CBLN2

Summary

CBLN2 (cerebellin 2 precursor, HGNC:1544) is a protein-coding gene on chromosome 18q22.3, encoding Cerebellin-2 (Q8IUK8). Acts as a synaptic organizer in specific subsets of neurons in the brain.

Predicted to be involved in maintenance of synapse structure and spontaneous synaptic transmission. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be located in synaptic cleft. Predicted to be part of trans-synaptic protein complex. Predicted to be active in glutamatergic synapse.

Source: NCBI Gene 147381 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_182511

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1544
Approved symbol	CBLN2
Name	cerebellin 2 precursor
Location	18q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141668
Ensembl biotype	protein_coding
OMIM	600433
Entrez	147381

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000269503, ENST00000580889, ENST00000581073, ENST00000581425, ENST00000582667, ENST00000583570, ENST00000583651, ENST00000584764, ENST00000585159, ENST00000881350, ENST00000881351, ENST00000881352, ENST00000971390, ENST00000971391

RefSeq mRNA: 1 — MANE Select: NM_182511 NM_182511

CCDS: CCDS11999

Canonical transcript exons

ENST00000269503 — 5 exons

Exon	Start	End
ENSE00000950357	72541804	72542326
ENSE00001305964	72543486	72543530
ENSE00001367303	72543977	72544342
ENSE00003504203	72538653	72538772
ENSE00003842223	72536681	72538373

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 95.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.6813 / max 753.2777, expressed in 176 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172385	0.8583	118
172387	0.8498	128
172393	0.2743	39
172392	0.2269	40
172394	0.1443	34
172388	0.1231	52
172383	0.0636	20
172390	0.0400	25
172384	0.0339	20
172391	0.0238	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
superior frontal gyrus	UBERON:0002661	95.97	gold quality
endothelial cell	CL:0000115	95.34	gold quality
middle temporal gyrus	UBERON:0002771	95.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.34	gold quality
prefrontal cortex	UBERON:0000451	93.63	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.31	gold quality
frontal cortex	UBERON:0001870	93.11	gold quality
frontal lobe	UBERON:0016525	93.11	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.89	gold quality
postcentral gyrus	UBERON:0002581	92.31	gold quality
parietal lobe	UBERON:0001872	91.38	gold quality
neocortex	UBERON:0001950	91.29	gold quality
right frontal lobe	UBERON:0002810	90.99	gold quality
anterior cingulate cortex	UBERON:0009835	90.05	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.33	gold quality
cerebral cortex	UBERON:0000956	88.18	gold quality
pons	UBERON:0000988	86.97	gold quality
primary visual cortex	UBERON:0002436	85.97	gold quality
occipital lobe	UBERON:0002021	83.76	gold quality
entorhinal cortex	UBERON:0002728	80.83	gold quality
substantia nigra pars compacta	UBERON:0001965	80.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.51	gold quality
temporal lobe	UBERON:0001871	77.26	gold quality
hypothalamus	UBERON:0001898	76.41	gold quality
substantia nigra pars reticulata	UBERON:0001966	76.01	gold quality
Ammon’s horn	UBERON:0001954	75.18	gold quality
forebrain	UBERON:0001890	74.68	gold quality
amygdala	UBERON:0001876	74.27	gold quality
midbrain	UBERON:0001891	73.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	1470.33
E-HCAD-25	yes	602.33
E-ANND-3	yes	3.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

115 targeting CBLN2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3913-5P	99.78	67.26	968

Literature-anchored findings (GeneRIF, showing 4)

• Transgenic Cbln2 can exhibit functional redundancy with Cbln1 in the cerebellum, but it does not have the same properties as Cbln1 in thalamic neurons. (PMID:22117778)
• Single nucleotide polymorphisms in CBLN2 gene is associated with pulmonary arterial hypertension. (PMID:23502781)
• an important role of CBLN2 in PAH onset despite different etiologies (PMID:30539924)
• Hominini-specific regulation of CBLN2 increases prefrontal spinogenesis. (PMID:34599306)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbln2a	ENSDARG00000074601
danio_rerio	cbln2b	ENSDARG00000077151
mus_musculus	Cbln2	ENSMUSG00000024647
rattus_norvegicus	Cbln2	ENSRNOG00000013654

Paralogs (3): CBLN4 (ENSG00000054803), CBLN1 (ENSG00000102924), CBLN3 (ENSG00000139899)

Protein

Protein identifiers

Cerebellin-2 — Q8IUK8 (reviewed: Q8IUK8)

All UniProt accessions (3): Q8IUK8, J3KST0, J3QS23

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a synaptic organizer in specific subsets of neurons in the brain. Essential for long-term maintenance but not establishment of excitatory synapses. Functions as part of a trans-synaptic complex by binding to postsynaptic GRID1 and presynaptic neurexins. This interaction helps regulate the activity of NMDA and AMPA receptors at hippocampal synapses without affecting synapse formation. NRXN1B-CBLN2-GRID1 complex transduce presynaptic signals into postsynaptic NMDAR response. NRXN3B-CBLN2-GRID1 complex transduce presynaptic signals into postsynaptic AMPAR response.

Subunit / interactions. Homohexamer; disulfide-linked homotrimers. The trimers are assembled via the globular C1q domains. The trimers associate via N-terminal cysteine residues to form disulfide-linked hexamers. May form homooligomers or heterooligomers with CBLN1 and CBLN3 prior to secretion. Once secreted, does not interact with other CBLN family members. Interacts with GRID2, and more weakly with GRID1. Interacts with NRXN1 and NRXN2 long and short isoforms produced by alternative promoter usage. Weakly interacts with NRXN3 short isoform and not at all with NRXN3 long isoform.

Subcellular location. Secreted.

RefSeq proteins (1): NP_872317* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001073	C1q_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR050822	Cerebellin_Synaptic_Org	Family

Pfam: PF00386

UniProt features (7 total): glycosylation site 2, disulfide bond 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUK8-F1	77.19	0.51

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 (2): 64, 68

Glycosylation sites (2): 53, 110

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 121 (showing top): AAGCAAT_MIR137, GOBP_SYNAPSE_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, ATGTTAA_MIR302C, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_SYNAPTIC_SIGNALING

GO Biological Process (6): synapse assembly (GO:0007416), synapse organization (GO:0050808), positive regulation of synapse assembly (GO:0051965), spontaneous synaptic transmission (GO:0098814), trans-synaptic signaling, modulating synaptic transmission (GO:0099550), maintenance of synapse structure (GO:0099558)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), synaptic cleft (GO:0043083), synapse (GO:0045202), trans-synaptic protein complex (GO:0098820), glutamatergic synapse (GO:0098978), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synapse organization	2
chemical synaptic transmission	2
cellular anatomical structure	2
nervous system development	1
cell junction assembly	1
cell junction organization	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
spontaneous neurotransmitter secretion	1
modulation of chemical synaptic transmission	1
trans-synaptic signaling	1
cell junction maintenance	1
binding	1
extracellular region	1
cell junction	1
protein-containing complex	1
synapse	1

Protein interactions and networks

STRING

1450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBLN2	GRID2	O43424	730
CBLN2	NRXN1	Q9ULB1	606
CBLN2	NRXN2	Q9P2S2	604
CBLN2	NRXN3	Q9Y4C0	577
CBLN2	KCNK3	O14649	506
CBLN2	BMPR2	Q13873	480
CBLN2	NLGN1	Q8N2Q7	472
CBLN2	CBLN3	Q6UW01	455
CBLN2	FOXP2	O15409	452
CBLN2	VSTM2L	Q96N03	447
CBLN2	NLGN2	Q8NFZ4	446
CBLN2	NLGN3	Q9NZ94	439
CBLN2	NR4A2	P43354	434
CBLN2	TBX4	P57082	432
CBLN2	CPNE8	Q86YQ8	426
CBLN2	CNTN4	Q8IWV2	426

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A1A5X5, A4IH36, D4AB34, O93449, O95150, O97605, O97626, P04088, P04924, P09529, P10600, P15203, P16047, P17125, P17491, P27093, P36939, P36940, P41047, P42917, P48023, P50591, P50592, P59694, P59695, P63306, P63307, P63308, Q04999, Q07258, Q5UBV8, Q5XIG2, Q6PGN1, Q80WL1, Q861W5, Q8BGU2, Q8BMF8, Q8IUK8, Q8K3Y7, Q8R2Z0

Diamond homologs: A0A060WQA3, A5PN28, A6NHN0, B2RNN3, O75973, O88992, P02745, P02746, P02747, P08125, P0C862, P14282, P23206, P23435, P25067, P25318, P27658, P31720, P63182, P83371, P86437, P98085, P98086, P98087, Q00780, Q02105, Q03692, Q05306, Q05A80, Q0II24, Q15848, Q17QF9, Q2KIV9, Q3Y5Z3, Q4ZJM7, Q4ZJM9, Q4ZJN1, Q5E9E3, Q5FVH0, Q5RJ80

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

749 predictions. Top by Δscore:

Variant	Effect	Δscore
18:72538369:CTGAC:C	acceptor_gain	1.0000
18:72543481:GTTA:G	donor_loss	1.0000
18:72543482:TTACC:T	donor_loss	1.0000
18:72543483:TACC:T	donor_loss	1.0000
18:72543484:A:C	donor_loss	1.0000
18:72543485:C:G	donor_loss	1.0000
18:72538373:CCTAA:C	acceptor_loss	0.9900
18:72541798:GCTGA:G	donor_loss	0.9900
18:72541799:CTGA:C	donor_loss	0.9900
18:72541800:TGACC:T	donor_loss	0.9900
18:72541801:GACC:G	donor_loss	0.9900
18:72541802:ACCTG:A	donor_loss	0.9900
18:72541803:C:CT	donor_loss	0.9900
18:72541839:T:C	donor_gain	0.9900
18:72543480:GGTTA:G	donor_loss	0.9900
18:72538268:C:A	donor_gain	0.9800
18:72538916:C:T	acceptor_gain	0.9400
18:72538374:C:CC	acceptor_gain	0.9300
18:72543487:TGGA:T	donor_gain	0.9100
18:72543494:T:TA	donor_gain	0.9100
18:72538916:C:CT	acceptor_gain	0.9000
18:72538371:GACCT:G	acceptor_gain	0.8900
18:72538372:ACCTA:A	acceptor_gain	0.8900
18:72538917:A:T	acceptor_gain	0.8900
18:72543204:TCCC:T	acceptor_gain	0.8900
18:72538370:TGAC:T	acceptor_gain	0.8800
18:72541804:C:G	donor_loss	0.8800
18:72538371:GAC:G	acceptor_gain	0.8700
18:72543484:A:AC	donor_gain	0.8700
18:72543485:C:CC	donor_gain	0.8700

AlphaMissense

1450 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:72538185:A:C	F222L	1.000
18:72538185:A:T	F222L	1.000
18:72538187:A:G	F222L	1.000
18:72538194:G:C	F219L	1.000
18:72538194:G:T	F219L	1.000
18:72538196:A:G	F219L	1.000
18:72538198:C:T	G218D	1.000
18:72538199:C:G	G218R	1.000
18:72538202:A:G	S217P	1.000
18:72538203:G:C	F216L	1.000
18:72538203:G:T	F216L	1.000
18:72538204:A:G	F216S	1.000
18:72538205:A:G	F216L	1.000
18:72538210:G:A	S214F	1.000
18:72538231:A:T	L207H	1.000
18:72538237:C:A	G205V	1.000
18:72538238:C:G	G205R	1.000
18:72538246:A:G	L202P	1.000
18:72538252:A:G	L200P	1.000
18:72538252:A:T	L200H	1.000
18:72538300:G:T	A184D	1.000
18:72538332:A:C	F173L	1.000
18:72538332:A:T	F173L	1.000
18:72538333:A:C	F173C	1.000
18:72538333:A:G	F173S	1.000
18:72538334:A:G	F173L	1.000
18:72538366:A:G	L162S	1.000
18:72538678:T:A	K151I	1.000
18:72538689:G:C	F147L	1.000
18:72538689:G:T	F147L	1.000

dbSNP variants (sampled 300 via entrez): RS1000077594 (18:72606465 G>A,T), RS1000099159 (18:72567404 C>A), RS1000102619 (18:72587525 A>G), RS1000136102 (18:72609921 T>G), RS1000148677 (18:72549626 C>T), RS1000160010 (18:72544298 G>A), RS1000182029 (18:72630945 G>A), RS1000185150 (18:72552702 T>A), RS1000203867 (18:72590967 C>G,T), RS1000208186 (18:72584596 C>A), RS1000240959 (18:72610347 G>C), RS1000256704 (18:72560158 G>A), RS1000301678 (18:72584975 G>T), RS1000318806 (18:72612374 A>G), RS1000366366 (18:72536275 T>A,C)

Disease associations

OMIM: gene MIM:600433 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000266_9	Multiple sclerosis (severity)	9.000000e-06
GCST001510_4	Response to TNF-alpha inhibitors in rheumatoid arthritis	4.000000e-06
GCST001908_1	Pulmonary arterial hypertension (without BMPR2 mutations)	7.000000e-10
GCST005149_39	Colorectal cancer	1.000000e-07
GCST005150_35	Colorectal cancer	4.000000e-07
GCST007018_15	Serum bilirubin levels in metabolic syndrome	3.000000e-09
GCST007018_6	Serum bilirubin levels in metabolic syndrome	1.000000e-06
GCST90026412_6	Severe autoimmune type 2 diabetes	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004653	response to TNF antagonist
EFO:0004570	bilirubin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
entinostat	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Clorgyline	increases expression	1
Nickel	decreases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Dronabinol	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	increases expression	1
Tunicamycin	decreases expression	1
Thapsigargin	decreases expression	1

Clinical trials (associated diseases)

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