CPLX2

Summary

CPLX2 (complexin 2, HGNC:2310) is a protein-coding gene on chromosome 5q35.2, encoding Complexin-2 (Q6PUV4). Negatively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons.

Proteins encoded by the complexin/synaphin gene family are cytosolic proteins that function in synaptic vesicle exocytosis. These proteins bind syntaxin, part of the SNAP receptor. The protein product of this gene binds to the SNAP receptor complex and disrupts it, allowing transmitter release. Two transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 10814 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 11 total
• MANE Select transcript: NM_001008220

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2310
Approved symbol	CPLX2
Name	complexin 2
Location	5q35.2
Locus type	gene with protein product
Status	Approved
Aliases	CPX-2, DKFZp547D155
Ensembl gene	ENSG00000145920
Ensembl biotype	protein_coding
OMIM	605033
Entrez	10814

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000359546, ENST00000393745, ENST00000502265, ENST00000506642, ENST00000509837, ENST00000512824, ENST00000514150, ENST00000515025, ENST00000515094, ENST00000515502, ENST00000899625, ENST00000899626, ENST00000899627, ENST00000899628, ENST00000899629, ENST00000899630, ENST00000971154

RefSeq mRNA: 2 — MANE Select: NM_001008220 NM_001008220, NM_006650

CCDS: CCDS4396

Canonical transcript exons

ENST00000393745 — 4 exons

Exon	Start	End
ENSE00000973070	175878908	175879083
ENSE00001129358	175878652	175878770
ENSE00002024679	175871578	175871705
ENSE00002062090	175879848	175884021

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 99.51.

FANTOM5 (CAGE): breadth broad, TPM avg 16.2384 / max 1449.7150, expressed in 226 samples.

FANTOM5 promoters (29 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60383	8.0841	167
60375	1.5744	130
60384	1.3448	116
60381	1.0763	112
60370	0.8956	106
60382	0.7277	109
60373	0.4011	98
60371	0.2671	88
60385	0.2292	77
60394	0.1848	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.51	gold quality
cerebellar hemisphere	UBERON:0002245	99.39	gold quality
cerebellar cortex	UBERON:0002129	99.26	gold quality
right frontal lobe	UBERON:0002810	99.06	gold quality
amygdala	UBERON:0001876	97.54	gold quality
cerebellum	UBERON:0002037	97.44	gold quality
caudate nucleus	UBERON:0001873	97.15	gold quality
cingulate cortex	UBERON:0003027	96.70	gold quality
anterior cingulate cortex	UBERON:0009835	96.70	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.68	gold quality
prefrontal cortex	UBERON:0000451	96.44	gold quality
nucleus accumbens	UBERON:0001882	96.18	gold quality
Ammon’s horn	UBERON:0001954	95.95	gold quality
temporal lobe	UBERON:0001871	95.93	gold quality
postcentral gyrus	UBERON:0002581	95.92	gold quality
putamen	UBERON:0001874	95.32	gold quality
entorhinal cortex	UBERON:0002728	95.27	gold quality
neocortex	UBERON:0001950	94.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.89	gold quality
frontal cortex	UBERON:0001870	94.87	gold quality
primary visual cortex	UBERON:0002436	94.84	gold quality
cortical plate	UBERON:0005343	94.67	gold quality
telencephalon	UBERON:0001893	94.58	gold quality
cerebral cortex	UBERON:0000956	94.57	gold quality
parietal lobe	UBERON:0001872	94.38	gold quality
superior frontal gyrus	UBERON:0002661	94.04	gold quality
forebrain	UBERON:0001890	93.74	gold quality
brain	UBERON:0000955	93.50	gold quality
central nervous system	UBERON:0001017	93.15	gold quality
middle temporal gyrus	UBERON:0002771	93.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	26.11
E-GEOD-81547	yes	21.94
E-GEOD-84465	yes	6.75
E-ANND-3	yes	3.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

230 targeting CPLX2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1229-3P	99.97	66.49	906
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-493-5P	99.96	72.47	2382
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1-3P	99.93	72.35	1914

Literature-anchored findings (GeneRIF, showing 11)

