LPAR6

Summary

LPAR6 (lysophosphatidic acid receptor 6, HGNC:15520) is a protein-coding gene on chromosome 13q14.2, encoding Lysophosphatidic acid receptor 6 (P43657). Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA).

The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene aligns with an internal intron of the retinoblastoma susceptibility gene in the reverse orientation. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 10161 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypotrichosis 8 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 113 total — 14 pathogenic, 12 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001162498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15520
Approved symbol	LPAR6
Name	lysophosphatidic acid receptor 6
Location	13q14.2
Locus type	gene with protein product
Status	Approved
Aliases	P2Y5
Ensembl gene	ENSG00000139679
Ensembl biotype	protein_coding
OMIM	609239
Entrez	10161

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding_CDS_not_defined, 4 protein_coding

ENST00000345941, ENST00000378434, ENST00000462781, ENST00000464486, ENST00000465365, ENST00000470937, ENST00000481832, ENST00000482024, ENST00000620633, ENST00000941181

RefSeq mRNA: 5 — MANE Select: NM_001162498 NM_001162497, NM_001162498, NM_001377316, NM_001377317, NM_005767

CCDS: CCDS9410

Canonical transcript exons

ENST00000620633 — 1 exons

Exon	Start	End
ENSE00003719419	48411138	48413113

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.6872 / max 419.5339, expressed in 1244 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137255	12.2826	1218
137254	1.7844	502
137253	0.5233	196
137256	0.0746	51
137257	0.0223	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	97.92	gold quality
gingiva	UBERON:0001828	97.78	gold quality
lower esophagus mucosa	UBERON:0035834	97.43	gold quality
monocyte	CL:0000576	96.93	gold quality
mononuclear cell	CL:0000842	96.84	gold quality
leukocyte	CL:0000738	96.72	gold quality
tongue squamous epithelium	UBERON:0006919	96.70	silver quality
esophagus mucosa	UBERON:0002469	96.47	gold quality
skin of hip	UBERON:0001554	95.96	gold quality
minor salivary gland	UBERON:0001830	95.89	gold quality
oral cavity	UBERON:0000167	95.86	gold quality
mouth mucosa	UBERON:0003729	95.77	gold quality
vagina	UBERON:0000996	95.60	gold quality
granulocyte	CL:0000094	95.15	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.10	gold quality
calcaneal tendon	UBERON:0003701	94.56	gold quality
gall bladder	UBERON:0002110	94.53	gold quality
cauda epididymis	UBERON:0004360	94.39	gold quality
saliva-secreting gland	UBERON:0001044	94.37	gold quality
squamous epithelium	UBERON:0006914	94.22	gold quality
upper leg skin	UBERON:0004262	94.17	gold quality
mammary duct	UBERON:0001765	94.05	gold quality
esophagus squamous epithelium	UBERON:0006920	93.84	gold quality
cervix epithelium	UBERON:0004801	93.67	gold quality
omental fat pad	UBERON:0010414	93.65	gold quality
peritoneum	UBERON:0002358	93.63	gold quality
prostate gland	UBERON:0002367	93.63	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.62	gold quality
seminal vesicle	UBERON:0000998	93.44	gold quality
parietal pleura	UBERON:0002400	93.42	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-76312	yes	2513.46
E-GEOD-110499	yes	162.38
E-HCAD-25	yes	19.46
E-ANND-3	yes	17.19
E-MTAB-6701	yes	12.47
E-CURD-112	yes	12.31
E-MTAB-9067	yes	6.77
E-CURD-97	no	1431.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting LPAR6, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5696	99.98	72.36	4487
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-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-593-5P	99.34	69.50	965

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 31)

