CBLN4

Summary

CBLN4 (cerebellin 4 precursor, HGNC:16231) is a protein-coding gene on chromosome 20q13.2, encoding Cerebellin-4 (Q9NTU7). Acts as a synaptic organizer in specific subsets of neurons in the brain.

This gene encodes a member of a family of small secreted proteins containing C1Q domains. Members of this family are involved in regulation of neurexin signalling during synapse development. The mouse homolog of the protein encoded by this gene competes with netrin to bind to the deleted in colorectal cancer receptor.

Source: NCBI Gene 140689 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 15 total
• MANE Select transcript: NM_080617

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16231
Approved symbol	CBLN4
Name	cerebellin 4 precursor
Location	20q13.2
Locus type	gene with protein product
Status	Approved
Aliases	dJ885A10.1
Ensembl gene	ENSG00000054803
Ensembl biotype	protein_coding
OMIM	615029
Entrez	140689

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000064571

RefSeq mRNA: 1 — MANE Select: NM_080617 NM_080617

CCDS: CCDS13448

Canonical transcript exons

ENST00000064571 — 3 exons

Exon	Start	End
ENSE00000512423	56003881	56005519
ENSE00000662870	56000731	56000847
ENSE00001271654	55997357	55998754

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 91.55.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4751 / max 52.1751, expressed in 94 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188082	0.3078	71
188081	0.1251	63
188080	0.0422	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	91.55	gold quality
caput epididymis	UBERON:0004358	86.90	gold quality
oocyte	CL:0000023	85.15	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.02	gold quality
endothelial cell	CL:0000115	85.00	gold quality
prefrontal cortex	UBERON:0000451	84.60	gold quality
entorhinal cortex	UBERON:0002728	83.94	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.91	gold quality
middle temporal gyrus	UBERON:0002771	82.86	gold quality
frontal cortex	UBERON:0001870	81.49	gold quality
superior frontal gyrus	UBERON:0002661	81.31	gold quality
neocortex	UBERON:0001950	80.51	gold quality
right adrenal gland cortex	UBERON:0035827	79.82	gold quality
anterior cingulate cortex	UBERON:0009835	79.68	gold quality
hypothalamus	UBERON:0001898	79.40	gold quality
adrenal cortex	UBERON:0001235	78.50	gold quality
right adrenal gland	UBERON:0001233	78.33	gold quality
postcentral gyrus	UBERON:0002581	78.32	gold quality
cerebral cortex	UBERON:0000956	78.27	gold quality
primary visual cortex	UBERON:0002436	78.22	gold quality
temporal lobe	UBERON:0001871	78.03	gold quality
left adrenal gland	UBERON:0001234	78.01	gold quality
left adrenal gland cortex	UBERON:0035825	78.00	gold quality
buccal mucosa cell	CL:0002336	77.89	silver quality
parietal lobe	UBERON:0001872	77.54	gold quality
right frontal lobe	UBERON:0002810	77.37	gold quality
adrenal gland	UBERON:0002369	76.60	gold quality
occipital lobe	UBERON:0002021	76.44	gold quality
Brodmann (1909) area 46	UBERON:0006483	76.15	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	11.05
E-GEOD-81608	yes	4.79
E-GEOD-83139	no	3.21
E-ANND-3	no	2.58

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HES1, SOX9, SRY

miRNA regulators (miRDB)

123 targeting CBLN4, 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-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbln4	ENSDARG00000061240
mus_musculus	Cbln4	ENSMUSG00000067578
rattus_norvegicus	Cbln4	ENSRNOG00000004372

Paralogs (3): CBLN1 (ENSG00000102924), CBLN3 (ENSG00000139899), CBLN2 (ENSG00000141668)

Protein

Protein identifiers

Cerebellin-4 — Q9NTU7 (reviewed: Q9NTU7)

Alternative names: Cerebellin-like glycoprotein 1

All UniProt accessions (1): Q9NTU7

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a synaptic organizer in specific subsets of neurons in the brain. Essential for the formation and maintenance of inhibitory GABAergic synapses. Promotes the development of dendrite-targeting inhibitory GABAergic synapses made by somatostatin-positive interneurons. May contribute to the function of ventral medial habenula region of the brain implicated in the regulation of anxiety-related behaviors. May play a role in CBLN3 export from the endoplasmic reticulum and secretion.

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 oligomers with CBLN1, CBLN2 and CBLN3 prior to secretion. Strongly interacts with DCC in a NTN1-displaceable fashion. Weakly binds to NRXN1 and NRXN2 long and short isoforms produced by alternative promoter usage. Interaction with NRXN3 short isoform is hardly detectable; no interaction at all with NRXN3 long isoform.

Subcellular location. Secreted. Synapse.

Post-translational modifications. Sialoglycoprotein.

RefSeq proteins (1): NP_542184* (*=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 (8 total): glycosylation site 2, disulfide bond 2, signal peptide 1, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTU7-F1	80.09	0.53

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): 40, 44

Glycosylation sites (2): 29, 88

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): RRAGTTGT_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_SYNAPSE_ASSEMBLY, NKX25_02, GOBP_CELLULAR_COMPONENT_MAINTENANCE, AP2_Q3, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_SECRETION, GOBP_SYNAPTIC_SIGNALING, AACTTT_UNKNOWN, GOBP_CELL_JUNCTION_ASSEMBLY, ACTTTAT_MIR1425P, TGCCTTA_MIR124A, CTAWWWATA_RSRFC4_Q2

GO Biological Process (3): protein secretion (GO:0009306), trans-synaptic signaling, modulating synaptic transmission (GO:0099550), inhibitory synapse assembly (GO:1904862)

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

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), synaptic cleft (GO:0043083), synapse (GO:0045202), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
synapse	2
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
chemical synaptic transmission	1
modulation of chemical synaptic transmission	1
trans-synaptic signaling	1
synapse assembly	1
binding	1
external encapsulating structure	1
extracellular region	1
cell junction	1

Protein interactions and networks

STRING

1400 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBLN4	DCC	P43146	631
CBLN4	NEO1	Q92859	623
CBLN4	GRID2	O43424	606
CBLN4	GLUD1	P00367	514
CBLN4	NRXN2	Q9P2S2	480
CBLN4	NRXN1	Q9ULB1	454
CBLN4	MC3R	P41968	450
CBLN4	NECAB2	Q7Z6G3	437
CBLN4	CHODL	Q9H9P2	431
CBLN4	TECTA	O75443	429
CBLN4	CBLN1	P02682	416
CBLN4	TECTB	Q96PL2	391
CBLN4	ESR2	Q92731	371
CBLN4	NXPH1	P58417	368
CBLN4	PCSK1N	Q9UHG2	361

IntAct

12 interactions, top by confidence:

A	B	Type	Score
HESX1	RBP4	psi-mi:“MI:0914”(association)	0.560
CBLN4	C1QL1	psi-mi:“MI:0914”(association)	0.530
CBLN4	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
CBLN4	ADAM11	psi-mi:“MI:0914”(association)	0.350
SLC5A11	LINGO1	psi-mi:“MI:0914”(association)	0.350
CBLN4	AGRN	psi-mi:“MI:0914”(association)	0.350
CBLN4	NRXN2	psi-mi:“MI:0914”(association)	0.350

BioGRID (135): TOPBP1 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), GTF2F2 (Affinity Capture-MS), NKIRAS1 (Affinity Capture-MS), NDUFAF2 (Affinity Capture-MS), DHFRL1 (Affinity Capture-MS), C1QL1 (Affinity Capture-MS), ADAM11 (Affinity Capture-MS), LRIF1 (Affinity Capture-MS), GNB2 (Affinity Capture-MS), C1QL4 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), NKIRAS2 (Affinity Capture-MS), CBLN4 (Affinity Capture-MS), CBLN4 (Affinity Capture-MS)

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

577 predictions. Top by Δscore:

Variant	Effect	Δscore
20:55998750:TTAAC:T	acceptor_gain	1.0000
20:55998751:TAAC:T	acceptor_gain	1.0000
20:55998752:AAC:A	acceptor_gain	1.0000
20:55998753:AC:A	acceptor_gain	1.0000
20:55998753:ACC:A	acceptor_loss	1.0000
20:55998754:CC:C	acceptor_gain	1.0000
20:55998754:CCTA:C	acceptor_loss	1.0000
20:55998755:C:CC	acceptor_gain	1.0000
20:55998756:T:A	acceptor_loss	0.9900
20:56000726:CACA:C	donor_loss	0.9900
20:56000727:ACAC:A	donor_loss	0.9900
20:56000728:CACCT:C	donor_loss	0.9900
20:56000729:A:T	donor_loss	0.9900
20:56000730:C:CG	donor_loss	0.9900
20:56000845:GATCT:G	acceptor_loss	0.9900
20:56000846:ATC:A	acceptor_loss	0.9900
20:56000847:TC:T	acceptor_loss	0.9900
20:56000848:C:CC	acceptor_gain	0.9900
20:56000849:T:C	acceptor_loss	0.9900
20:56003916:T:C	donor_gain	0.9900
20:56000844:GGAT:G	acceptor_gain	0.9800
20:56003875:TCTGA:T	donor_loss	0.9800
20:56003876:CTGA:C	donor_loss	0.9800
20:56003877:TGA:T	donor_loss	0.9800
20:56003878:GAC:G	donor_loss	0.9800
20:56003879:A:T	donor_loss	0.9800
20:55998644:AT:A	donor_gain	0.9700
20:56003370:C:CT	donor_gain	0.9700
20:56003376:G:A	donor_gain	0.9700
20:56005264:T:A	donor_gain	0.9700

AlphaMissense

1294 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:55998579:C:T	G195D	1.000
20:55998580:C:G	G195R	1.000
20:55998583:A:G	S194P	1.000
20:55998618:C:A	G182V	1.000
20:55998619:C:G	G182R	1.000
20:55998627:A:G	L179P	1.000
20:55998633:A:G	L177P	1.000
20:55998681:G:T	A161D	1.000
20:55998713:A:C	F150L	1.000
20:55998713:A:T	F150L	1.000
20:55998714:A:C	F150C	1.000
20:55998715:A:G	F150L	1.000
20:56000786:C:T	G118E	1.000
20:56000787:C:G	G118R	1.000
20:56000787:C:T	G118R	1.000
20:56000804:A:G	F112S	1.000
20:56003887:G:C	F95L	1.000
20:56003887:G:T	F95L	1.000
20:56003888:A:C	F95C	1.000
20:56003889:A:G	F95L	1.000
20:56003942:C:G	R77P	1.000
20:56003952:A:G	S74P	1.000
20:56003953:G:C	F73L	1.000
20:56003953:G:T	F73L	1.000
20:56003954:A:G	F73S	1.000
20:56003955:A:G	F73L	1.000
20:56003957:G:T	A72D	1.000
20:56004054:A:G	C40R	1.000
20:55998566:G:C	F199L	0.999
20:55998566:G:T	F199L	0.999

dbSNP variants (sampled 300 via entrez): RS1000223400 (20:56005370 C>T), RS1000251847 (20:56002129 T>C), RS1000300008 (20:56000071 G>A), RS1000351889 (20:55999768 T>G), RS1000572286 (20:56005531 G>A), RS1000721767 (20:55997447 T>A), RS1001177140 (20:56006772 C>G), RS1001352947 (20:56001071 C>T), RS1001524554 (20:56003633 T>C), RS1001648048 (20:56006452 T>G), RS1001878923 (20:56005015 G>A,T), RS1002412505 (20:55999321 A>G,T), RS1002772067 (20:55999060 T>C), RS1003158193 (20:56000731 C>G), RS1003425371 (20:55997523 C>T)

Disease associations

OMIM: gene MIM:615029 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002759_7	Motion sickness	7.000000e-21
GCST004904_209	Body mass index	1.000000e-09
GCST004904_8	Body mass index	3.000000e-08
GCST005023_30	Initial pursuit acceleration	1.000000e-06
GCST005950_8	Body mass index x sex x age interaction (4df test)	2.000000e-06
GCST005951_199	Body mass index	7.000000e-06
GCST005953_2	Body mass index (age <50)	9.000000e-08
GCST010396_108	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-07
GCST010988_329	Adult body size	8.000000e-09
GCST010989_159	Body size at age 10	8.000000e-16
GCST011703_96	Smoking initiation	5.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0006928	motion sickness
EFO:0004340	body mass index
EFO:0008434	initial pursuit acceleration
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007874	gut microbiome measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0005670	smoking initiation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation	1
arsenite	increases methylation	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
perfluorohexanesulfonic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Benzo(a)pyrene	increases expression	1
Copper	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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