CELSR1

Summary

CELSR1 (cadherin EGF LAG seven-pass G-type receptor 1, HGNC:1850) is a protein-coding gene on chromosome 22q13.31, encoding Cadherin EGF LAG seven-pass G-type receptor 1 (Q9NYQ6). Receptor that may have an important role in cell/cell signaling during nervous system formation.

The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consists of nonclassic-type cadherins; a subpopulation that does not interact with catenins. The flamingo cadherins are located at the plasma membrane and have nine cadherin domains, seven epidermal growth factor-like repeats and two laminin A G-type repeats in their ectodomain. They also have seven transmembrane domains, a characteristic unique to this subfamily. It is postulated that these proteins are receptors involved in contact-mediated communication, with cadherin domains acting as homophilic binding regions and the EGF-like domains involved in cell adhesion and receptor-ligand interactions. This particular member is a developmentally regulated, neural-specific gene which plays an unspecified role in early embryogenesis.

Source: NCBI Gene 9620 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphatic malformation 9 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 963 total — 8 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 7
• MANE Select transcript: NM_001378328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1850
Approved symbol	CELSR1
Name	cadherin EGF LAG seven-pass G-type receptor 1
Location	22q13.31
Locus type	gene with protein product
Status	Approved
Aliases	ME2, HFMI2, FMI2, CDHF9, ADGRC1
Ensembl gene	ENSG00000075275
Ensembl biotype	protein_coding
OMIM	604523
Entrez	9620

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 5 retained_intron

ENST00000262738, ENST00000454637, ENST00000468025, ENST00000473624, ENST00000497509, ENST00000674159, ENST00000674312, ENST00000674315, ENST00000674341, ENST00000674359, ENST00000674379, ENST00000674423, ENST00000674500

RefSeq mRNA: 2 — MANE Select: NM_001378328 NM_001378328, NM_014246

CCDS: CCDS14076, CCDS93179

Canonical transcript exons

ENST00000674500 — 35 exons

Exon	Start	End
ENSE00000657321	46363996	46364251
ENSE00000657327	46365586	46365689
ENSE00000657329	46366386	46366480
ENSE00000657333	46367729	46367855
ENSE00000657335	46369179	46369258
ENSE00000657339	46372883	46373057
ENSE00000657343	46378591	46378717
ENSE00000657345	46380788	46380955
ENSE00000657351	46386402	46386585
ENSE00000657353	46389290	46389499
ENSE00000657355	46390392	46390486
ENSE00000657357	46391186	46391287
ENSE00000657359	46391633	46391816
ENSE00000657361	46394142	46394262
ENSE00000657363	46396605	46396746
ENSE00000657365	46397674	46397848
ENSE00000657367	46398524	46398637
ENSE00000657369	46399717	46399902
ENSE00000657371	46408996	46409162
ENSE00000657373	46409755	46409880
ENSE00000657375	46410398	46410561
ENSE00000657376	46411602	46411759
ENSE00000657377	46433393	46433481
ENSE00000657378	46436174	46436289
ENSE00000657380	46463707	46464345
ENSE00000935971	46369692	46369804
ENSE00001046850	46366993	46367118
ENSE00001668343	46384543	46384686
ENSE00001755460	46533627	46537620
ENSE00001773003	46381846	46382050
ENSE00001775696	46439189	46439411
ENSE00003617540	46365231	46365380
ENSE00003621316	46377061	46377261
ENSE00003631636	46364512	46364736
ENSE00003898403	46361174	46363247

Expression profiles

Bgee: expression breadth ubiquitous, 224 present calls, max score 97.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.0453 / max 128.9819, expressed in 1067 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194613	4.6855	1025
194612	2.3598	678

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.67	gold quality
lower esophagus mucosa	UBERON:0035834	96.83	gold quality
bronchial epithelial cell	CL:0002328	96.74	gold quality
right uterine tube	UBERON:0001302	96.04	gold quality
epithelium of bronchus	UBERON:0002031	95.74	gold quality
bronchus	UBERON:0002185	95.18	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.93	gold quality
ganglionic eminence	UBERON:0004023	92.89	gold quality
esophagus mucosa	UBERON:0002469	91.54	gold quality
skin of abdomen	UBERON:0001416	89.98	gold quality
adenohypophysis	UBERON:0002196	88.80	gold quality
skin of leg	UBERON:0001511	88.73	gold quality
secondary oocyte	CL:0000655	88.36	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.30	gold quality
metanephros cortex	UBERON:0010533	87.39	gold quality
epithelium of nasopharynx	UBERON:0001951	87.36	gold quality
zone of skin	UBERON:0000014	87.35	gold quality
nasal cavity mucosa	UBERON:0001826	87.28	gold quality
palpebral conjunctiva	UBERON:0001812	86.95	gold quality
right lung	UBERON:0002167	86.71	gold quality
buccal mucosa cell	CL:0002336	86.65	gold quality
esophagus squamous epithelium	UBERON:0006920	86.47	gold quality
upper lobe of left lung	UBERON:0008952	86.35	gold quality
upper lobe of lung	UBERON:0008948	85.62	gold quality
pituitary gland	UBERON:0000007	85.55	gold quality
nasal cavity epithelium	UBERON:0005384	85.01	gold quality
epithelium of esophagus	UBERON:0001976	84.97	gold quality
minor salivary gland	UBERON:0001830	84.94	gold quality
mouth mucosa	UBERON:0003729	84.39	gold quality
vagina	UBERON:0000996	84.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	204.45
E-ANND-3	yes	12.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting CELSR1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524

Literature-anchored findings (GeneRIF, showing 29)

• exclusion as a candidate gene for schizophrenia– a cadhrin gene (PMID:11807409)
• Variations in the nine ectodomains of CELSR1 do not increase susceptibility to schizophrenia. (PMID:12782967)
• Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study. (PMID:19403135)
• The planar cell polarity genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis. (PMID:20223754)
• CELSR1 may have a role in ischemic stroke, as shown in a Portuguese case-control cohort (PMID:21511255)
• Missense variants in CELSR1 may represent a cause of craniorachischisis in humans, as in mice, with defective planar cell polarity protein trafficking to the plasma membrane a likely pathogenic mechanism. (PMID:22095531)
• CELSR1 is a risk factor for neural tube defects or caudal agenesis via pathogenic role of planar cell polarity signaling in these malformations. (PMID:22371354)
• Celsr1 regulates dynamic cell movements by inhibiting stabilization of VE-cadherin and maturation of adherens junctions. (PMID:23792146)
• CELSR1 mutations contribute to the risk of spina bifida in a cohort of spina bifida patients from California (PMID:24632739)
• the present study has proven for the first time that CELSR1 is a susceptibility gene for ischaemic stroke in the Chinese Han population, especially for large artery atherosclerosis. (PMID:25117632)
• Single nucleotide polymorphisms in nNOS, renalase, MTHFR, CELSR1 and XYLB genes were found significantly associated with ischemic stroke in Chinese patients. (PMID:25855559)
• Upregulating CELSR1 expression significantly promoted cell growth, while knocking down CELSR1 inhibited the growth and decreased tube formation. (PMID:27301287)
• Patients with CELSR1 mutations and spina bifida can have significant renal malformations. (PMID:27597235)
• This single-nucleotide polymorphism-by-sex genome-wide association analysis identified the fetal lung development gene, CELSR1, as a potential sex-specific risk factor for Chronic obstructive pulmonary disease. (PMID:27854507)
• These data confirm GJA1 association with heart rate (HR) in the setting of reduced ejection fraction (HFrEF) and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts. (PMID:31113495)
• Since the percentage of lymphedema patients carrying CELSR1 variants is not negligible, we do not hesitate to recommend including this gene in routine genetic testing. (PMID:31215153)
• Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family. (PMID:31403174)
• CELSR1 Promotes Neuroprotection in Cerebral Ischemic Injury Mainly Through the Wnt/PKC Signaling Pathway. (PMID:32070035)
• Somatic mutations in planar cell polarity genes in neural tissue from human fetuses with neural tube defects. (PMID:32356230)
• circCELSR1 facilitates ovarian cancer proliferation and metastasis by sponging miR-598 to activate BRD4 signals. (PMID:32640974)
• A CELSR1 variant in a patient with pulmonary arterial hypertension. (PMID:34435352)
• CELSR1 Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left Heart Syndrome. (PMID:35133174)
• CELSR1 variants are associated with partial epilepsy of childhood. (PMID:36453712)
• The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. (PMID:37224017)
• Ureteropelvic junction obstruction with primary lymphoedema associated with CELSR1 variants. (PMID:37225411)
• Lymphedema is associated with CELSR1 in Phelan-McDermid syndrome. (PMID:37232218)
• Upregulation of CELSR1 expression promotes ovarian cancer cell proliferation, migration, and invasion. (PMID:38070011)
• De novo heterozygous missense variants in CELSR1 as cause of fetal pleural effusions and progressive fetal hydrops. (PMID:38272662)
• CELSR1, a core planar cell polarity protein, features a weakly adhesive and flexible cadherin ectodomain. (PMID:38307021)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	celsr1b	ENSDARG00000058259
danio_rerio	celsr1a	ENSDARG00000069185
mus_musculus	Celsr1	ENSMUSG00000016028
rattus_norvegicus	Celsr1	ENSRNOG00000021285
drosophila_melanogaster	stan	FBGN0024836
caenorhabditis_elegans		WBGENE00001475
caenorhabditis_elegans	hmr-1	WBGENE00001980
caenorhabditis_elegans	Y52B11A.11	WBGENE00014914

Paralogs (6): CELSR3 (ENSG00000008300), FAT1 (ENSG00000083857), FAT2 (ENSG00000086570), CELSR2 (ENSG00000143126), FAT3 (ENSG00000165323), FAT4 (ENSG00000196159)

Protein

Protein identifiers

Cadherin EGF LAG seven-pass G-type receptor 1 — Q9NYQ6 (reviewed: Q9NYQ6)

Alternative names: Cadherin family member 9, Flamingo homolog 2

All UniProt accessions (8): Q9NYQ6, A0A6I8PIW5, A0A6I8PIX5, A0A6I8PL36, A0A6I8PRD4, A0A6I8PRU0, A0A6I8PRV8, H0Y7R9

UniProt curated annotations — full annotation on UniProt →

Function. Receptor that may have an important role in cell/cell signaling during nervous system formation.

Subcellular location. Cell membrane.

Post-translational modifications. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains.

Disease relevance. Neural tube defects (NTD) [MIM:182940] Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy. Failure of neural tube closure can occur at any level of the embryonic axis. Common NTD forms include anencephaly, myelomeningocele and spina bifida, which result from the failure of fusion in the cranial and spinal region of the neural tube. NTDs have a multifactorial etiology encompassing both genetic and environmental components. The disease may be caused by variants affecting the gene represented in this entry. Lymphatic malformation 9 (LMPHM9) [MIM:619319] A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. Impaired lymphatic drainage in the fetus can develop into hydrops fetalis, a severe condition characterized by excessive fluid accumulation in more than two fetal extra-vascular compartments and body cavities, placental enlargement and edema, pericardial or pleural effusion, or ascites. LMPHM9 is an autosomal dominant form with variable expressivity and incomplete penetrance, characterized by the onset of lower-extremity lymphedema in the first decades of life. The disease is caused by variants affecting the gene represented in this entry. Yellow nail syndrome (YNS) [MIM:153300] An autosomal dominant disorder characterized by yellow, dystrophic, thick and slowly growing nails, associated with lymphedema and respiratory involvement. Lymphedema occurs more often in the lower limbs. Additional variable features may include protein-losing enteropathy, primary intestinal lymphangiectasia, ocular involvement, and autoimmune disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 2 family. LN-TM7 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYQ6-1	1	yes
Q9NYQ6-2	2

RefSeq proteins (2): NP_001365257, NP_055061 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000203	GPS	Conserved_site
IPR000742	EGF	Domain
IPR000832	GPCR_2_secretin-like	Family
IPR001791	Laminin_G	Domain
IPR001879	GPCR_2_extracellular_dom	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002049	LE_dom	Domain
IPR002126	Cadherin-like_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR017981	GPCR_2-like_7TM	Domain
IPR020894	Cadherin_CS	Conserved_site
IPR032471	AGRL2-4_GAIN_subdom_A	Domain
IPR036445	GPCR_2_extracell_dom_sf	Homologous_superfamily
IPR046338	GAIN_dom_sf	Homologous_superfamily
IPR056286	Cadherin_CELSR1-3_9th	Domain
IPR057244	GAIN_B	Domain

Pfam: PF00002, PF00008, PF00028, PF00053, PF01825, PF02210, PF02793, PF16489, PF23592

UniProt features (181 total): sequence variant 31, strand 31, disulfide bond 29, domain 21, glycosylation site 20, topological domain 8, turn 8, transmembrane region 7, compositionally biased region 7, modified residue 6, region of interest 5, helix 3, splice variant 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7SZ8	X-RAY DIFFRACTION	2.34
8D40	X-RAY DIFFRACTION	3.55

Predicted structure (AlphaFold)

No AlphaFold model available for Q9NYQ6 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (6): 1666, 1889, 2761, 2764, 2871, 2873

Disulfide bonds (29): 2005–2015, 2024–2033, 2036–2048, 2411–2443, 2431–2445, 1307–1318, 1312–1349, 1351–1360, 1367–1378, 1372–1387, 1389–1398, 1407–1418, 1412–1428, 1430–1440, 1620–1646, 1653–1664, 1658–1673, 1675–1684, 1840–1870, 1876–1887 …

Glycosylation sites (20): 403, 546, 634, 778, 1114, 1139, 1213, 1249, 1259, 1287, 1576, 1623, 1640, 1979, 2103, 2122, 2257, 2415, 2437, 2523

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 424 (showing top): GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_NADPPLUS_METABOLIC_PROCESS, GOBP_EPITHELIAL_TUBE_BRANCHING_INVOLVED_IN_LUNG_MORPHOGENESIS, YANG_BREAST_CANCER_ESR1_BULK_UP, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_LUNG_MORPHOGENESIS, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN

GO Biological Process (28): establishment of planar polarity (GO:0001736), neuron migration (GO:0001764), neural tube closure (GO:0001843), homophilic cell-cell adhesion (GO:0007156), Rho protein signal transduction (GO:0007266), axonogenesis (GO:0007409), central nervous system development (GO:0007417), regulation of actin cytoskeleton organization (GO:0032956), establishment of planar polarity of embryonic epithelium (GO:0042249), cell-cell adhesion mediated by cadherin (GO:0044331), apical protein localization (GO:0045176), establishment of body hair planar orientation (GO:0048105), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), orthogonal dichotomous subdivision of terminal units involved in lung branching morphogenesis (GO:0060488), planar dichotomous subdivision of terminal units involved in lung branching morphogenesis (GO:0060489), lateral sprouting involved in lung morphogenesis (GO:0060490), protein localization involved in establishment of planar polarity (GO:0090251), hair follicle development (GO:0001942), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway (GO:0007186), nervous system development (GO:0007399), locomotory behavior (GO:0007626), anterior/posterior pattern specification (GO:0009952), wound healing (GO:0042060), inner ear morphogenesis (GO:0042472), motor neuron migration (GO:0097475)

GO Molecular Function (3): G protein-coupled receptor activity (GO:0004930), calcium ion binding (GO:0005509), transmembrane signaling receptor activity (GO:0004888)

GO Cellular Component (4): nucleoplasm (GO:0005654), plasma membrane (GO:0005886), adherens junction (GO:0005912), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	2
establishment of planar polarity	2
intracellular protein localization	2
dichotomous subdivision of terminal units involved in lung branching	2
cellular process	2
cellular anatomical structure	2
morphogenesis of a polarized epithelium	1
establishment of tissue polarity	1
cell migration	1
generation of neurons	1
primary neural tube formation	1
tube closure	1
small GTPase-mediated signal transduction	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
nervous system development	1
system development	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
establishment of body hair or bristle planar orientation	1
non-canonical Wnt signaling pathway	1
epithelial tube branching involved in lung morphogenesis	1
lateral sprouting from an epithelium	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
metal ion binding	1
signaling receptor activity	1
nuclear lumen	1
membrane	1
cell periphery	1
cell-cell junction	1

