CRB2

Summary

CRB2 (crumbs cell polarity complex component 2, HGNC:18688) is a protein-coding gene on chromosome 9q33.3, encoding Protein crumbs homolog 2 (Q5IJ48). Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo.

This gene encodes a member of a family of proteins that are components of the Crumbs cell polarity complex. In mammals, members of this family are thought to play a role in many cellular processes in early embryonic development. A similar protein in Drosophila determines apicobasal polarity in embryonic epithelial cells. Mutations in this gene are associated with focal segmental glomerulosclerosis 9, and with ventriculomegaly with cystic kidney disease.

Source: NCBI Gene 286204 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal segmental glomerulosclerosis 9 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 865 total — 27 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_173689

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18688
Approved symbol	CRB2
Name	crumbs cell polarity complex component 2
Location	9q33.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ38464, FLJ16786
Ensembl gene	ENSG00000148204
Ensembl biotype	protein_coding
OMIM	609720
Entrez	286204

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000359999, ENST00000373631, ENST00000460253, ENST00000896214, ENST00000896215

RefSeq mRNA: 1 — MANE Select: NM_173689 NM_173689

CCDS: CCDS6852

Canonical transcript exons

ENST00000373631 — 13 exons

Exon	Start	End
ENSE00000983726	123375217	123375343
ENSE00001386595	123373134	123373920
ENSE00001388114	123374579	123374695
ENSE00001403109	123370108	123370980
ENSE00001403926	123367172	123367357
ENSE00001408546	123365917	123366112
ENSE00001409237	123367573	123367686
ENSE00001413829	123366227	123366366
ENSE00001417934	123362865	123363188
ENSE00001425765	123372177	123372342
ENSE00001432552	123371070	123371578
ENSE00001461068	123376838	123378753
ENSE00001948626	123356197	123356354

Expression profiles

Bgee: expression breadth broad, 99 present calls, max score 94.04.

FANTOM5 (CAGE): breadth broad, TPM avg 7.4525 / max 249.1384, expressed in 375 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98439	6.7241	366
98438	0.5346	213
98441	0.1339	83
98442	0.0599	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	94.04	gold quality
ganglionic eminence	UBERON:0004023	80.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.25	silver quality
Brodmann (1909) area 9	UBERON:0013540	74.47	gold quality
amygdala	UBERON:0001876	73.89	gold quality
right frontal lobe	UBERON:0002810	73.47	gold quality
caudate nucleus	UBERON:0001873	72.43	gold quality
anterior cingulate cortex	UBERON:0009835	72.27	gold quality
putamen	UBERON:0001874	72.13	gold quality
prefrontal cortex	UBERON:0000451	71.80	gold quality
nucleus accumbens	UBERON:0001882	69.84	gold quality
hypothalamus	UBERON:0001898	67.87	gold quality
neocortex	UBERON:0001950	67.82	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	67.44	gold quality
frontal cortex	UBERON:0001870	67.10	gold quality
forebrain	UBERON:0001890	65.05	gold quality
adult mammalian kidney	UBERON:0000082	64.96	gold quality
cerebral cortex	UBERON:0000956	64.83	gold quality
substantia nigra	UBERON:0002038	64.83	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	64.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	64.06	gold quality
brain	UBERON:0000955	64.05	gold quality
Ammon’s horn	UBERON:0001954	63.30	gold quality
spinal cord	UBERON:0002240	62.71	gold quality
midbrain	UBERON:0001891	61.87	gold quality
bone marrow cell	CL:0002092	61.45	gold quality
cerebellar cortex	UBERON:0002129	61.02	gold quality
cerebellar hemisphere	UBERON:0002245	60.91	gold quality
temporal lobe	UBERON:0001871	60.77	gold quality
colonic epithelium	UBERON:0000397	60.38	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	17.23
E-MTAB-6108	no	243.49
E-ANND-3	no	1.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting CRB2, 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-8485	100.00	77.57	4731
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6832-5P	99.58	64.82	1132