• role in synaptic vesicle exocytosis (PMID:12058476)
• altered immunoreactivity of this protein in prefrontal cortex in severe mental illness (PMID:12082566)
• in huntingtin mutation, the decline in neurotransmitter release is a direct consequence of complexin II depletion (PMID:12807877)
• In schizophrenia, complexin II was reduced in dorsolateral prefrontal cortex and superior temporal cortex. The impairment of synaptic transmission may contribute to the dysfunction of cortical neural circuits that characterises the disorder. (PMID:15653259)
• CX2 level increased between the fetal and the 6-10 years groups and then plateaued (PMID:18240322)
• Then results indicated that CPLX2 may be involved in the etiology of schizophrenia and one of its potential biological mechanisms by studying the effects of CPLX2 risk variants on working memory load-dependent neural activity in a frontoparietal network. (PMID:25297695)
• CPLX2 rs1366116*T variant represents a risk factor of schizophrenia, and , at the same time, CPLX2 rs3892909*T variant is protective against schizophrenia (study performed in Armenians). (PMID:25564026)
• These results suggested that CPLX2 participated in synaptic taste transduction. (PMID:25692331)
• This study demonstrated that complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease. (PMID:27866231)
• CPLX2 Regulates Ferroptosis and Apoptosis Through NRF2 Pathway in Human Hepatocellular Carcinoma Cells. (PMID:36107387)
• CPLX2 is a novel tumor suppressor and improves the prognosis in glioma. (PMID:38427133)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cplx2b	ENSDARG00000061918
mus_musculus	Cplx2	ENSMUSG00000025867
rattus_norvegicus	Cplx2	ENSRNOG00000000105
drosophila_melanogaster	cpx	FBGN0041605
caenorhabditis_elegans		WBGENE00010520
caenorhabditis_elegans	cpx-1	WBGENE00022271

Paralogs (3): CPLX4 (ENSG00000166569), CPLX1 (ENSG00000168993), CPLX3 (ENSG00000213578)

Protein

Protein identifiers

Complexin-2 — Q6PUV4 (reviewed: Q6PUV4)

Alternative names: Complexin II, Synaphin-1

All UniProt accessions (6): D6R960, D6RBA5, D6RDN3, D6RGY3, D6RI05, Q6PUV4

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. Also involved in mast cell exocytosis.

Subunit / interactions. Binds to the SNARE core complex containing SNAP25, VAMP2 and STX1A.

Subcellular location. Cytoplasm. Cytosol. Presynapse. Nucleus. Perikaryon.

Tissue specificity. Nervous system. In hippocampus and cerebellum, expressed mainly by excitatory neurons. Down-regulated in brain cortex from patients suffering from Huntington disease, bipolar disorder or major depression. Down-regulated in cerebellum from patients with schizophrenia.

Similarity. Belongs to the complexin/synaphin family.

RefSeq proteins (2): NP_001008221, NP_006641 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008849	Synaphin	Family

Pfam: PF05835

UniProt features (6 total): region of interest 2, chain 1, coiled-coil region 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PUV4-F1	71.01	0.18

Functional residue map

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

Post-translational modifications (1): 93

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 254 (showing top): GOBP_REGULATION_OF_VESICLE_FUSION, GOBP_VESICLE_ORGANIZATION, AAGCCAT_MIR135A_MIR135B, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GGGTGGRR_PAX4_03, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_CELL_CELL_SIGNALING, GOBP_MEMBRANE_DOCKING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, NFKB_Q6, PATIL_LIVER_CANCER, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (11): obsolete vesicle docking involved in exocytosis (GO:0006904), nervous system development (GO:0007399), synaptic vesicle exocytosis (GO:0016079), regulation of exocytosis (GO:0017157), cell differentiation (GO:0030154), regulation of synaptic vesicle fusion to presynaptic active zone membrane (GO:0031630), positive regulation of synaptic plasticity (GO:0031915), mast cell degranulation (GO:0043303), modulation of chemical synaptic transmission (GO:0050804), neurotransmitter transport (GO:0006836), exocytosis (GO:0006887)

GO Molecular Function (5): SNARE binding (GO:0000149), syntaxin-1 binding (GO:0017075), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515), syntaxin binding (GO:0019905)

GO Cellular Component (16): nucleus (GO:0005634), cytosol (GO:0005829), dendrite (GO:0030425), SNARE complex (GO:0031201), terminal bouton (GO:0043195), perikaryon (GO:0043204), calyx of Held (GO:0044305), synaptobrevin 2-SNAP-25-syntaxin-1a-complexin II complex (GO:0070033), synaptobrevin 2-SNAP-25-syntaxin-3-complexin complex (GO:0070554), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cell projection (GO:0042995), neuronal cell body (GO:0043025), synapse (GO:0045202), presynapse (GO:0098793)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
synapse	3
presynapse	2
protein binding	2
cytoplasm	2
axon terminus	2
SNARE complex	2
system development	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
cellular developmental process	1
regulation of vesicle fusion	1
synaptic vesicle fusion to presynaptic active zone membrane	1
regulation of synaptic vesicle membrane organization	1
regulation of synaptic plasticity	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
transport	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
syntaxin binding	1
calcium ion binding	1
binding	1
SNARE binding	1
intracellular membrane-bounded organelle	1
neuron projection	1
dendritic tree	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

23 interactions, top by confidence:

A	B	Type	Score
CPLX2	NDRG4	psi-mi:“MI:0915”(physical association)	0.560
CPLX2	PBX3	psi-mi:“MI:0915”(physical association)	0.560
CPLX2	MYG1	psi-mi:“MI:0915”(physical association)	0.560
TSFM	CPLX2	psi-mi:“MI:0915”(physical association)	0.560
CPLX2	DEGS1	psi-mi:“MI:0914”(association)	0.530
CPLX1	VAMP3	psi-mi:“MI:0914”(association)	0.530
CPLX2	CPLX1	psi-mi:“MI:0914”(association)	0.530
CPLX2	PTCHD1	psi-mi:“MI:0915”(physical association)	0.370
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
SNAP25	STX7	psi-mi:“MI:0914”(association)	0.350
CPLX1	HSPA8	psi-mi:“MI:0914”(association)	0.350
PBX3	CPLX2	psi-mi:“MI:0915”(physical association)	0.000
MYG1	CPLX2	psi-mi:“MI:0915”(physical association)	0.000
TSFM	CPLX2	psi-mi:“MI:0915”(physical association)	0.000
NDRG4	CPLX2	psi-mi:“MI:0915”(physical association)	0.000
CPLX2	ETS1	psi-mi:“MI:0915”(physical association)	0.000
PCBD1	CPLX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): CPLX2 (Affinity Capture-MS), ANKRD13C (Affinity Capture-MS), FAM21A (Affinity Capture-MS), RAP1A (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), SCCPDH (Affinity Capture-MS), CPLX2 (Two-hybrid), CPLX2 (Two-hybrid), CPLX2 (Two-hybrid), PBX3 (Two-hybrid), CPLX2 (Affinity Capture-Western), CPLX2 (Affinity Capture-MS), CPLX2 (Affinity Capture-MS), DEGS1 (Affinity Capture-MS), ANKRD13C (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GV96, A0MZ66, A0MZ67, A2VDA9, A5PJI6, A6NKN8, A8R4Q8, E7F7X0, O14990, O19021, O42932, O62770, O62771, P13505, P36425, P48539, P54866, P63054, P63055, P84086, P84087, P84088, Q04504, Q0P561, Q148C4, Q15506, Q28IH8, Q3UYG8, Q4R615, Q5F3A1, Q5M8L3, Q5R4Q3, Q5ZM33, Q62252, Q62736, Q6DBA5, Q6GNQ4, Q6NWC9, Q6P3G4, Q6PUV4

Diamond homologs: O14810, O42105, O42106, P63040, P63041, P84086, P84087, P84088, Q0IIL7, Q4R4N1, Q60PP8, Q6PUV4, Q9GUM7, Q8I6U3, Q8IPM8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1284 predictions. Top by Δscore:

Variant	Effect	Δscore
5:175878648:GCA:G	acceptor_loss	1.0000
5:175878651:G:GT	acceptor_loss	1.0000
5:175878651:GGTT:G	acceptor_gain	1.0000
5:175878769:AG:A	donor_loss	1.0000
5:175878770:GG:G	donor_loss	1.0000
5:175878771:G:GA	donor_loss	1.0000
5:175878772:T:G	donor_loss	1.0000
5:175878893:A:AG	acceptor_gain	1.0000
5:175878894:C:G	acceptor_gain	1.0000
5:175878903:C:CA	acceptor_gain	1.0000
5:175878905:TA:T	acceptor_loss	1.0000
5:175878906:A:AG	acceptor_gain	1.0000
5:175878906:A:T	acceptor_loss	1.0000
5:175878906:AG:A	acceptor_gain	1.0000
5:175878906:AGG:A	acceptor_gain	1.0000
5:175878906:AGGG:A	acceptor_gain	1.0000
5:175878907:G:GT	acceptor_gain	1.0000
5:175878907:GG:G	acceptor_gain	1.0000
5:175878907:GGG:G	acceptor_gain	1.0000
5:175878907:GGGG:G	acceptor_gain	1.0000
5:175878907:GGGGC:G	acceptor_gain	1.0000
5:175879079:A:G	donor_gain	1.0000
5:175879081:AAG:A	donor_loss	1.0000
5:175879083:GGT:G	donor_loss	1.0000
5:175879084:GTC:G	donor_loss	1.0000
5:175879844:CCAGT:C	acceptor_loss	1.0000
5:175879845:CAGTA:C	acceptor_loss	1.0000
5:175879846:A:AG	acceptor_gain	1.0000
5:175879846:AG:A	acceptor_loss	1.0000
5:175879846:AGTAT:A	acceptor_gain	1.0000

AlphaMissense

883 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:175879018:C:A	R48S	1.000
5:175879076:G:C	R67P	1.000
5:175878746:T:C	F3L	0.999
5:175878748:C:A	F3L	0.999
5:175878748:C:G	F3L	0.999
5:175878986:G:C	R37P	0.999
5:175878994:G:C	A40P	0.999
5:175878998:T:C	L41P	0.999
5:175879001:G:C	R42P	0.999
5:175879007:A:C	Q44P	0.999
5:175879018:C:T	R48C	0.999
5:175879019:G:C	R48P	0.999
5:175879045:G:C	A57P	0.999
5:175879051:C:T	R59W	0.999
5:175879052:G:C	R59P	0.999
5:175879064:G:A	R63Q	0.999
5:175879073:T:A	I66N	0.999
5:175879073:T:C	I66T	0.999
5:175879073:T:G	I66S	0.999
5:175879075:C:G	R67G	0.999
5:175879076:G:A	R67Q	0.999
5:175879083:G:C	K69N	0.999
5:175879083:G:T	K69N	0.999
5:175879855:T:C	L72P	0.999
5:175878747:T:G	F3C	0.998
5:175878750:T:A	V4D	0.998
5:175878768:G:A	G10E	0.998
5:175878914:C:T	T13I	0.998
5:175878932:T:C	M19T	0.998
5:175879030:C:G	H52D	0.998

dbSNP variants (sampled 300 via entrez): RS1000003219 (5:175840156 CT>C), RS1000031761 (5:175882174 G>A), RS1000040278 (5:175802505 T>C), RS1000050367 (5:175841080 A>AAG), RS1000059782 (5:175882009 G>C), RS1000133001 (5:175834373 C>T), RS1000156446 (5:175840444 T>C,G), RS1000170459 (5:175858523 C>T), RS1000183038 (5:175795417 C>A,T), RS1000201389 (5:175858674 G>A), RS1000207427 (5:175816442 A>G), RS1000235251 (5:175797067 G>A,T), RS1000242425 (5:175846772 C>G), RS1000276259 (5:175806191 C>T), RS1000316298 (5:175846451 A>T)

Disease associations

OMIM: gene MIM:605033 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_917	Obesity-related traits	3.000000e-07
GCST002498_2	Age-related nuclear cataracts	1.000000e-06
GCST007576_353	Chronotype	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

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
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
dicrotophos	increases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
licochalcone B	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Ethanol	decreases expression	1
Allergens	increases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases abundance, increases expression	1
Diazinon	increases methylation	1
Dimethyl Sulfoxide	decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects response to substance, affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

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