• Autosomal recessive form of hypotrichosis simplex mapped to chromosome 13q14.11-13q21.33, and identified homozygous truncating mutations in P2RY5. (PMID:18297070)
• Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair. (PMID:18297072)
• In the present study, 14 of 22 families with autosomal recessive hypotrichosis show linkage to LAH3 locus on chromosome 13q14.11-q21.32. Affected individuals of all the 22 families have common clinical features. (PMID:18461368)
• Our findings show that mutations in P2RY5 display variable expressivity, underlying both hypotrichosis and woolly hair, and underscore the essential role of P2RY5 in the tissue integrity and maintenance of the hair follicle. (PMID:18692127)
• There is an involvement of P2RY5 mutations in hereditary hair diseases. (PMID:18803659)
• LIPH is a second causative gene for ARWH/hypotrichosis, giving rise to a phenotype clinically indistinguishable from P2RY5 mutations (PMID:18830268)
• gene is involved in genetics of hypotrichosis simplex and autosomal recessive wooly hair syndrome. (PMID:19061667)
• Mutations revealed in the results extend the body of evidence implicating the P2RY5 gene in the pathogenesis of human hereditary hair loss. (PMID:19292720)
• study increases the spectrum of known P2RY5 mutations and highlights the importance of this receptor in human hair growth and texture (PMID:19529952)
• 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)
• 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)
• These findings extend the spectrum of known LPAR6 mutations and suggest a founder effect of the p.G146R mutation in the Pakistani population (PMID:22531990)
• homozygous loss of the entire LPAR6 gene in a Turkish family with hypotrichosis and woolly hair (PMID:22621192)
• LPA2 and LPA6 receptor subtypes are predominant in both HPAECs and HMVECs (PMID:23084965)
• We have identified a novel deletion mutation in LPAR6, which was responsible for autosomal woolly hair syndrome with hypotrichosis in a consanguineous Chinese family. (PMID:23773027)
• Missense mutations in LPAR6 reveal abnormal phospholipid signaling pathways leading to hypotrichosis. (PMID:25119526)
• LPAR6 has a role in tumorigenicity of hepatocellular carcinoma (PMID:25589345)
• These results suggest that the diverse roles of LPA4, LPA5 and LPA6 are involved in the activation of tumor progression in pancreatic cancer cells. (PMID:25849892)
• LPA2 mRNA levels were associated with poorer differentiation, and higher LPA6 levels were associated with microvascular invasion in HCC; both became a risk factor for recurrence after surgical treatment when combined with increased serum ATX levels (PMID:27583415)
• Novel sequence variants in the LIPH and LPAR6 genes underlies autosomal recessive woolly hair/hypotrichosis in three consanguineous Pakistani families. (PMID:28425126)
• DLD-C-F cells formed large-sized colonies, but not DLD-F-C cells, correlating with LPAR1 and LPAR6 gene expression levels. These results suggest that LPA1 and LPA6 may regulate the colony formation activity in DLD1 cells treated with anticancer drugs. (PMID:29369010)
• mRNA expression analyses revealed that ADSCs and MES largely expressed LPA receptor 1 (LPAR1) while epithelial cells mainly expressed LPAR6. LPA 18:1 activated all the cell populations and cell lines by rise in cytosolic free calcium concentrations. MES and ADSCs expressed ATX whereas epithelial cells did not. (PMID:30567518)
• LPAR6 was downregulated in breast cancer(BC), and low LPAR6 expression was related to poor prognosis. The anti-tumor drug 5-Aza significantly upregulated LPAR6 expression in vitro, and LPAR6 might act as a tumor suppressor in BC. (PMID:30694446)
• Study revealed a novel homozygous missense mutation c.47A>T (p.Lys16Met) in the LPAR6 gene in Pakistani family with autosomal recessive wooly hair/hypotrichosis. (PMID:31077348)
• A potential target for liver cancer management, lysophosphatidic acid receptor 6 (LPAR6), is transcriptionally up-regulated by the NCOA3 coactivator. (PMID:31914406)
• A distinctive protein signature induced by lysophosphatidic acid receptor 6 (LPAR6) expression in hepatocellular carcinoma cells. (PMID:32321639)
• Autosomal recessive woolly hair and hypotrichosis in two Caucasian dizygotic twins. Description of a novel biallelic mutation in the LPAR6 gene. (PMID:33017051)
• Lysophosphatidic Acid Receptor 6 (LPAR6) Is a Potential Biomarker Associated with Lung Adenocarcinoma. (PMID:34769557)
• Cell-trafficking impairment in disease-associated LPA6 missense mutants and a potential pharmacoperone therapy for autosomal recessive woolly hair/hypotrichosis. (PMID:36173926)
• Loss of LPAR6 and CAB39L dysregulates the basal-to-luminal urothelial differentiation program, contributing to bladder carcinogenesis. (PMID:38676926)
• Expression of turkey (Meleagris gallopavo) 6H1/p2y5 receptor in human astrocytoma cells and measurement of second mesenger levels indicate it is not a member of the P2Y receptor family. (PMID:9240460)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lpar6a	ENSDARG00000062552
danio_rerio	lpar6b	ENSDARG00000069441
mus_musculus	Lpar6	ENSMUSG00000033446
rattus_norvegicus	Lpar6	ENSRNOG00000086236

Paralogs (16): P2RY10 (ENSG00000078589), GPR18 (ENSG00000125245), F2RL3 (ENSG00000127533), GPR55 (ENSG00000135898), GPR65 (ENSG00000140030), GPR17 (ENSG00000144230), LPAR4 (ENSG00000147145), CYSLTR2 (ENSG00000152207), F2RL2 (ENSG00000164220), F2RL1 (ENSG00000164251), CYSLTR1 (ENSG00000173198), GPR4 (ENSG00000177464), GPR35 (ENSG00000178623), F2R (ENSG00000181104), P2RY8 (ENSG00000182162), GPR20 (ENSG00000204882)

Protein

Protein identifiers

Lysophosphatidic acid receptor 6 — P43657 (reviewed: P43657)

Alternative names: Oleoyl-L-alpha-lysophosphatidic acid receptor, P2Y purinoceptor 5, Purinergic receptor 5, RB intron encoded G-protein coupled receptor

All UniProt accessions (1): P43657

UniProt curated annotations — full annotation on UniProt →

Function. Binds to oleoyl-L-alpha-lysophosphatidic acid (LPA). Intracellular cAMP is involved in the receptor activation. Important for the maintenance of hair growth and texture.

Subcellular location. Cell membrane.

Tissue specificity. Expressed ubiquitously, including in skin and hair follicle cells. Detected in both Henle’s and Huxley’s layers of the inner root sheath of the hair follicle and in suprabasal layers of the epidermis (at protein level). Expressed at low levels in peripheral blood leukocytes.

Disease relevance. Woolly hair autosomal recessive 1 with or without hypotrichosis (ARWH1) [MIM:278150] 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 exhibit features of hypotrichosis. The disease is caused by variants affecting the gene represented in this entry. Hypotrichosis 8 (HYPT8) [MIM:278150] A condition characterized by the presence of less than the normal amount of hair and abnormal hair follicles and shafts, which are thin and atrophic. The disorder affects the trunk and extremities as well as the scalp, and the eyebrows and eyelashes may also be involved, whereas beard, pubic, and axillary hairs are largely spared. In addition, patients can develop hyperkeratotic follicular papules, erythema, and pruritus in affected areas. In some patients with congenital hypotrichosis, monilethrix-like hairs showing elliptical nodes have been observed. HYPT8 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. This is a nested gene within intron 17 of the retinoblastoma gene.

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (5): NP_001155969, NP_001155970, NP_001364245, NP_001364246, NP_005758 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (55 total): helix 15, sequence variant 12, topological domain 8, transmembrane region 7, strand 4, sequence conflict 3, chain 1, lipid moiety-binding region 1, glycosylation site 1, disulfide bond 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9ITB	ELECTRON MICROSCOPY	2.89
9ITE	ELECTRON MICROSCOPY	3.06

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43657-F1	84.48	0.49

Antibody-complex structures (SAbDab): 2 — 9ITB, 9ITE

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 (1): 284

Disulfide bonds (1): 89–168

Glycosylation sites (1): 5

Mutagenesis-validated functional residues (1):

Position	Phenotype
246	loss of g protein-coupled receptor signaling. reduced localization to cell membrane. decreased protein abundance. increa

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-416476	G alpha (q) signalling events
R-HSA-417957	P2Y receptors
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-418038	Nucleotide-like (purinergic) receptors
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 300 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, MODULE_64, REACTOME_P2Y_RECEPTORS, GOZGIT_ESR1_TARGETS_DN, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, MODULE_289, MODULE_171, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION

GO Biological Process (3): blastocyst hatching (GO:0001835), G protein-coupled receptor signaling pathway (GO:0007186), signal transduction (GO:0007165)

GO Molecular Function (3): lysophosphatidic acid receptor activity (GO:0070915), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Nucleotide-like (purinergic) receptors	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
blastocyst development	1
hatching	1
G protein-coupled receptor activity	1
signal transduction	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
lysophosphatidic acid binding	1
bioactive lipid receptor activity	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LPAR6	LIPH	Q8WWY8	949
LPAR6	GNA12	Q03113	948
LPAR6	LPAR3	Q9UBY5	940
LPAR6	LPAR1	P78351	923
LPAR6	LPAR2	Q9HBW0	880
LPAR6	KRT74	Q7RTS7	863
LPAR6	GNAQ	P50148	771
LPAR6	DSG4	Q86SJ6	758
LPAR6	ENPP2	Q13822	735
LPAR6	GDPD1	Q8N9F7	704
LPAR6	PLA1A	Q53H76	693
LPAR6	GDPD3	Q7L5L3	691
LPAR6	DSC3	Q14574	685
LPAR6	DSC2	Q02487	684
LPAR6	POU2F3	Q9UKI9	652

IntAct

19 interactions, top by confidence:

A	B	Type	Score
LPAR6	SMIM3	psi-mi:“MI:0915”(physical association)	0.560
LPAR6	RPRM	psi-mi:“MI:0915”(physical association)	0.560
LPAR6	EMP1	psi-mi:“MI:0915”(physical association)	0.560
LPAR6	SEC22A	psi-mi:“MI:0915”(physical association)	0.560
LPAR6	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
LPAR6	bipA	psi-mi:“MI:0915”(physical association)	0.370
LPAR6	DEGS1	psi-mi:“MI:0914”(association)	0.350
LPAR6	STX10	psi-mi:“MI:0914”(association)	0.350
LPAR6	GAPDHS	psi-mi:“MI:0914”(association)	0.350
SMIM3	LPAR6	psi-mi:“MI:0915”(physical association)	0.000
SEC22A	LPAR6	psi-mi:“MI:0915”(physical association)	0.000
RPRM	LPAR6	psi-mi:“MI:0915”(physical association)	0.000
EMP1	LPAR6	psi-mi:“MI:0915”(physical association)	0.000
	LPAR6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (115): RARS2 (Affinity Capture-MS), ARL5B (Affinity Capture-MS), LMBRD2 (Affinity Capture-MS), ATP8B2 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), ZDHHC17 (Affinity Capture-MS), KDELR3 (Affinity Capture-MS), ATM (Affinity Capture-MS), LRIG3 (Affinity Capture-MS), IPO11 (Affinity Capture-MS), COG1 (Affinity Capture-MS), VMP1 (Affinity Capture-MS), BDH1 (Affinity Capture-MS), PKP2 (Affinity Capture-MS), ATL3 (Affinity Capture-MS)

ESM2 similar proteins: A0A4W3GG95, A7YY44, B0F9W3, B0UXR0, B2GV46, B3G515, B5X337, E7FEL0, O00398, O46685, O70526, P21556, P25023, P25105, P25116, P26824, P30411, P30558, P32299, P43657, P46002, P46093, P49019, P50132, P56488, Q00991, Q15743, Q1JQB3, Q28642, Q3UFD7, Q4G072, Q4KLH9, Q61038, Q62035, Q80Z39, Q8BFQ3, Q8BFU7, Q8BLG2, Q8BMC0, Q8BUD0

Diamond homologs: A5PLE7, B0UXR0, B5X337, D4A7K7, F1MV99, O08858, O35210, O35811, O77590, O88634, P11613, P21556, P25025, P25095, P25104, P25106, P26824, P29089, P29754, P29755, P30555, P30556, P30937, P30938, P31391, P32249, P32250, P32300, P33396, P33535, P34976, P35346, P35366, P35372, P35373, P35383, P41143, P41231, P41232, P42866

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
LPAR6	up-regulates	GNAQ	binding
LPAR6	“up-regulates activity”	GNAI1	binding
LPAR6	“up-regulates activity”	GNAI3	binding
LPAR6	“up-regulates activity”	GNAO1	binding
LPAR6	“up-regulates activity”	GNAZ	binding
LPAR6	“up-regulates activity”	GNA14	binding
LPAR6	“up-regulates activity”	GNA12	binding
LPAR6	“up-regulates activity”	GNA13	binding
“lysophosphatidic acid”	“up-regulates activity”	LPAR6	“chemical activation”
LPAR6	“up-regulates activity”	GNAS	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	12
Uncertain significance	45
Likely benign	24
Benign	11

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1070856	NC_000013.10:g.(?48877851)(49054207_?)del	Pathogenic
1071014	NC_000013.10:g.(?48985727)(49039514_?)dup	Pathogenic
1323245	NM_000321.3(RB1):c.1695+30914_1695+30917dup	Pathogenic
1457430	NC_000013.10:g.(?48517506)(49070513_?)del	Pathogenic
1685927	NM_001162498.3(LPAR6):c.1A>G (p.Met1Val)	Pathogenic
1802233	NM_001162498.3(LPAR6):c.207_210dup (p.Pro71fs)	Pathogenic
2506997	NM_001162498.3(LPAR6):c.145C>T (p.Arg49Ter)	Pathogenic
3244120	NC_000013.10:g.(?48877814)(49054207_?)del	Pathogenic
3244128	NC_000013.10:g.(?48916725)(49054207_?)del	Pathogenic
3244130	NC_000013.10:g.(?48934141)(49054207_?)del	Pathogenic
831300	NC_000013.11:g.(?48302747)(48482890_?)del	Pathogenic
831520	NC_000013.11:g.(?48303701)(48480071_?)del	Pathogenic
832525	NC_000013.11:g.(?48303701)(48412896_?)del	Pathogenic
832535	NC_000013.11:g.(?48379574)(48480071_?)del	Pathogenic
1824	NM_001162498.3(LPAR6):c.463C>T (p.Gln155Ter)	Likely pathogenic
1828	NM_001162498.3(LPAR6):c.436G>A (p.Gly146Arg)	Likely pathogenic
217499	NM_001162498.3(LPAR6):c.188A>T (p.Asp63Val)	Likely pathogenic
2505340	NM_001162498.3(LPAR6):c.742A>T (p.Asn248Tyr)	Likely pathogenic
2505341	NM_001162498.3(LPAR6):c.830T>C (p.Leu277Pro)	Likely pathogenic
2505342	NM_001162498.3(LPAR6):c.833G>A (p.Cys278Tyr)	Likely pathogenic
3250465	NM_001162498.3(LPAR6):c.924del (p.Val309fs)	Likely pathogenic
3367022	NM_001162498.3(LPAR6):c.255del (p.Asp86fs)	Likely pathogenic
3768194	NM_001162498.3(LPAR6):c.736A>G (p.Asn246Asp)	Likely pathogenic
3891587	NM_001162498.3(LPAR6):c.787_788del (p.Cys263fs)	Likely pathogenic
4073585	NM_001162498.3(LPAR6):c.84del (p.Phe28fs)	Likely pathogenic
592094	NM_001162498.3(LPAR6):c.373_374del (p.Lys125fs)	Likely pathogenic

SpliceAI

1038 predictions. Top by Δscore:

Variant	Effect	Δscore
13:48415811:C:CC	acceptor_gain	0.9900
13:48416496:A:C	donor_gain	0.9900
13:48444548:CTTA:C	donor_loss	0.9900
13:48444549:TTA:T	donor_loss	0.9900
13:48444550:TA:T	donor_loss	0.9900
13:48444551:A:AC	donor_gain	0.9900
13:48444551:A:C	donor_loss	0.9900
13:48444552:C:CC	donor_gain	0.9900
13:48413107:TTTCT:T	acceptor_gain	0.9800
13:48413108:TTCT:T	acceptor_gain	0.9800
13:48413110:CT:C	acceptor_gain	0.9800
13:48413112:C:CC	acceptor_gain	0.9800
13:48413117:G:GC	acceptor_gain	0.9800
13:48416473:AGGC:A	donor_gain	0.9800
13:48415807:GGGA:G	acceptor_gain	0.9700
13:48415808:GGA:G	acceptor_gain	0.9700
13:48415823:G:GT	donor_gain	0.9700
13:48417166:CA:C	donor_gain	0.9700
13:48444552:CCGG:C	donor_gain	0.9700
13:48444552:CCGGT:C	donor_gain	0.9700
13:48413111:TCTGA:T	acceptor_loss	0.9600
13:48413112:CTGAA:C	acceptor_loss	0.9600
13:48413113:T:A	acceptor_loss	0.9600
13:48413379:T:TC	acceptor_gain	0.9600
13:48416467:C:CT	donor_gain	0.9600
13:48413117:G:C	acceptor_gain	0.9500
13:48417165:A:AC	donor_gain	0.9500
13:48417166:C:CC	donor_gain	0.9500
13:48443220:G:C	acceptor_gain	0.9500
13:48444551:AC:A	donor_gain	0.9500

AlphaMissense

2289 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:48412083:C:G	R114P	0.999
13:48412236:T:G	D63A	0.999
13:48411698:A:C	F242L	0.998
13:48411698:A:T	F242L	0.998
13:48411700:A:G	F242L	0.998
13:48412003:A:G	W141R	0.998
13:48412003:A:T	W141R	0.998
13:48412091:A:C	S111R	0.998
13:48412091:A:T	S111R	0.998
13:48412093:T:G	S111R	0.998
13:48412178:C:A	W82C	0.998
13:48412178:C:G	W82C	0.998
13:48412235:G:C	D63E	0.998
13:48412235:G:T	D63E	0.998
13:48412236:T:A	D63V	0.998
13:48412333:C:G	G31R	0.998
13:48412333:C:T	G31R	0.998
13:48411693:G:C	P244R	0.997
13:48411893:C:A	W177C	0.997
13:48411893:C:G	W177C	0.997
13:48412013:G:C	C137W	0.997
13:48412040:T:A	R128S	0.997
13:48412040:T:G	R128S	0.997
13:48412099:A:G	C109R	0.997
13:48412115:G:C	S103R	0.997
13:48412115:G:T	S103R	0.997
13:48412117:T:G	S103R	0.997
13:48412236:T:C	D63G	0.997
13:48412237:C:G	D63H	0.997
13:48412248:A:C	L59W	0.997

dbSNP variants (sampled 300 via entrez): RS1000025805 (13:48392012 G>T), RS1000040980 (13:48420125 G>A), RS1000109211 (13:48421757 A>G), RS1000191108 (13:48434868 C>A), RS1000193168 (13:48401232 A>T), RS1000269743 (13:48416237 C>T), RS1000275591 (13:48439014 G>A,T), RS1000288037 (13:48401009 C>A,T), RS1000306594 (13:48442458 T>C), RS1000422125 (13:48442271 A>G), RS1000525679 (13:48399431 A>G), RS1000620397 (13:48399114 A>C), RS1000631201 (13:48394611 G>A,C), RS1000631661 (13:48402304 A>G), RS1000744260 (13:48432374 A>T)

Disease associations

OMIM: gene MIM:609239 | disease phenotypes: MIM:278150, MIM:616760, MIM:612073

GenCC curated gene-disease

Disease	Classification	Inheritance
hypotrichosis 8	Strong	Autosomal recessive
wooly hair, autosomal recessive 1, with or without hypotrichosis	Strong	Autosomal recessive
isolated familial wooly hair disorder	Supportive	Autosomal dominant
hypotrichosis simplex	Supportive	Autosomal dominant

Mondo (7): retinoblastoma (MONDO:0008380), hypotrichosis 8 (MONDO:0010206), wooly hair, autosomal recessive 3 (MONDO:0014765), wooly hair, autosomal recessive 1, with or without hypotrichosis (MONDO:0800312), mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (MONDO:0012791), isolated familial wooly hair disorder (MONDO:0008686), hypotrichosis simplex (MONDO:0018914)

Orphanet (4): Retinoblastoma (Orphanet:790), Woolly hair (Orphanet:170), Hypotrichosis simplex (Orphanet:55654), Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (Orphanet:1933)

HPO phenotypes

28 total (28 of 28 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:0000975	Hyperhidrosis
HP:0001596	Alopecia
HP:0001803	Nail pits
HP:0001807	Ridged nail
HP:0002208	Coarse hair
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:0002286	Fair 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:0011359	Dry hair
HP:0025249	Comedo
HP:0045075	Sparse eyebrow

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002388_449	Lymphocyte count	4.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D012175	Retinoblastoma	C04.557.465.625.600.725; C04.557.470.670.725; C04.557.580.625.600.725; C04.588.364.818.760; C11.270.862; C11.319.475.760; C11.768.717.760
C537160	Hypotrichosis simplex (supp.)
C566950	Hypotrichosis, Localized, Autosomal Recessive, 3 (supp.)
C567624	Mitochondrial Dna Depletion Syndrome, Encephalomyopathic Form, With Methylmalonic Aciduria, Autosomal Recessive (supp.)
C536745	Woolly hair, congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331058 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Lysophospholipid (LPA) receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
LPA	Agonist	6.0	pEC50

ChEMBL bioactivities

22 potent at pChembl≥5 of 22 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.41	EC50	39	nM	CHEMBL2335052
7.41	EC50	38.9	nM	CHEMBL2335052
7.24	EC50	58	nM	CHEMBL153043
7.23	EC50	58.88	nM	CHEMBL153043
7.18	EC50	66	nM	CHEMBL2335049
7.18	EC50	66.07	nM	CHEMBL2335049
7.12	EC50	76	nM	CHEMBL2335051
7.12	EC50	75.86	nM	CHEMBL2335051
7.11	EC50	78	nM	CHEMBL2335050
7.11	EC50	77.62	nM	CHEMBL2335050
7.10	EC50	79	nM	CHEMBL357053
7.10	EC50	79.43	nM	CHEMBL357053
7.07	EC50	86	nM	CHEMBL2017139
7.07	EC50	85.11	nM	CHEMBL2017139
7.05	EC50	90	nM	CHEMBL2335047
7.05	EC50	89.13	nM	CHEMBL2335047
6.98	EC50	105	nM	CHEMBL2335048
6.98	EC50	104.7	nM	CHEMBL2335048
6.03	EC50	930	nM	CHEMBL364797
6.03	EC50	933.2	nM	CHEMBL364797
6.01	EC50	970	nM	LYSOPHOSPHATIDIC ACID
6.01	EC50	977.2	nM	LYSOPHOSPHATIDIC ACID

PubChem BioAssay actives

22 with measured affinity, of 36 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
dihydroxy-(2-methoxy-3-octadecoxypropoxy)-sulfanylidene-lambda5-phosphane	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0389	uM
[(2R)-3-dihydroxyphosphinothioyloxy-2-methoxypropyl] octadecanoate	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0580	uM
sodium (2-hexadecoxy-3-methoxypropoxy)-hydroxy-oxido-sulfanylidene-lambda5-phosphane	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0660	uM
sodium [1-[hydroxy(oxido)phosphinothioyl]oxy-3-methoxypropan-2-yl] octadecanoate	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0759	uM
sodium (2-heptadecoxy-3-methoxypropoxy)-hydroxy-oxido-sulfanylidene-lambda5-phosphane	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0776	uM
[(2S)-3-dihydroxyphosphinothioyloxy-2-methoxypropyl] octadecanoate	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0790	uM
(3-dihydroxyphosphinothioyloxy-2-methoxypropyl) octadecanoate	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0851	uM
dihydroxy-[(2S)-2-methoxy-3-octadecoxypropoxy]-sulfanylidene-lambda5-phosphane	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.0891	uM
dihydroxy-[(2R)-2-methoxy-3-octadecoxypropoxy]-sulfanylidene-lambda5-phosphane	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.1047	uM
[(2R)-2-hydroxy-3-phosphonooxypropyl] hexadecanoate	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.9300	uM
[(2R)-2-hydroxy-3-phosphonooxypropyl] (Z)-octadec-9-enoate	733687: Agonist activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425	ec50	0.9700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	7
Benzo(a)pyrene	decreases expression, increases expression	6
Tobacco Smoke Pollution	decreases methylation, increases expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	3
bisphenol A	affects expression, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Endosulfan	decreases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
aminomethylphosphonic acid (AMPA)	increases expression	1
dicrotophos	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
quercitrin	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
potassium chromate(VI)	decreases expression	1
nickel sulfate	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 4 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2344989	Binding	Intrinsic activity at human LPA6 receptor transfected in HEK293 cells after 1 hr by TGFalpha shedding assay in presence of Ki16425 relative to LPA	Phosphorothioate analogs of sn-2 radyl lysophosphatidic acid (LPA): metabolically stabilized LPA receptor agonists. — Bioorg Med Chem Lett
CHEMBL4610710	Functional	Agonist activity at human LPA6 expressed in rat B103 cells assessed as increase in intracellular calcium level by Fluo-4 NW dye based fluorescence assay	A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration. — J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7TT	Ubigene A-549 LPAR6 KO	Cancer cell line	Male
CVCL_D9IR	Ubigene HEK293 LPAR6 KO	Transformed cell line	Female
CVCL_E5J3	RH7777-p2y5	Cancer cell line	Female
CVCL_E5J5	B103-p2y5	Cancer cell line	Sex unspecified
CVCL_H523	RH7777/P2Y5	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT02319486	PHASE4	COMPLETED	CEV With/Without Periocular Carboplatin Chemotherapy for Extraocular Retinoblastoma
NCT02933333	PHASE4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT00186888	PHASE3	COMPLETED	Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma
NCT01906814	PHASE3	UNKNOWN	Adjuvant Chemotherapy for High-risk Retinoblastoma After Enucleation
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT02137928	PHASE3	UNKNOWN	Carboplatin Periocular Injection for Retinoblastoma
NCT04799002	PHASE3	RECRUITING	Topotecan and Melphalan for Retinoblastoma
NCT05080010	PHASE3	RECRUITING	Adjuvant Chemotherapy for High-risk Postenucleation Retinoblastoma
NCT03492866	PHASE2	UNKNOWN	Efficacy of Topical Gentamycin for Hereditary Hypotrichosis Simplex Caused by Nonsense Mutations in CDSN
NCT00002515	PHASE2	COMPLETED	Combination Chemotherapy Followed by Bone Marrow Transplantation in Treating Patients With Rare Cancer
NCT00002675	PHASE2	COMPLETED	Chemotherapy in Treating Patients With Retinoblastoma
NCT00002794	PHASE2	COMPLETED	Carboplatin Plus Vincristine in Treating Children With Retinoblastoma
NCT00003173	PHASE2	COMPLETED	High-Dose Thiotepa Plus Peripheral Stem Cell Transplantation in Treating Patients With Refractory Solid Tumors
NCT00003273	PHASE2	WITHDRAWN	Chemotherapy Followed by Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Brain Tumor
NCT00004006	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Bone Marrow Transplantation in Treating Patients With Retinoblastoma
NCT00006102	PHASE2	COMPLETED	Rebeccamycin Analogue in Treating Children With Solid Tumors or Non-Hodgkin’s Lymphoma
NCT00024258	PHASE2	COMPLETED	Arsenic Trioxide in Treating Patients With Advanced Neuroblastoma or Other Childhood Solid Tumors
NCT00110110	PHASE2	UNKNOWN	Combination Chemotherapy and Cyclosporine Followed by Focal Therapy for Bilateral Retinoblastoma
NCT00179920	PHASE2	COMPLETED	Chemotherapy Treatment for Children With Intraocular Germ-Line Retinoblastoma
NCT00432445	PHASE2	TERMINATED	Proton Beam Radiation Therapy for Intraocular and Periocular Retinoblastoma
NCT00445965	PHASE2	COMPLETED	Iodine I 131 Monoclonal Antibody 3F8 in Treating Patients With Central Nervous System Cancer or Leptomeningeal Cancer
NCT00831844	PHASE2	COMPLETED	Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors
NCT01151748	PHASE2	WITHDRAWN	Intra-arterial Chemotherapy for Advanced Intraocular Retinoblastoma
NCT01293539	PHASE2	TERMINATED	Intra-arterial Chemotherapy for the Treatment of Intraocular Retinoblastoma
NCT01393769	PHASE2	TERMINATED	Intra-arterial Chemotherapy With Melphalan for the Treatment of Retinoblastoma (RTB) in Advanced Intraocular Stage
NCT01783535	PHASE2	ACTIVE_NOT_RECRUITING	Protocol for the Study and Treatment of Participants With Intraocular Retinoblastoma
NCT01857752	PHASE2	TERMINATED	Phase II Study Temozolomide for Retinoblastoma Metastatic to the Central Nervous System for Patients From Guatemala
NCT01899066	PHASE2	UNKNOWN	Efficacy Study of Lucentis in the Treatment of Retinoblastoma
NCT02866136	PHASE2	ACTIVE_NOT_RECRUITING	Conservative Treatments of Retinoblastoma
NCT02870907	PHASE2	ACTIVE_NOT_RECRUITING	Adjuvant Treatment in Extensive Unilateral Retinoblastoma Primary Enucleated (RB SFCE 2009)
NCT04455139	PHASE2	TERMINATED	A Prospective International Multicenter Clinical Trial for Eyes With Relapsed Retinoblastoma
NCT04990271	PHASE2	UNKNOWN	A Clinical Study on the Efficacy and Safety of VEC Intravenous Chemotherapy Combined With Conbercept Intravitreal Injection in the Treatment of Retinoblastoma
NCT05504291	PHASE2	RECRUITING	A Study to Give Treatment Inside the Eye to Treat Retinoblastoma
NCT06679634	PHASE2	RECRUITING	Retinoblastoma Phase II Expanded Access Clinical Trial
NCT00003022	PHASE1	COMPLETED	Monoclonal Antibody Therapy in Treating Patients With Leptomeningeal Cancer
NCT00003926	PHASE1	TERMINATED	Amifostine to Protect From Side Effects of PSCT in Treating Patients With Solid Tumors
NCT00006246	PHASE1	COMPLETED	Busulfan in Treating Children and Adolescents With Refractory CNS Cancer
NCT00012181	PHASE1	COMPLETED	Flavopiridol in Treating Children With Relapsed or Refractory Solid Tumors or Lymphomas
NCT00053118	PHASE1	COMPLETED	Chemotherapy and Stem Cell Transplantation in Treating Children With Central Nervous System Cancer