Protein interactions and networks

STRING

1009 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CELSR1	FZD6	O60353	980
CELSR1	VANGL2	Q9ULK5	972
CELSR1	VANGL1	Q8TAA9	958
CELSR1	FZD3	Q9NPG1	872
CELSR1	DVL1	O14640	822
CELSR1	SCRIB	Q14160	803
CELSR1	DVL2	O14641	785
CELSR1	ARHGEF11	O15085	765
CELSR1	PTK7	Q13308	764
CELSR1	PRICKLE1	Q96MT3	763
CELSR1	PRICKLE3	O43900	758
CELSR1	PRICKLE2	Q7Z3G6	757
CELSR1	PRICKLE4	Q2TBC4	750
CELSR1	FZD9	O00144	740
CELSR1	DAAM1	Q9Y4D1	716

IntAct

71 interactions, top by confidence:

A	B	Type	Score
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
CELSR1	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.350
SIRT6	HDAC3	psi-mi:“MI:0914”(association)	0.350
SLAMF1	RTCA	psi-mi:“MI:0914”(association)	0.350
CLU	TOR1A	psi-mi:“MI:0914”(association)	0.350
PCDH12	PCDH17	psi-mi:“MI:0914”(association)	0.350
ZBBX	ZZEF1	psi-mi:“MI:0914”(association)	0.350
NXPH2	PCDH7	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
ADAMTS13	C2CD4B	psi-mi:“MI:0914”(association)	0.350
C2CD4B	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
RYK	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
CD160	PLXNB2	psi-mi:“MI:0914”(association)	0.350
LAG3	PCDH7	psi-mi:“MI:0914”(association)	0.350
DCANP1	IDE	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS), CELSR1 (Affinity Capture-MS)

ESM2 similar proteins: D3ZE55, O14917, O35161, O95206, Q5DRE1, Q5DRE2, Q5DRE3, Q5DRE4, Q5DRE5, Q5DRE6, Q5DRE7, Q5DRE8, Q5DRE9, Q5DRF0, Q5DRF1, Q5DRF2, Q5DRF3, Q5DRF4, Q5DRF5, Q5JZY3, Q63315, Q6PFX6, Q767I8, Q7TSK3, Q86UP0, Q8BYG9, Q91Y11, Q91Y13, Q91Y20, Q91ZI0, Q9H158, Q9NPG4, Q9NYQ6, Q9NYQ7, Q9P2E7, Q9UJ99, Q9UN72, Q9UN73, Q9UN74, Q9UN75

Diamond homologs: A0A8M9PFP2, B0S5G3, F1R520, O02840, O55111, O88278, O94985, P30944, P33151, P55287, P55288, Q0VCN6, Q14517, Q5DRC8, Q5R9Q9, Q63418, Q6Q0N0, Q6URK6, Q6V1P9, Q86UP0, Q8BNA6, Q8R553, Q8VDA1, Q96JQ0, Q99JH7, Q9BQT9, Q9EPL2, Q9ER65, Q9H4D0, Q9HCU4, Q9NYQ6, Q9R0M0, A6QLU6, C0HL12, D4A3T6, E9Q4J9, G5ECX0, G5EDW2, O14514, O35161

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLK1	“down-regulates activity”	CELSR1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	8
Uncertain significance	655
Likely benign	141
Benign	89

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1096924	NM_001378328.1(CELSR1):c.5871G>A (p.Trp1957Ter)	Pathogenic
1096930	NM_001378328.1(CELSR1):c.5121dup (p.Ile1708fs)	Pathogenic
3898672	NM_001378328.1(CELSR1):c.103_122dup (p.Phe42fs)	Pathogenic
4087731	CELSR1, MET284THR	Pathogenic
4087732	NM_001378328.1(CELSR1):c.8555-2A>G	Pathogenic
4087733	C1936Y	Pathogenic
598932	NM_001378328.1(CELSR1):c.5226+2T>A	Pathogenic
598933	NM_001378328.1(CELSR1):c.6739+1G>A	Pathogenic
3075687	NM_001378328.1(CELSR1):c.5512C>T (p.Arg1838Ter)	Likely pathogenic
4073567	NM_001378328.1(CELSR1):c.2935C>T (p.Leu979Phe)	Likely pathogenic
4073568	NM_001378328.1(CELSR1):c.2018T>C (p.Val673Ala)	Likely pathogenic
4077063	NM_001378328.1(CELSR1):c.847_856del (p.Tyr283fs)	Likely pathogenic
4293727	NM_001378328.1(CELSR1):c.5412+1G>C	Likely pathogenic
590904	NM_001378328.1(CELSR1):c.868G>T (p.Glu290Ter)	Likely pathogenic
598923	NM_001378328.1(CELSR1):c.5702-1G>C	Likely pathogenic
598924	NM_001378328.1(CELSR1):c.2042del (p.Asn681fs)	Likely pathogenic

SpliceAI

10259 predictions. Top by Δscore:

Variant	Effect	Δscore
18:50879306:CTGG:C	donor_loss	1.0000
18:50879308:GGTA:G	donor_loss	1.0000
18:50879309:G:GG	donor_gain	1.0000
18:50879310:T:G	donor_loss	1.0000
18:50895926:AAGGT:A	donor_loss	1.0000
18:50895927:AGG:A	donor_loss	1.0000
18:50895928:GGTT:G	donor_loss	1.0000
18:50895929:G:C	donor_loss	1.0000
18:50895930:T:A	donor_loss	1.0000
18:50908059:TTA:T	acceptor_loss	1.0000
18:50908060:TAGGG:T	acceptor_loss	1.0000
18:50908061:A:AG	acceptor_gain	1.0000
18:50908061:A:T	acceptor_loss	1.0000
18:50908061:AG:A	acceptor_gain	1.0000
18:50908061:AGG:A	acceptor_gain	1.0000
18:50908062:G:GC	acceptor_gain	1.0000
18:50908062:GG:G	acceptor_gain	1.0000
18:50908062:GGG:G	acceptor_gain	1.0000
18:50908062:GGGA:G	acceptor_gain	1.0000
18:50908062:GGGAA:G	acceptor_gain	1.0000
18:50908192:GAAAA:G	donor_gain	1.0000
18:50908194:AAA:A	donor_gain	1.0000
18:50908195:AA:A	donor_gain	1.0000
18:50908195:AAGTA:A	donor_loss	1.0000
18:50908196:AGT:A	donor_loss	1.0000
18:50908197:G:A	donor_loss	1.0000
18:50908197:G:GG	donor_gain	1.0000
18:50908198:T:A	donor_loss	1.0000
18:50912944:GACC:G	donor_gain	1.0000
18:50912947:C:CG	donor_gain	1.0000

AlphaMissense

19721 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:46390449:C:A	W2096C	1.000
22:46390449:C:G	W2096C	1.000
22:46391241:C:A	W2065C	1.000
22:46391241:C:G	W2065C	1.000
22:46535631:C:A	G514W	1.000
22:46535651:A:G	F507S	1.000
22:46535795:A:C	F459C	1.000
22:46535795:A:G	F459S	1.000
22:46535801:G:T	P457H	1.000
22:46535820:C:G	D451H	1.000
22:46390451:A:G	W2096R	0.999
22:46390451:A:T	W2096R	0.999
22:46436227:T:A	D1490V	0.999
22:46463810:G:C	C1360W	0.999
22:46463811:C:G	C1360S	0.999
22:46463811:C:T	C1360Y	0.999
22:46463812:A:T	C1360S	0.999
22:46463844:C:G	C1349S	0.999
22:46463845:A:T	C1349S	0.999
22:46463936:G:C	C1318W	0.999
22:46463937:C:G	C1318S	0.999
22:46463938:A:G	C1318R	0.999
22:46463938:A:T	C1318S	0.999
22:46463955:C:T	C1312Y	0.999
22:46463969:G:C	C1307W	0.999
22:46463970:C:G	C1307S	0.999
22:46463970:C:T	C1307Y	0.999
22:46463971:A:G	C1307R	0.999
22:46463971:A:T	C1307S	0.999
22:46464272:G:C	S1206R	0.999

dbSNP variants (sampled 300 via entrez): RS1000017756 (22:46525803 C>T), RS1000025828 (22:46456556 G>A,C), RS1000033673 (22:46499148 C>G,T), RS1000044224 (22:46405524 A>C), RS1000059653 (22:46377917 C>G), RS1000063966 (22:46511366 C>G,T), RS1000079897 (22:46415534 G>C,T), RS1000102684 (22:46374126 T>G), RS1000149670 (22:46430693 A>G), RS1000154276 (22:46459316 T>C,G), RS1000154879 (22:46373533 T>C), RS1000203682 (22:46492315 T>C), RS1000222062 (22:46431705 G>A), RS1000230838 (22:46410641 G>A,C,T), RS1000284841 (22:46377546 C>T)

Disease associations

OMIM: gene MIM:604523 | disease phenotypes: MIM:619319, MIM:182940, MIM:600057, MIM:153300, MIM:153100, MIM:236670

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphatic malformation 9	Strong	Autosomal dominant
neural tube defects, susceptibility to	Moderate	Autosomal dominant
epilepsy	Limited	Autosomal dominant
genetic developmental and epileptic encephalopathy	Limited	Autosomal recessive
hydrops fetalis	Limited	Autosomal dominant

Mondo (10): lymphatic malformation 9 (MONDO:0030270), neural tube defects, susceptibility to (MONDO:0020705), long QT syndrome (MONDO:0002442), bladder exstrophy-epispadias-cloacal exstrophy complex (MONDO:0700039), yellow nail syndrome (MONDO:0007921), lymphatic malformation (MONDO:0019313), muscular dystrophy-dystroglycanopathy, type A (MONDO:0000171), epilepsy (MONDO:0005027), genetic developmental and epileptic encephalopathy (MONDO:0100062), hydrops fetalis (MONDO:0015193)

Orphanet (4): Situs ambiguus (Orphanet:157769), Classic bladder exstrophy (Orphanet:93930), Lymphedema with yellow nails (Orphanet:662), Walker-Warburg syndrome (Orphanet:899)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001004	Lymphedema
HP:0003550	Predominantly lower limb lymphedema
HP:0003759	Hypoplasia of lymphatic vessels
HP:0008383	Slow-growing nails
HP:0011367	Yellow nails
HP:0033986	Tortuous lymphatic vessels

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002828_20	Urate levels in obese individuals	9.000000e-06
GCST004763_6	HDL cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	7.000000e-07
GCST006979_835	Heel bone mineral density	2.000000e-09
GCST007743_9	Iris color (L* coordinate)	4.000000e-06
GCST009144_11	Disease progression in age-related macular degeneration (adjusted for baseline)	9.000000e-06
GCST90010427_1	Left–right brain asymmetry	3.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0007805	HDL cholesterol change measurement
EFO:0009270	heel bone mineral density
EFO:0009764	eye colour measurement
EFO:0008336	disease progression measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D015160	Hydrops Fetalis	C12.050.703.277.060.480; C15.378.295.480; C15.378.420.826.100.350; C16.300.060.480; C16.320.365.826.100.350; C20.306.480; C23.888.277.395
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D058494	Walker-Warburg Syndrome	C10.500.507.450.499.249.500; C11.270.881; C16.131.666.507.450.499.249.500; C16.320.577.750
D056684	Yellow Nail Syndrome	C16.320.962; C17.800.529.819; C17.800.621.968; C23.300.820.500

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: gpcr — Adhesion Class GPCRs

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	5
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation, increases mutagenesis	4
Air Pollutants	increases abundance, increases expression	2
Smoke	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation	1
Calcitriol	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy