CELSR2

Summary

CELSR2 (cadherin EGF LAG seven-pass G-type receptor 2, HGNC:3231) is a protein-coding gene on chromosome 1p13.3, encoding Cadherin EGF LAG seven-pass G-type receptor 2 (Q9HCU4). 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. The specific function of this particular member has not been determined.

Source: NCBI Gene 1952 — RefSeq curated summary.

At a glance

• GWAS associations: 154
• Clinical variants (ClinVar): 812 total — 2 likely-pathogenic
• MANE Select transcript: NM_001408

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3231
Approved symbol	CELSR2
Name	cadherin EGF LAG seven-pass G-type receptor 2
Location	1p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0279, MEGF3, Flamingo1, CDHF10, ADGRC2
Ensembl gene	ENSG00000143126
Ensembl biotype	protein_coding
OMIM	604265
Entrez	1952

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000271332, ENST00000459940, ENST00000489018, ENST00000498157

RefSeq mRNA: 1 — MANE Select: NM_001408 NM_001408

CCDS: CCDS796

Canonical transcript exons

ENST00000271332 — 34 exons

Exon	Start	End
ENSE00000958214	109249539	109253389
ENSE00000958215	109258432	109259079
ENSE00000958217	109261513	109261628
ENSE00000958218	109261808	109261896
ENSE00000958219	109262287	109262444
ENSE00000958220	109262806	109262969
ENSE00000958221	109263142	109263267
ENSE00000958222	109263611	109263777
ENSE00000958223	109264078	109264365
ENSE00000958224	109264454	109264628
ENSE00000958225	109264868	109265009
ENSE00000958226	109265191	109265311
ENSE00000958228	109266105	109266206
ENSE00000958229	109267548	109267642
ENSE00000958230	109267851	109268060
ENSE00000958231	109268581	109268764
ENSE00000958232	109268880	109269008
ENSE00000958233	109269110	109269290
ENSE00000958234	109269424	109269591
ENSE00000958235	109269694	109269820
ENSE00000958236	109269933	109270133
ENSE00000958237	109270426	109270600
ENSE00000958238	109270927	109271039
ENSE00000958240	109271386	109271512
ENSE00001639600	109261042	109261264
ENSE00001813109	109274022	109275751
ENSE00003252093	109271600	109271722
ENSE00003370777	109272640	109272728
ENSE00003469354	109265735	109265918
ENSE00003482811	109271217	109271296
ENSE00003508849	109272833	109273027
ENSE00003571987	109273436	109273670
ENSE00003588301	109273166	109273336
ENSE00003665062	109272278	109272405

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 96.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8356 / max 223.8229, expressed in 1043 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4398	10.3574	1022
4397	1.5303	203
4404	0.3231	63
4406	0.2760	101
4403	0.1640	56
4401	0.1313	79
4402	0.0319	20
4405	0.0215	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	96.94	gold quality
ventricular zone	UBERON:0003053	95.88	gold quality
right frontal lobe	UBERON:0002810	94.33	gold quality
prefrontal cortex	UBERON:0000451	94.19	gold quality
primary visual cortex	UBERON:0002436	93.83	gold quality
Ammon’s horn	UBERON:0001954	93.79	gold quality
postcentral gyrus	UBERON:0002581	93.57	gold quality
frontal cortex	UBERON:0001870	93.50	gold quality
cortical plate	UBERON:0005343	93.46	gold quality
lower esophagus mucosa	UBERON:0035834	93.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.31	gold quality
neocortex	UBERON:0001950	93.06	gold quality
cerebral cortex	UBERON:0000956	92.83	gold quality
superior frontal gyrus	UBERON:0002661	92.53	gold quality
parietal lobe	UBERON:0001872	92.46	gold quality
entorhinal cortex	UBERON:0002728	92.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.37	gold quality
occipital lobe	UBERON:0002021	92.12	gold quality
CA1 field of hippocampus	UBERON:0003881	92.09	gold quality
spinal cord	UBERON:0002240	92.02	gold quality
telencephalon	UBERON:0001893	91.92	gold quality
right uterine tube	UBERON:0001302	91.71	gold quality
skin of abdomen	UBERON:0001416	91.68	gold quality
middle temporal gyrus	UBERON:0002771	91.31	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.14	gold quality
cingulate cortex	UBERON:0003027	91.11	gold quality
temporal lobe	UBERON:0001871	91.02	gold quality
anterior cingulate cortex	UBERON:0009835	91.00	gold quality
skin of leg	UBERON:0001511	90.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

151 targeting CELSR2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-96-5P	99.95	72.80	2140
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394

Literature-anchored findings (GeneRIF, showing 11)

• The novel CAD-associated locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1 probably enhances CAD risk through an effect on plasma LDL cholesterol. (PMID:18649068)
• CELSR2 in the cholesterol gene cluster shows a significant association with coronary artery disease and its single nucleotide polymorphism regulates plasma cholesterol levels. (PMID:24674750)
• no association was found between the SNPs of rs599839, rs464218 and rs6698843 at the CELSR2-PSRC1-SORT1 and the risk of coronary artery disease or ischemic stroke (PMID:26464717)
• we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. (PMID:28052552)
• findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population (PMID:29240829)
• Both CELSR2 and ING4 display increased cytoplasmic staining in breast cancer cells compared to benign epithelium, suggesting a possible role of both genes in the pathogenesis of human mammary neoplasia. (PMID:29489009)
• Identification of CELSR2 as a novel prognostic biomarker for hepatocellular carcinoma. (PMID:32293343)
• rs629301 CELSR2 polymorphism confers a ten-year equivalent risk of critical stenosis assessed by coronary angiography. (PMID:33810964)
• CELSR2 deficiency suppresses lipid accumulation in hepatocyte by impairing the UPR and elevating ROS level. (PMID:34478580)
• Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human. (PMID:34983065)
• The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. (PMID:37224017)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	celsr2	ENSDARG00000019726
mus_musculus	Celsr2	ENSMUSG00000068740
rattus_norvegicus	Celsr2	ENSRNOG00000020058
drosophila_melanogaster	stan	FBGN0024836
caenorhabditis_elegans		WBGENE00001475
caenorhabditis_elegans	hmr-1	WBGENE00001980
caenorhabditis_elegans	Y52B11A.11	WBGENE00014914

Paralogs (6): CELSR3 (ENSG00000008300), CELSR1 (ENSG00000075275), FAT1 (ENSG00000083857), FAT2 (ENSG00000086570), FAT3 (ENSG00000165323), FAT4 (ENSG00000196159)

Protein

Protein identifiers

Cadherin EGF LAG seven-pass G-type receptor 2 — Q9HCU4 (reviewed: Q9HCU4)

Alternative names: Cadherin family member 10, Epidermal growth factor-like protein 2, Flamingo homolog 3, Multiple epidermal growth factor-like domains protein 3

All UniProt accessions (1): Q9HCU4

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Heterodimer of 2 chains generated by proteolytic processing; the large extracellular N-terminal fragment and the membrane-bound C-terminal fragment predominantly remain associated and non-covalently linked.

Subcellular location. Cell membrane.

Tissue specificity. Highest expression in brain and testis.

Post-translational modifications. The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains. Autoproteolytically processed at the GPS region of the GAIN-B domain; this cleavage modulates receptor activity.

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

RefSeq proteins (1): NP_001399* (*=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, PF16489, PF23592

UniProt features (102 total): disulfide bond 29, domain 20, glycosylation site 17, topological domain 8, transmembrane region 7, compositionally biased region 6, sequence variant 5, region of interest 5, modified residue 2, signal peptide 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q9HCU4 — 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.

Catalytic / active sites (1): 2356–2357 (cleavage; by autolysis)

Post-translational modifications (2): 1591, 1810

Disulfide bonds (29): 1232–1243, 1237–1274, 1276–1285, 1292–1303, 1297–1312, 1314–1323, 1332–1343, 1337–1353, 1355–1365, 1545–1571, 1578–1589, 1583–1598, 1600–1609, 1761–1791, 1797–1808, 1802–1817, 1819–1828, 1832–1843, 1837–1855, 1857–1866 …

Glycosylation sites (17): 486, 557, 701, 1036, 1076, 1182, 1212, 1501, 1565, 1741, 1827, 1900, 2024, 2043, 2061, 2323, 2345

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 212 (showing top): GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_NEUROGENESIS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_VENTRICULAR_SYSTEM_DEVELOPMENT, EFC_Q6, GOBP_CELL_CELL_ADHESION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, MARTINEZ_RB1_TARGETS_DN, GOBP_ANTERIOR_POSTERIOR_PATTERN_SPECIFICATION

GO Biological Process (23): cilium movement (GO:0003341), regulation of DNA-templated transcription (GO:0006355), homophilic cell-cell adhesion (GO:0007156), G protein-coupled receptor signaling pathway (GO:0007186), axonogenesis (GO:0007409), Wnt signaling pathway (GO:0016055), ventricular system development (GO:0021591), neural plate anterior/posterior regionalization (GO:0021999), regulation of cell-cell adhesion (GO:0022407), regulation of protein localization (GO:0032880), cerebrospinal fluid secretion (GO:0033326), cell-cell adhesion mediated by cadherin (GO:0044331), dendrite morphogenesis (GO:0048813), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), cilium assembly (GO:0060271), motor neuron migration (GO:0097475), cell adhesion (GO:0007155), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), nervous system development (GO:0007399), anterior/posterior pattern specification (GO:0009952), animal organ development (GO:0048513), plasma membrane bounded cell projection organization (GO:0120036)

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): cytoplasm (GO:0005737), 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	3
signal transduction	2
cell morphogenesis involved in neuron differentiation	2
neuron projection morphogenesis	2
system development	2
cellular process	2
cellular anatomical structure	2
microtubule-based movement	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
G protein-coupled receptor activity	1
axon development	1
cell surface receptor signaling pathway	1
brain development	1
anterior/posterior pattern specification	1
neural plate regionalization	1
regulation of cell adhesion	1
intracellular protein localization	1
regulation of localization	1
body fluid secretion	1
secretion by tissue	1
dendrite development	1
non-canonical Wnt signaling pathway	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
neuron migration	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

Protein interactions and networks

STRING

1240 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CELSR2	PSRC1	Q6PGN9	986
CELSR2	SORT1	Q99523	947
CELSR2	PCSK9	Q8NBP7	798
CELSR2	FZD3	Q9NPG1	726
CELSR2	MYBPHL	A2RUH7	718
CELSR2	VANGL1	Q8TAA9	709
CELSR2	VANGL2	Q9ULK5	698
CELSR2	SORCS1	Q8WY21	685
CELSR2	SORCS2	Q96PQ0	662
CELSR2	FZD9	O00144	658
CELSR2	SORCS3	Q9UPU3	649
CELSR2	PRICKLE2	Q7Z3G6	604
CELSR2	FZD8	Q9H461	604
CELSR2	HMGCR	P04035	602
CELSR2	SORL1	Q92673	589

IntAct

140 interactions, top by confidence:

A	B	Type	Score
MCM5	MCM3	psi-mi:“MI:0914”(association)	0.850
TSPAN5	ADAM10	psi-mi:“MI:0914”(association)	0.800
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
SOCS7	NCK2	psi-mi:“MI:0914”(association)	0.670
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
DKKL1	DENND11	psi-mi:“MI:0914”(association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
LYPD6	PLXNB2	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
USP36	NPM1	psi-mi:“MI:0914”(association)	0.530
CDH8	ARVCF	psi-mi:“MI:0914”(association)	0.530
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530

BioGRID (159): CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS), CELSR2 (Affinity Capture-MS)

ESM2 similar proteins: D4ACX8, E9PVD3, O35161, O60500, P33146, P55291, Q2PZL6, Q5DRA2, Q5DRA3, Q5DRA4, Q5DRC3, Q5DRC4, Q5DRC6, Q5DRC7, Q5DRC8, Q5DRC9, Q5DRD1, Q5DRD2, Q5DRD3, Q5DRD6, Q5DRD9, Q5DRF1, Q5SZK8, Q6PFX6, Q6V0I7, Q6V1P9, Q86UP0, Q91XZ2, Q91XZ4, Q96JQ0, Q96MS0, Q96TA0, Q9HCU4, Q9NRJ7, Q9NYQ6, Q9QYP2, Q9R0M0, Q9UN66, Q9UN67, Q9UN70

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, A0A1D5PUP4, A0JP86, A2ASQ1, A3KN33, A5YT95, E9Q7X7, G4V4G1, G5ECE3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 191 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Downstream signal transduction	6	18.1×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	541
Likely benign	164
Benign	70

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
402154	NM_001408.3(CELSR2):c.3830C>T (p.Pro1277Leu)	Likely pathogenic
916557	NM_001408.3(CELSR2):c.2858A>G (p.Asn953Ser)	Likely pathogenic

SpliceAI

5250 predictions. Top by Δscore:

Variant	Effect	Δscore
1:109253389:GGTAA:G	donor_loss	1.0000
1:109253390:GT:G	donor_loss	1.0000
1:109253391:T:G	donor_loss	1.0000
1:109258430:AGAC:A	acceptor_gain	1.0000
1:109258431:GAC:G	acceptor_gain	1.0000
1:109258431:GACG:G	acceptor_gain	1.0000
1:109261040:A:T	acceptor_loss	1.0000
1:109261041:GGT:G	acceptor_gain	1.0000
1:109261260:CTCTC:C	donor_gain	1.0000
1:109261261:TCTC:T	donor_gain	1.0000
1:109261262:CTC:C	donor_gain	1.0000
1:109261263:TC:T	donor_gain	1.0000
1:109261265:G:GG	donor_gain	1.0000
1:109261806:A:AG	acceptor_gain	1.0000
1:109261806:AGG:A	acceptor_gain	1.0000
1:109261807:G:GG	acceptor_gain	1.0000
1:109261807:GGG:G	acceptor_gain	1.0000
1:109261807:GGGGA:G	acceptor_gain	1.0000
1:109261892:ATAAG:A	donor_loss	1.0000
1:109261897:G:T	donor_loss	1.0000
1:109261898:T:A	donor_loss	1.0000
1:109262278:T:TA	acceptor_gain	1.0000
1:109262285:A:AG	acceptor_gain	1.0000
1:109262286:G:GC	acceptor_gain	1.0000
1:109262286:GC:G	acceptor_gain	1.0000
1:109262286:GCC:G	acceptor_gain	1.0000
1:109262286:GCCA:G	acceptor_gain	1.0000
1:109262286:GCCAC:G	acceptor_gain	1.0000
1:109262433:T:TA	donor_gain	1.0000
1:109262434:GGC:G	donor_gain	1.0000

AlphaMissense

18957 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:109250978:A:T	E300V	1.000
1:109251011:T:A	V311D	1.000
1:109251125:T:A	I349N	1.000
1:109251250:G:C	D391H	1.000
1:109251258:T:A	N393K	1.000
1:109251258:T:G	N393K	1.000
1:109251269:C:A	P397H	1.000
1:109251275:T:C	F399S	1.000
1:109251359:A:C	D427A	1.000
1:109251359:A:T	D427V	1.000
1:109251419:T:C	F447S	1.000
1:109251511:G:C	D478H	1.000
1:109251587:C:A	P503H	1.000
1:109252046:T:C	F656S	1.000
1:109252184:T:A	V702D	1.000
1:109252197:C:A	N706K	1.000
1:109252197:C:G	N706K	1.000
1:109252207:C:T	P710S	1.000
1:109252208:C:A	P710H	1.000
1:109252208:C:G	P710R	1.000
1:109252213:T:C	F712L	1.000
1:109252214:T:C	F712S	1.000
1:109252215:T:A	F712L	1.000
1:109252215:T:G	F712L	1.000
1:109252286:C:A	A736D	1.000
1:109252297:G:C	D740H	1.000
1:109252298:A:C	D740A	1.000
1:109252298:A:T	D740V	1.000
1:109252324:T:G	Y749D	1.000
1:109252352:T:C	F758S	1.000

dbSNP variants (sampled 300 via entrez): RS1000025173 (1:109274866 C>A,G,T), RS1000058721 (1:109254979 C>T), RS1000166284 (1:109253707 C>A,T), RS1000251270 (1:109257084 G>A), RS1000476751 (1:109263339 A>G), RS1000531056 (1:109270625 G>C), RS1000704794 (1:109253565 C>A,G,T), RS1000878362 (1:109268390 G>A,T), RS1000894582 (1:109275592 A>G), RS1001311244 (1:109254661 C>A,T), RS1001322842 (1:109248993 A>T), RS1001360726 (1:109260749 G>A), RS1001408635 (1:109254484 A>G), RS1001455922 (1:109260486 A>G), RS1001626176 (1:109275867 G>A)

Disease associations

OMIM: gene MIM:604265 | disease phenotypes: MIM:258850, MIM:189960

GenCC curated gene-disease

Mondo (4): orofaciodigital syndrome III (MONDO:0009793), idiopathic scoliosis (MONDO:0000726), intellectual disability (MONDO:0001071), esophageal atresia/tracheoesophageal fistula (MONDO:0008586)

Orphanet (3): Orofaciodigital syndrome type 3 (Orphanet:2752), Esophageal atresia (Orphanet:1199), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

154 associations (top):

Study	Trait	p-value
GCST000131_1	LDL cholesterol	1.000000e-07
GCST000132_7	LDL cholesterol	6.000000e-33
GCST000134_1	LDL cholesterol	3.000000e-29
GCST000151_1	LDL cholesterol	1.000000e-33
GCST000282_2	LDL cholesterol	8.000000e-23
GCST000283_1	LDL cholesterol	2.000000e-12
GCST000285_14	Cholesterol, total	9.000000e-22
GCST000287_7	LDL cholesterol	2.000000e-42
GCST000340_7	Myocardial infarction (early onset)	8.000000e-12
GCST000533_33	Lipid metabolism phenotypes	2.000000e-53
GCST000533_34	Lipid metabolism phenotypes	4.000000e-39
GCST000533_8	Lipid metabolism phenotypes	2.000000e-20
GCST000533_9	Lipid metabolism phenotypes	2.000000e-27
GCST000635_10	Response to statin therapy	4.000000e-06
GCST000759_23	LDL cholesterol	1.000000e-170
GCST000760_5	Cholesterol, total	6.000000e-131
GCST000807_1	LDL cholesterol	1.000000e-26
GCST000911_1	Progranulin levels	2.000000e-30
GCST000975_10	LDL cholesterol	9.000000e-29
GCST000999_17	Coronary heart disease	6.000000e-10
GCST001233_13	Metabolite levels	2.000000e-19
GCST001247_1	Cardiovascular disease risk factors	2.000000e-22
GCST001273_1	Lipoprotein-associated phospholipase A2 activity and mass	1.000000e-17
GCST002467_1	Cholesterol, total	1.000000e-08
GCST002896_36	Cholesterol, total	2.000000e-64
GCST002898_33	LDL cholesterol	2.000000e-91
GCST002899_31	HDL cholesterol	2.000000e-09
GCST003302_2	Cholesterol, total	9.000000e-27
GCST003303_1	LDL cholesterol	1.000000e-28
GCST003678_9	C-reactive protein levels or total cholesterol levels (pleiotropy)	6.000000e-132

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004529	lipid measurement
EFO:0004625	progranulin measurement
EFO:0004746	lipoprotein-associated phospholipase A(2) measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004458	C-reactive protein measurement
EFO:0008395	response to darapladib
EFO:0008432	lipoprotein-associated phospholipase A(2) change measurement
EFO:0009270	heel bone mineral density
EFO:0009925	Antithrombotic agent use measurement
EFO:0009929	Beta blocking agent use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004329	alcohol drinking
EFO:0007796	parental longevity
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0007804	LDL cholesterol change measurement
EFO:0009762	healthspan
EFO:0005689	non-high density lipoprotein cholesterol measurement
EFO:0006925	lipoprotein A measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)
C557817	Orofaciodigital syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs646776	Efficacy	3	HMG-CoA reductase inhibitors

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs602633	CELSR2, PSRC1		0.00	0
rs646776	CELSR2	3	1.25	1	HMG-CoA reductase inhibitors
rs629301	CELSR2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Adhesion Class GPCRs

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression	6
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	4
Cyclosporine	decreases expression	3
bisphenol A	increases expression, increases methylation	2
indeno(1,2,3-cd)pyrene	decreases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	2
Tobacco Smoke Pollution	decreases expression	2
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
hydroxyhydroquinone	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases reaction, increases phosphorylation, decreases activity	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
benzo(k)fluoranthene	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	increases methylation	1
benz(a)anthracene	decreases expression	1
picene	decreases expression	1
IC 261	decreases reaction, increases phosphorylation, decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol Z	increases expression	1

Cellosaurus cell lines

70 cell lines: 70 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_YY32	FHS001i-sh10950A	Induced pluripotent stem cell	Male
CVCL_YY33	FHS002i-sh10950C	Induced pluripotent stem cell	Male
CVCL_YY34	FHS003i-sh12022B	Induced pluripotent stem cell	Female
CVCL_YY35	FHS004i-sh12022C	Induced pluripotent stem cell	Female
CVCL_YY36	FHS005i-sh1236B	Induced pluripotent stem cell	Female
CVCL_YY37	FHS006i-sh1236C	Induced pluripotent stem cell	Female
CVCL_YY38	FHS007i-sh12569A	Induced pluripotent stem cell	Female
CVCL_YY39	FHS008i-sh12569B	Induced pluripotent stem cell	Female
CVCL_YY40	FHS009i-sh12888A	Induced pluripotent stem cell	Female
CVCL_YY41	FHS010i-sh12888B	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01325493	PHASE4	COMPLETED	Low Dose Ketamine Study on Opioid Tolerance and Hyperalgesia
NCT01932424	PHASE4	COMPLETED	Blood Propofol Concentrations in Children During Spinal Surgery
NCT02651324	PHASE4	COMPLETED	Efficacy of Ketamine for Improvement in Postoperative Pain Control After Spinal Fusion for Idiopathic Scoliosis
NCT03190668	PHASE4	COMPLETED	Skeletal Muscle and Adipose Tissue Study
NCT05938959	PHASE4	UNKNOWN	Erector Spinae Plane Block for Pediatric Idiopathic Scoliosis Surgery
NCT05956899	PHASE4	COMPLETED	Palonosetron vs Ondansetron In PONV Prophylaxis Among Idiopathic Scoliosis Patients
NCT06086431	PHASE4	COMPLETED	Dexamethasone Vs. Dexmedetomidine for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT06616220	PHASE4	COMPLETED	Dexamethasone for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT06789016	PHASE4	COMPLETED	Dexmedetomidine for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03867240	PHASE3	WITHDRAWN	Gabapentin and Chronic Post Surgical Pain
NCT06626503	PHASE3	RECRUITING	Evaluation of Analgesia for Spine Fusion Elective Surgery in Children
NCT06774898	PHASE3	NOT_YET_RECRUITING	Spinal Bracing in Adults With Painful Degenerative Scoliosis: a Randomized Controlled Open Trial
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01795495	PHASE2	COMPLETED	Methadone vs Magnesium in Spinal Fusion
NCT03968146	PHASE2	COMPLETED	Erector Spinae Plane Block in Scoliotic Adolescents
NCT04922983	PHASE2	UNKNOWN	Incobotulinumtoxin A and Yoga-like Isometric Exercise in Adolescent Idiopathic Lumbar Scoliosis
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06822374	PHASE2/PHASE3	WITHDRAWN	Hypertonic Saline in Posterior Spinal Fusion
NCT01019109	Not specified	COMPLETED	Scoliosis Surgery Using the PASS® LP System
NCT01549873	Not specified	COMPLETED	Anesthesia During Neurophysiologic Monitoring in Scoliosis Patients
NCT01761305	Not specified	ACTIVE_NOT_RECRUITING	Trial on Three Treatments for Scoliosis
NCT01772459	Not specified	COMPLETED	Paper vs. Internet
NCT02084342	Not specified	UNKNOWN	Study of DDAVP Combined With TXA on the Blood Loss and Transfusion Need During and After Scoliosis Correction Surgery
NCT02199314	Not specified	COMPLETED	Anesthesia and Motor Evoked Potential (MEP) Recruitment
NCT02409615	Not specified	COMPLETED	Complementary Therapies in Spinal Fusion Patients
NCT02607150	Not specified	COMPLETED	Changes in Cerebral Oxygenation During the Administration of Cell Saver Blood and Allogeneic Blood
NCT02926404	Not specified	TERMINATED	UNiD Rods Register
NCT03110965	Not specified	COMPLETED	Yoga in the Treatment of Adolescent Idiopathic and Degenerative Scoliosis