Literature-anchored findings (GeneRIF, showing 22)

• Crumbs homolog 2 gene maps to human chromosome 9q33.3 (PMID:14767562)
• The CRB2 gene encodes a transmembrane protein (1285 aa) and a secreted protein (1176 aa). The transmembrane isoform consists of 14 extracellular EGF-like domains, 3 extracellular laminin G-like domains, and a Crb cytoplasmic tail domain. (PMID:14767562)
• This study shows that CRB2 sequence variants are not a common cause of autosomal recessive RP and LCA. (PMID:15851977)
• Using X-ray crystallography and NMR spectroscopy, we show that, despite low amino acid sequence conservation, both 53BP1 and Crb2 contain tandem tudor domains that interact with histone H4 specifically dimethylated at Lys20 (H4-K20me2). (PMID:17190600)
• overexpression of human CRB1 and related isoforms, CRB2 and CRB3, had no effect on the levels of presenilin complex components, on NCT maturation or on PS endoproteolysis (PMID:17988153)
• results suggest that CRB2 functions as an inhibitory binding protein that is involved in the formation of a mature but inactive pool of the gamma-secretase complex (PMID:20299451)
• Study showed that CRB1 and CRB2 in human retinas have an opposite pattern of expression in Muller glia and photoreceptor cells compared with mouse retinas, and that Crb2 influences the severity of the murine Crb1-linked retinal dystrophies. (PMID:24565864)
• We demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to Nephrotic syndrome in humans. (PMID:25557779)
• The three families with six affected individuals present compelling evidence for the role of CRB2 in human disease, with a phenotype comprising severe, congenital neurological and renal involvement. (PMID:25557780)
• Clinically, CRB2 should be assessed when ciliopathy is suspected, especially in Ashkenazi Jews, where we found that p.N800K carrier frequency is 1 of 64. Patients harboring CRB2 mutations should be tested for the complete range of ciliopathy manifestations. (PMID:26925547)
• Additional sequence variants in genes involved in kidney development were found in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype. (PMID:27004616)
• These findings demonstrate that Crb2 abnormalities caused by these mutations are the mechanism of steroid-resistant nephrotic syndrome (PMID:27942854)
• Case Report: steroid-resistant nephrotic syndrome caused by a novel Crumbs homolog 2 mutation. (PMID:29473663)
• CRB2 may play an important role in the mechanistic pathway of developing podocytes through tyrosine phosphorylation by associating with mTORC1 activation. (PMID:30125302)
• Thus, we conclude that CRB2 p.R1249G mutation causes retinitis pigmentosa (RP) via accelerating epithelial-mesenchymal transition (EMT), dysfunction and loss of retinal pigment epithelium cells, and establish CRB2 as a novel Crumbs family member associated with non-syndromic RP. (PMID:30593785)
• Data show that crumbs homolog 2 protein (CRB2) protein precedes the expression of crumbs homologue 1 protein (CRB1) in the developing retina. (PMID:30956116)
• Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis. (PMID:34654837)
• CRB2 enhances malignancy of glioblastoma via activation of the NF-kappaB pathway. (PMID:35219647)
• Loss of surface transport is a main cellular pathomechanism of CRB2 variants causing podocytopathies. (PMID:36549870)
• Exome Sequencing Revealed a Novel Splice Site Variant in the CRB2 Gene Underlying Nephrotic Syndrome. (PMID:36556986)
• Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla. (PMID:36803301)
• Human CRB1 and CRB2 form homo- and heteromeric protein complexes in the retina. (PMID:38570189)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	crb2b	ENSDARG00000060081
mus_musculus	Crb2	ENSMUSG00000035403
rattus_norvegicus	Crb2	ENSRNOG00000025498

Paralogs (3): SCARF1 (ENSG00000074660), CRB3 (ENSG00000130545), SCARF2 (ENSG00000244486)

Protein

Protein identifiers

Protein crumbs homolog 2 — Q5IJ48 (reviewed: Q5IJ48)

