis. (PMID:29346610)
• Study analyzed a Japanese family with autosomal recessive woolly hair and identified a novel splice site mutation c.982+2T>A; +7_+21del in the LIPH gene, which caused skipping of exon 7 in cultured cells. (PMID:29974973)
• High LIPH expression is associated with Coronary Artery Disease. (PMID:30651409)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	lipia	ENSDARG00000007108
mus_musculus	Liph	ENSMUSG00000044626
rattus_norvegicus	AABR07034648.1	ENSRNOG00000047894
drosophila_melanogaster	CG5162	FBGN0030828
drosophila_melanogaster	CG6675	FBGN0032973
drosophila_melanogaster	CG6472	FBGN0034166
drosophila_melanogaster	CG5665	FBGN0036977
drosophila_melanogaster	sxe2	FBGN0038398
drosophila_melanogaster	CG4582	FBGN0039344
drosophila_melanogaster	CG6296	FBGN0039470
drosophila_melanogaster	CG6295	FBGN0039471
drosophila_melanogaster	CG17192	FBGN0039472
drosophila_melanogaster	CG17191	FBGN0039473
drosophila_melanogaster	CG6283	FBGN0039474
drosophila_melanogaster	CG6277	FBGN0039475
drosophila_melanogaster	CG6271	FBGN0039476
drosophila_melanogaster	CG4267	FBGN0264979
drosophila_melanogaster	CG18258	FBGN0265267

Paralogs (9): LIPG (ENSG00000101670), PLA1A (ENSG00000144837), LIPC (ENSG00000166035), LPL (ENSG00000175445), PNLIP (ENSG00000175535), PNLIPRP1 (ENSG00000187021), LIPI (ENSG00000188992), PNLIPRP3 (ENSG00000203837), PNLIPRP2 (ENSG00000266200)

Protein

Protein identifiers

Lipase member H — Q8WWY8 (reviewed: Q8WWY8)

Alternative names: LPD lipase-related protein, Membrane-associated phosphatidic acid-selective phospholipase A1-alpha, Phospholipase A1 member B

All UniProt accessions (5): A2IBA6, Q8WWY8, F8WE09, H7BZL3, H7C2X1

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid. Does not hydrolyze other phospholipids, like phosphatidylserine (PS), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) or triacylglycerol (TG).

Subunit / interactions. Interacts with TTMP/C3orf52.

Subcellular location. Secreted. Cell membrane.

Tissue specificity. Present in intestine (at protein level). Expressed in colon, prostate, kidney, pancreas, ovary, testis, intestine, lung and pancreas. Expressed at lower level in brain, spleen and heart. In the skin, it is prominently expressed in hair follicles, including the stem cell-rich bulge region and the inner root sheath.

Disease relevance. Hypotrichosis 7 (HYPT7) [MIM:604379] A condition characterized by the presence of less than the normal amount of hair. Affected individuals have sparse or absent scalp, axillary and body hair and sparse eyebrows and eyelashes. HYPT7 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Woolly hair autosomal recessive 2 (ARWH2) [MIM:604379] A hair shaft disorder characterized by fine and tightly curled hair. Compared to normal curly hair that is observed in some populations, woolly hair grows slowly and stops growing after a few inches. Under light microscopy, woolly hair shows some structural anomalies, including trichorrhexis nodosa and tapered ends. Some individuals may present with hypotrichosis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by sodium vanadate.

Similarity. Belongs to the AB hydrolase superfamily. Lipase family.

RefSeq proteins (1): NP_640341* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000734	TAG_lipase	Family
IPR013818	Lipase	Domain
IPR016272	Lipase_LIPH	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR033906	Lipase_N	Domain

Pfam: PF00151

Enzyme classification (BRENDA):

• EC 3.1.1.32 — phospholipase A1 (BRENDA: 55 organisms, 221 substrates, 99 inhibitors, 14 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

10 substrates with measured Km, best-characterized 10. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHATIDYLCHOLINE	0.11–4	4
1-PALMITOYL-2-ARACHIDONOYLGLYCEROPHOSPHOCHOLINE	0.5	1
DIACYL-SN-GLYCERO-3-PHOSPHORYLCHOLINE	0.6	1
DIACYL-SN-GLYCERO-3-PHOSPHORYLETHANOLAMINE	0.92	1
DIACYL-SN-GLYCERO-3-PHOSPHORYLSERINE	1.19	1
PHOSPHATIDIC ACID	2.38	1
PHOSPHATIDYLGLYCEROL	0.0003	1
SOYBEAN LECITHIN	18.53	1
TRIACYLGLYCEROL	1.53	1
HIGH-DENSITY LIPOPROTEIN	—	0

Catalyzed reactions (Rhea), 1 shown:

• 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 2-(9Z-octadecenoyl)-sn-glycero-3-phosphate + hexadecanoate + H(+) (RHEA:40943)

UniProt features (16 total): disulfide bond 4, sequence variant 3, active site 3, glycosylation site 3, signal peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WWY8-F1	90.89	0.80

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 (3): 154 (nucleophile); 178 (charge relay system); 248 (charge relay system)

Disulfide bonds (4): 284–292, 427–446, 233–246, 270–281

Glycosylation sites (3): 50, 66, 357

Mutagenesis-validated functional residues (1):

Position	Phenotype
154	loss of lipase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1483166	Synthesis of PA
R-HSA-1430728	Metabolism
R-HSA-1483206	Glycerophospholipid biosynthesis
R-HSA-1483257	Phospholipid metabolism
R-HSA-556833	Metabolism of lipids

MSigDB gene sets: 147 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, FISCHER_G1_S_CELL_CYCLE, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_GLYCEROLIPID_BIOSYNTHETIC_PROCESS, GOBP_GLYCEROPHOSPHOLIPID_METABOLIC_PROCESS, GOBP_LIPID_METABOLIC_PROCESS, GOMF_GLYCOSAMINOGLYCAN_BINDING, DOUGLAS_BMI1_TARGETS_DN, GOBP_LIPID_BIOSYNTHETIC_PROCESS, GOBP_LIPID_CATABOLIC_PROCESS, CERVERA_SDHB_TARGETS_1_UP, RICKMAN_TUMOR_DIFFERENTIATED_MODERATELY_VS_POORLY_UP

GO Biological Process (3): phosphatidic acid biosynthetic process (GO:0006654), lipid catabolic process (GO:0016042), lipid metabolic process (GO:0006629)

GO Molecular Function (6): glycerophospholipase activity (GO:0004620), heparin binding (GO:0008201), carboxylic ester hydrolase activity (GO:0052689), protein binding (GO:0005515), lipase activity (GO:0016298), hydrolase activity (GO:0016787)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1
Phospholipid metabolism	1
Metabolism of lipids	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hydrolase activity, acting on ester bonds	2
cellular anatomical structure	2
phosphatidic acid metabolic process	1
glycerophospholipid biosynthetic process	1
lipid metabolic process	1
catabolic process	1
primary metabolic process	1
phospholipase activity	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
catalytic activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

526 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LIPH	LPAR6	P43657	949
LIPH	POU2F3	Q9UKI9	905
LIPH	LPAR3	Q9UBY5	885
LIPH	DDHD2	O94830	582
LIPH	DSG4	Q86SJ6	572
LIPH	Q5T8A5	Q5T8A5	495
LIPH	KRT74	Q7RTS7	484
LIPH	ENPP2	Q13822	447
LIPH	GDPD1	Q8N9F7	447
LIPH	DDHD1	Q8NEL9	447
LIPH	PLAAT1	Q9HDD0	446
LIPH	C3orf52	Q5BVD1	434
LIPH	GDPD3	Q7L5L3	432
LIPH	HSPA13	P48723	426
LIPH	FBXO6	Q9NRD1	411

IntAct

7 interactions, top by confidence:

A	B	Type	Score
LIPH	LRP5	psi-mi:“MI:0914”(association)	0.530
LIPH	H1-0	psi-mi:“MI:0915”(physical association)	0.400
LIPH	H3-4	psi-mi:“MI:0915”(physical association)	0.400
LIPH	B4GALT5	psi-mi:“MI:0914”(association)	0.350
TTMP	NBAS	psi-mi:“MI:0914”(association)	0.350
CEACAM21	GAPDHS	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): MSTO1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), DYRK1A (Affinity Capture-MS), DHX32 (Affinity Capture-MS), PTER (Affinity Capture-MS), FLT4 (Affinity Capture-MS), RTEL1 (Affinity Capture-MS), P3H4 (Affinity Capture-MS), DNAJC12 (Affinity Capture-MS), BRIP1 (Affinity Capture-MS), NAA10 (Affinity Capture-MS), TUBA1A (Affinity Capture-MS), ZNHIT6 (Affinity Capture-MS), NAGLU (Affinity Capture-MS), CAMK2B (Affinity Capture-MS)

ESM2 similar proteins: A1A4K5, A2BGL3, J3RZ81, O46559, O46647, P06858, P07867, P11150, P11151, P11152, P11153, P11602, P13612, P22413, P27656, P28825, P49060, P49923, P55031, P97535, Q06000, Q08761, Q13219, Q16819, Q29524, Q2TBF2, Q32PY2, Q3SZ79, Q53H76, Q5E9H0, Q5NDE3, Q5NDE4, Q5NDE5, Q5NDE8, Q5RBQ5, Q5XGE9, Q641F6, Q64230, Q64610, Q6DBU8

Diamond homologs: A0A0M3KKW3, A2VBC4, C0HLL3, O46559, P06857, P07867, P0CH47, P0CH86, P0CH87, P0DMB4, P0DMB5, P0DMB7, P0DMB8, P0DPT0, P0DSI2, P11150, P11602, P27656, P29183, P49369, P51528, P53357, P54315, P54316, P81139, Q02157, Q06478, Q3SZ79, Q3ZU95, Q5BKQ4, Q5XGE9, Q68KK0, Q6NYZ4, Q6Q249, Q6Q250, Q6Q251, Q6Q252, Q6XZB0, Q7M3V3, Q7M3V4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LIPH	up-regulates	LPAR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	3
Uncertain significance	71
Likely benign	21
Benign	26

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
2671619	Single allele	Pathogenic
3301	NG_012183.1:g.(2711_2742)_(3942_3973)del	Pathogenic
3302	NM_139248.3(LIPH):c.346_350del (p.Ile116fs)	Pathogenic
3303	NM_139248.3(LIPH):c.659_660del (p.Ile220fs)	Pathogenic
3304	NM_139248.3(LIPH):c.886+405_1094+962del	Pathogenic
3305	NM_139248.3(LIPH):c.322T>C (p.Trp108Arg)	Pathogenic
3306	NM_139248.3(LIPH):c.280_369dup (p.Lys123_Thr124insGlyLeuLeuSerValGluAspMetAsnValValValValAspTrpAsnArgGlyAlaThrThrLeuIleTyrThrHisAlaSerSerLys)	Pathogenic
3391346	NM_139248.3(LIPH):c.263del (p.Met88fs)	Likely pathogenic
3682459	NM_139248.3(LIPH):c.982+1G>C	Likely pathogenic
3775180	NM_139248.3(LIPH):c.686delinsGTAGAACCCAACCTGGCT (p.Asp229fs)	Likely pathogenic

SpliceAI

2140 predictions. Top by Δscore:

Variant	Effect	Δscore
3:185514404:A:C	donor_gain	1.0000
3:185514406:TTA:T	donor_loss	1.0000
3:185514407:TACTG:T	donor_loss	1.0000
3:185514408:A:AC	donor_gain	1.0000
3:185514408:ACTGA:A	donor_loss	1.0000
3:185514409:C:CA	donor_gain	1.0000
3:185514409:C:T	donor_loss	1.0000
3:185514409:CT:C	donor_gain	1.0000
3:185514409:CTG:C	donor_gain	1.0000
3:185514409:CTGA:C	donor_gain	1.0000
3:185514409:CTGAT:C	donor_gain	1.0000
3:185514517:ATACA:A	acceptor_gain	1.0000
3:185514518:TACA:T	acceptor_gain	1.0000
3:185514519:ACA:A	acceptor_gain	1.0000
3:185514520:CA:C	acceptor_gain	1.0000
3:185514520:CAC:C	acceptor_gain	1.0000
3:185514522:C:A	acceptor_loss	1.0000
3:185514522:C:CC	acceptor_gain	1.0000
3:185517065:A:AC	donor_gain	1.0000
3:185517066:C:CC	donor_gain	1.0000
3:185517066:CTG:C	donor_gain	1.0000
3:185517087:G:C	donor_gain	1.0000
3:185519315:T:TC	acceptor_gain	1.0000
3:185533703:T:TC	acceptor_gain	1.0000
3:185508875:GGCC:G	acceptor_loss	0.9900
3:185508876:GCCT:G	acceptor_loss	0.9900
3:185508878:C:A	acceptor_loss	0.9900
3:185508878:C:CC	acceptor_gain	0.9900
3:185511549:A:C	donor_gain	0.9900
3:185514405:CTTA:C	donor_gain	0.9900

AlphaMissense

2975 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:185533635:A:C	S154R	0.996
3:185533635:A:T	S154R	0.996
3:185533637:T:G	S154R	0.996
3:185534860:A:G	W108R	0.996
3:185534860:A:T	W108R	0.996
3:185519291:C:G	C246S	0.995
3:185519292:A:T	C246S	0.995
3:185524091:C:G	C233S	0.995
3:185524092:A:T	C233S	0.995
3:185534858:C:A	W108C	0.995
3:185534858:C:G	W108C	0.995
3:185527582:A:G	L177P	0.993
3:185534923:A:G	W87R	0.993
3:185534923:A:T	W87R	0.993
3:185534948:G:C	F78L	0.993
3:185534948:G:T	F78L	0.993
3:185534950:A:G	F78L	0.993
3:185519286:G:C	H248D	0.992
3:185524092:A:G	C233R	0.992
3:185527534:A:G	L193S	0.992
3:185519291:C:A	C246F	0.990
3:185527579:T:C	D178G	0.990
3:185534865:A:T	V106D	0.990
3:185534921:C:A	W87C	0.990
3:185534921:C:G	W87C	0.990
3:185527499:G:C	H205D	0.989
3:185533628:C:G	A157P	0.989
3:185533636:C:A	S154I	0.989
3:185519292:A:G	C246R	0.988
3:185527520:C:G	A198P	0.988

dbSNP variants (sampled 300 via entrez): RS1000073853 (3:185507919 T>C), RS1000083417 (3:185549734 A>G), RS1000183663 (3:185508514 C>G,T), RS1000372242 (3:185515698 T>C), RS1000417805 (3:185538575 T>C,G), RS1000462789 (3:185525636 A>G), RS1000516090 (3:185523134 G>A), RS1000663963 (3:185543779 A>G), RS1000667584 (3:185519203 A>C,G,T), RS1000765087 (3:185525999 A>G), RS1000801451 (3:185530244 T>C), RS1000902066 (3:185512613 C>T), RS1001053734 (3:185549845 C>T), RS1001113425 (3:185543303 C>A,T), RS1001139170 (3:185528345 A>T)

Disease associations

OMIM: gene MIM:607365 | disease phenotypes: MIM:604379

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotrichosis 7	Definitive	Autosomal recessive
isolated familial wooly hair disorder	Supportive	Autosomal dominant
hypotrichosis simplex	Supportive	Autosomal dominant

Mondo (3): hypotrichosis 7 (MONDO:0011452), hypotrichosis simplex (MONDO:0018914), isolated familial wooly hair disorder (MONDO:0008686)

Orphanet (1): Hypotrichosis simplex (Orphanet:55654)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000479	Abnormal retinal morphology
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000615	Abnormal pupil morphology
HP:0000653	Sparse eyelashes
HP:0000951	Abnormality of the skin
HP:0000971	Abnormal sweat gland morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0002209	Sparse scalp hair
HP:0002213	Fine hair
HP:0002215	Sparse axillary hair
HP:0002217	Slow-growing hair
HP:0002224	Woolly hair
HP:0002231	Sparse body hair
HP:0002299	Brittle hair
HP:0003577	Congenital onset
HP:0005338	Sparse lateral eyebrow
HP:0005599	Hypopigmentation of hair
HP:0008070	Sparse hair
HP:0010719	Abnormality of hair texture
HP:0025249	Comedo
HP:0045075	Sparse eyebrow

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST012227_1011	Hip circumference adjusted for BMI	8.000000e-09
GCST012227_1012	Hip circumference adjusted for BMI	8.000000e-09
GCST90020028_1694	Hip circumference adjusted for BMI	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C537160	Hypotrichosis simplex (supp.)
C536973	Total Hypotrichosis, Mari type (supp.)
C536745	Woolly hair, congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, decreases reaction, affects cotreatment, increases expression	5
sodium arsenite	increases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression	2
Nickel	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Glyphosate	decreases expression	1
Arsenic	affects methylation	1
Bleomycin	decreases expression	1
Cadmium	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03492866	PHASE2	UNKNOWN	Efficacy of Topical Gentamycin for Hereditary Hypotrichosis Simplex Caused by Nonsense Mutations in CDSN