Alternative names: Crumbs-like protein 2

All UniProt accessions (1): Q5IJ48

UniProt curated annotations — full annotation on UniProt →

Function. Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo. Acts by promoting cell ingression, the process by which cells leave the epithelial epiblast and move inside the embryo to form a new tissue layer. The anisotropic distribution of CRB2 and MYH10/myosin-IIB at cell edges define which cells will ingress: cells with high apical CRB2 are probably extruded from the epiblast by neighboring cells with high levels of apical MYH10/myosin-IIB. Plays a role in the maintenance of retinal neuroepithelium organization, structural integrity, adhesion, photoreceptor polarity and retinal photoreceptor layer thickness. May play a role in determining the length of cone photoreceptor outer segments and proliferation of late-born progenitor cells. Also required for maintenance of the apical polarity complex during development of the cortex. Inhibits gamma-secretase-dependent cleavage of APP and secretion of amyloid-beta peptide 40 and amyloid-beta peptide 42, and thereby inhibits gamma-secretase-dependent Notch transcription.

Subunit / interactions. Associates with the gamma-secretase complex via interaction (via the transmembrane domain) with PSEN1/PS1. Interacts (via intracellular domain) with EPB41L5. Interacts with PALS1.

Subcellular location. Apical cell membrane. Cytoplasm. Cell junction Secreted.

Tissue specificity. Expressed in glomeruli, podocytes of the glomerular capillary loops, and parietal glomerular epithelial cells in the kidney (at protein level). Expressed in retina, fetal eye and brain. Also expressed in kidney, RPE/choroid, and at low levels in lung, placenta, and heart.

Post-translational modifications. O-glucosylated by POGLUT1 at Ser-267; consists of an O-glucose trisaccharide, in which the O-glucose is elongated by the addition of two xylose residues. O-glucosylation is required for localization at the plasma membrane. N-glycosylated.

Disease relevance. Focal segmental glomerulosclerosis 9 (FSGS9) [MIM:616220] A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa (RP) [MIM:268000] A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Retinitis pigmentosa can be inherited as an autosomal dominant, autosomal recessive or X-linked condition. Disease susceptibility may be associated with variants affecting the gene represented in this entry. Ventriculomegaly with cystic kidney disease (VMCKD) [MIM:219730] A severe autosomal recessive developmental disorder manifesting in utero. It is characterized by cerebral ventriculomegaly, echogenic kidneys, microscopic renal tubular cysts and findings of congenital nephrosis. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Crumbs protein family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5IJ48-1	1	yes
Q5IJ48-2	2
Q5IJ48-3	3

RefSeq proteins (1): NP_775960* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR013032	EGF-like_CS	Conserved_site
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site

Pfam: PF00008, PF02210, PF12661

UniProt features (128 total): disulfide bond 48, sequence variant 32, domain 18, glycosylation site 14, sequence conflict 4, splice variant 4, mutagenesis site 3, region of interest 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2WO6	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5IJ48-F1	76.95	0.16

Functional residue map

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

Disulfide bonds (48): 71–82, 76–94, 96–105, 112–123, 117–132, 134–143, 150–161, 155–170, 172–181, 188–199, 193–208, 210–220, 227–238, 232–247, 249–258, 265–276, 270–306, 308–317, 324–335, 329–344 …

Glycosylation sites (14): 235, 267, 438, 478, 669, 690, 786, 800, 836, 886, 926, 1009, 1141, 1158

Mutagenesis-validated functional residues (3):

Position	Phenotype
1258	no effect on secretion of app amyloid-beta peptide 40 and amyloid-beta peptide 42; when associated with p-1260 and e-126
1260	no effect on secretion of app amyloid-beta peptide 40 and amyloid-beta peptide 42; when associated with y-1258 and e-126
1264	no effect on secretion of app amyloid-beta peptide 40 and amyloid-beta peptide 42; when associated with y-1258 and p-126

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 249 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOBP_NEUROGENESIS, GOBP_NEURAL_RETINA_DEVELOPMENT, GOBP_GASTRULATION_WITH_MOUTH_FORMING_SECOND, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, GOBP_CELL_CELL_ADHESION, GOBP_ESTABLISHMENT_OF_CELL_POLARITY

GO Biological Process (18): mesoderm formation (GO:0001707), somitogenesis (GO:0001756), retina homeostasis (GO:0001895), heterophilic cell-cell adhesion (GO:0007157), visual perception (GO:0007601), regulation of gastrulation (GO:0010470), positive regulation of epithelial to mesenchymal transition (GO:0010718), negative regulation of endopeptidase activity (GO:0010951), notochord formation (GO:0014028), establishment of cell polarity (GO:0030010), positive regulation of BMP signaling pathway (GO:0030513), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), maintenance of epithelial cell apical/basal polarity (GO:0045199), photoreceptor cell maintenance (GO:0045494), retinal cone cell development (GO:0046549), ingression involved in gastrulation with mouth forming second (GO:0055111), circulatory system development (GO:0072359), gastrulation (GO:0007369)

GO Molecular Function (4): calcium ion binding (GO:0005509), aspartic-type endopeptidase inhibitor activity (GO:0019828), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (13): cytoplasm (GO:0005737), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), apicolateral plasma membrane (GO:0016327), protein-containing complex (GO:0032991), subapical complex (GO:0035003), apical junction complex (GO:0043296), extracellular exosome (GO:0070062), extracellular region (GO:0005576), membrane (GO:0016020), cell junction (GO:0030054), apical part of cell (GO:0045177), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
anatomical structure formation involved in morphogenesis	2
binding	2
plasma membrane region	2
formation of primary germ layer	1
mesoderm morphogenesis	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
somite development	1
tissue homeostasis	1
cell-cell adhesion	1
sensory perception of light stimulus	1
gastrulation	1
regulation of anatomical structure morphogenesis	1
regulation of embryonic development	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
endopeptidase activity	1
negative regulation of peptidase activity	1
regulation of endopeptidase activity	1
nervous system development	1
notochord morphogenesis	1
establishment or maintenance of cell polarity	1
BMP signaling pathway	1
regulation of BMP signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
establishment or maintenance of apical/basal cell polarity	1
maintenance of apical/basal cell polarity	1
establishment or maintenance of epithelial cell apical/basal polarity	1
retina homeostasis	1
multicellular organismal process	1
eye photoreceptor cell development	1
retinal cone cell differentiation	1
gastrulation with mouth forming second	1
cell migration involved in gastrulation	1
system development	1
ectoderm formation	1

Protein interactions and networks

STRING

1508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRB2	PALS1	Q8N3R9	997
CRB2	PATJ	Q8NI35	995
CRB2	CRB3	Q9BUF7	904
CRB2	EPB41L5	Q9HCM4	857
CRB2	TP53BP1	Q12888	822
CRB2	RAD9A	Q99638	814
CRB2	H2AC19	P20670	758
CRB2	H2AC20	Q16777	757
CRB2	CHEK1	O14757	754
CRB2	DENND1A	Q8TEH3	707
CRB2	EPB41	P11171	704
CRB2	NEK6	Q9HC98	667
CRB2	NEK7	Q8TDX7	656
CRB2	NXN	Q6DKJ4	647
CRB2	PARD3	Q8TEW0	621

IntAct

128 interactions, top by confidence:

A	B	Type	Score
CRB2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	CRB2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	MPP2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	HTRA2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	AHNAK	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	TJP2	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	FRMPD1	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	MPDZ	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
CRB2	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (4): CRB2 (Affinity Capture-Western), CRB2 (Affinity Capture-MS), CRB2 (Affinity Capture-MS), HIST1H4A (Co-crystal Structure)

ESM2 similar proteins: A1L0T3, A1L4H1, D3ZTE0, G3V801, O08762, O43866, O75636, O95428, O97507, P00748, P22457, P56730, P58215, P69525, P69526, P85521, P98140, Q02853, Q04756, Q04962, Q24K22, Q2VL90, Q2VLG4, Q2VLG6, Q2VLH6, Q499S5, Q4G0T1, Q5G265, Q5G268, Q5G269, Q5G270, Q5G271, Q5IJ48, Q6QNF4, Q70UZ7, Q769J6, Q76LX8, Q7Z410, Q80YA8, Q80YC5

Diamond homologs: A2RUV0, A4FV93, B2LW77, B8JI71, D3ZHH1, D3ZUK3, O35474, O70534, O88277, P10041, P21783, P31695, P78504, P80370, P97607, Q09163, Q2PZL6, Q5IJ48, Q5R6R1, Q5ZQU0, Q63722, Q6DCQ6, Q6QNF4, Q6UY11, Q6V0I7, Q70E20, Q8JZM4, Q8K1E3, Q8NFT8, Q8TER0, Q8VHS2, Q90Y54, Q90Y57, Q9JI71, Q9QXX0, Q9QYE5, Q9Y219, O43854, P18168, P82279

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Ras activation upon Ca2+ influx through NMDA receptor	5	53.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	51.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	51.3×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	47.9×	5e-13
Dopamine Neurotransmitter Release Cycle	5	46.8×	2e-06
Long-term potentiation	5	44.9×	2e-06
Neurexins and neuroligins	12	44.6×	4e-15
Protein-protein interactions at synapses	7	35.1×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	66.2×	3e-12
protein localization to synapse	6	58.2×	8e-08
receptor clustering	7	55.3×	8e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	43.9×	3e-08
cell-cell adhesion	10	12.8×	5e-07
protein-containing complex assembly	7	10.1×	3e-04
chemical synaptic transmission	7	6.8×	2e-03
protein transport	8	4.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	14
Uncertain significance	383
Likely benign	275
Benign	75

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076302	NM_173689.7(CRB2):c.1920C>A (p.Cys640Ter)	Pathogenic
1322160	NM_173689.7(CRB2):c.2336del (p.Phe779fs)	Pathogenic
1335737	NM_173689.7(CRB2):c.755-1G>A	Pathogenic
1418242	NM_173689.7(CRB2):c.2360C>G (p.Ser787Ter)	Pathogenic
1451639	NM_173689.7(CRB2):c.3485dup (p.Glu1163fs)	Pathogenic
1451919	NM_173689.7(CRB2):c.2445_2446del (p.Cys816fs)	Pathogenic
1453388	NM_173689.7(CRB2):c.2795dup (p.Val933fs)	Pathogenic
180702	NM_173689.7(CRB2):c.1886G>C (p.Cys629Ser)	Pathogenic
180704	NM_173689.7(CRB2):c.2277G>A (p.Trp759Ter)	Pathogenic
180707	NM_173689.7(CRB2):c.1897C>T (p.Arg633Trp)	Pathogenic
2034504	NM_173689.7(CRB2):c.2904_2905insGCCACCTCGCGCTGGCT (p.Thr969fs)	Pathogenic
2772517	NM_173689.7(CRB2):c.1266del (p.Ser421_Tyr422insTer)	Pathogenic
2841977	NM_173689.7(CRB2):c.1186C>T (p.Gln396Ter)	Pathogenic
2957210	NM_173689.7(CRB2):c.951C>A (p.Cys317Ter)	Pathogenic
3255213	NM_173689.7(CRB2):c.823C>T (p.Arg275Ter)	Pathogenic
3269430	NM_173689.7(CRB2):c.793dup (p.Cys265fs)	Pathogenic
3348771	NM_173689.7(CRB2):c.3145del (p.Ala1049fs)	Pathogenic
3610435	NM_173689.7(CRB2):c.382_386dup (p.Tyr130fs)	Pathogenic
3902743	NM_173689.7(CRB2):c.1006C>T (p.Gln336Ter)	Pathogenic
419404	NM_173689.7(CRB2):c.3291_3292del (p.Cys1098fs)	Pathogenic
4292766	NM_173689.7(CRB2):c.445G>T (p.Glu149Ter)	Pathogenic
4696635	NM_173689.7(CRB2):c.635del (p.Gly212fs)	Pathogenic
4777584	NM_173689.7(CRB2):c.1205_1230dup (p.Cys411fs)	Pathogenic
4812235	NM_173689.7(CRB2):c.1140T>A (p.Tyr380Ter)	Pathogenic
546072	NM_173689.7(CRB2):c.2400C>G (p.Asn800Lys)	Pathogenic
829899	NM_173689.7(CRB2):c.3613G>A (p.Gly1205Ser)	Pathogenic
974481	NM_173689.7(CRB2):c.1827C>A (p.Cys609Ter)	Pathogenic
1526302	NM_173689.7(CRB2):c.514T>C (p.Cys172Arg)	Likely pathogenic
1679728	NM_173689.7(CRB2):c.1054+2T>G	Likely pathogenic
2506114	NC_000009.11:g.(126129637_126129851)_(126136200_126136857)del	Likely pathogenic

SpliceAI

2337 predictions. Top by Δscore:

Variant	Effect	Δscore
9:123366111:GG:G	donor_gain	1.0000
9:123366112:GG:G	donor_gain	1.0000
9:123367170:A:AG	acceptor_gain	1.0000
9:123367171:G:GG	acceptor_gain	1.0000
9:123367356:GG:G	donor_gain	1.0000
9:123367357:GG:G	donor_gain	1.0000
9:123370103:CAAAG:C	acceptor_loss	1.0000
9:123370104:AAAG:A	acceptor_gain	1.0000
9:123370106:A:C	acceptor_loss	1.0000
9:123370106:A:G	acceptor_gain	1.0000
9:123370106:AG:A	acceptor_gain	1.0000
9:123370107:G:GG	acceptor_gain	1.0000
9:123370107:GG:G	acceptor_gain	1.0000
9:123371574:GCAGT:G	donor_gain	1.0000
9:123371577:GT:G	donor_gain	1.0000
9:123371579:G:GG	donor_gain	1.0000
9:123356350:GGCTG:G	donor_gain	0.9900
9:123356351:GCTGG:G	donor_gain	0.9900
9:123363186:CAGG:C	donor_loss	0.9900
9:123363188:G:GC	donor_loss	0.9900
9:123363189:G:A	donor_loss	0.9900
9:123365905:T:A	acceptor_gain	0.9900
9:123365911:GTCCA:G	acceptor_loss	0.9900
9:123365912:TCCA:T	acceptor_loss	0.9900
9:123365913:CCAG:C	acceptor_loss	0.9900
9:123365915:A:AC	acceptor_loss	0.9900
9:123365915:A:AG	acceptor_gain	0.9900
9:123365916:G:GT	acceptor_gain	0.9900
9:123365916:GGC:G	acceptor_gain	0.9900
9:123365916:GGCGT:G	acceptor_gain	0.9900

AlphaMissense

8232 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:123363104:T:A	C112S	0.996
9:123363105:G:C	C112S	0.996
9:123363083:T:A	C105S	0.994
9:123363084:G:C	C105S	0.994
9:123363068:T:C	F100L	0.993
9:123363069:T:G	F100C	0.993
9:123363070:C:A	F100L	0.993
9:123363070:C:G	F100L	0.993
9:123372218:G:C	W826C	0.993
9:123372218:G:T	W826C	0.993
9:123373230:T:C	F900S	0.992
9:123367189:T:A	C258S	0.991
9:123367190:G:C	C258S	0.991
9:123363084:G:A	C105Y	0.990
9:123363084:G:T	C105F	0.990
9:123363137:T:A	C123S	0.990
9:123363138:G:C	C123S	0.990
9:123363104:T:C	C112R	0.989
9:123363083:T:C	C105R	0.988
9:123373399:G:C	W956C	0.988
9:123373399:G:T	W956C	0.988
9:123363074:G:T	G102C	0.987
9:123363138:G:A	C123Y	0.987
9:123370925:G:C	W624C	0.987
9:123370925:G:T	W624C	0.987
9:123366039:T:A	C181S	0.986
9:123366040:G:C	C181S	0.986
9:123367190:G:A	C258Y	0.986
9:123363105:G:A	C112Y	0.985
9:123370447:T:C	F465S	0.985

dbSNP variants (sampled 300 via entrez): RS1000075295 (9:123356191 G>A,C,T), RS1000246767 (9:123375146 C>A,T), RS1000435350 (9:123379412 G>A), RS1000454305 (9:123366859 G>C), RS1000653596 (9:123362238 A>T), RS1000678947 (9:123365582 C>A,T), RS1000741922 (9:123366593 A>G,T), RS1000777337 (9:123360150 G>A), RS1000933285 (9:123366911 C>T), RS1001119390 (9:123372707 G>A), RS1001194594 (9:123365768 C>T), RS1001211234 (9:123359739 T>C), RS1001452423 (9:123362718 G>A,C), RS1001493623 (9:123353188 C>A,T), RS1001512830 (9:123374259 G>A,C,T)

Disease associations

OMIM: gene MIM:609720 | disease phenotypes: MIM:616220, MIM:219730, MIM:614699, MIM:614615

GenCC curated gene-disease

Disease	Classification	Inheritance
focal segmental glomerulosclerosis 9	Definitive	Autosomal recessive
ventriculomegaly-cystic kidney disease	Definitive	Autosomal recessive
familial idiopathic steroid-resistant nephrotic syndrome	Supportive	Autosomal dominant
retinitis pigmentosa	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
focal segmental glomerulosclerosis 9	Definitive	AR

Mondo (9): focal segmental glomerulosclerosis (MONDO:0100313), focal segmental glomerulosclerosis 9 (MONDO:0014539), ventriculomegaly-cystic kidney disease (MONDO:0009063), immunodeficiency, common variable, 7 (MONDO:0013862), steroid-resistant nephrotic syndrome (MONDO:0044765), obesity disorder (MONDO:0011122), Joubert syndrome 17 (MONDO:0013824), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006), retinitis pigmentosa (MONDO:0019200)

Orphanet (7): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Ventriculomegaly-cystic kidney disease (Orphanet:443988), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Common variable immunodeficiency phenotype due to CD21 deficiency (Orphanet:696894), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Isolated Joubert syndrome (Orphanet:475), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000108	Renal corticomedullary cysts
HP:0000238	Hydrocephalus
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000969	Edema
HP:0001250	Seizure
HP:0001561	Polyhydramnios
HP:0001622	Premature birth
HP:0001629	Ventricular septal defect
HP:0001945	Fever
HP:0001967	Diffuse mesangial sclerosis
HP:0002027	Abdominal pain
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0002315	Headache
HP:0002586	Peritonitis
HP:0002617	Vascular dilatation
HP:0003073	Hypoalbuminemia
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003774	Stage 5 chronic kidney disease
HP:0004719	Hyperechogenic kidneys
HP:0011432	Elevated maternal circulating alpha-fetoprotein concentration
HP:0011461	Fetal onset
HP:0011463	Childhood onset
HP:0011947	Respiratory tract infection

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002783_401	Body mass index	7.000000e-08
GCST002783_527	Body mass index	2.000000e-07
GCST008129_68	Body mass index	4.000000e-10
GCST010703_296	Brain morphology (MOSTest)	2.000000e-14
GCST010988_407	Adult body size	4.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases methylation	4
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
sodium arsenate	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	decreases expression	1
arsenite	increases expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	decreases reaction, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases reaction, increases expression, decreases expression	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression	1
Formaldehyde	increases expression	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
1-Methyl-4-phenylpyridinium	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT03408405	PHASE4	WITHDRAWN	ACTHAR Gel for Drug REsistant Nephrotic Syndrome in Children
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition