CPLX1

Summary

CPLX1 (complexin 1, HGNC:2309) is a protein-coding gene on chromosome 4p16.3, encoding Complexin-1 (O14810). Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles.

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.

Source: NCBI Gene 10815 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental and epileptic encephalopathy, 63 (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 94 total — 3 likely-pathogenic
• GTEx eGene: eQTL in 40 tissues, sQTL in 4 (q < 0.05)
• Phenotypes (HPO): 194
• Constraint (gnomAD): pLI 0.44 (intermediate), LOEUF 0.76 (unconstrained)
• MANE Select transcript: NM_006651

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2309
Approved symbol	CPLX1
Name	complexin 1
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	CPX-I
Ensembl gene	ENSG00000168993
Ensembl biotype	protein_coding
OMIM	605032
Entrez	10815

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

MANE Select: ENST00000304062

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 2, TSL 3: 1

ENST00000304062, ENST00000504062, ENST00000505203, ENST00000506404, ENST00000892263, ENST00000892264, ENST00000892265, ENST00000892266, ENST00000892267, ENST00000944762, ENST00001054877, ENST00001140405

RefSeq mRNA: 1 — MANE Select: NM_006651 NM_006651

CCDS: CCDS46995

Canonical transcript exons

ENST00000304062 — 4 exons

Exon	Start	End
ENSE00001293910	826046	826129
ENSE00002068152	784957	786698
ENSE00003373475	824492	824601
ENSE00003616973	792433	792608

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 99.72.

FANTOM5 (CAGE): breadth broad, TPM avg 10.5687 / max 701.2164, expressed in 601 samples.

Highest expression (Bgee): lateral nuclear group of thalamus, lateral globus pallidus, postcentral gyrus, parietal lobe, pons.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CPLX1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 40 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 44 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	1.9e-49	-0.44	4:789840:G:T
Nerve Tibial	eqtl	4.0e-41	-0.47	4:786919:G:T
Adipose Subcutaneous	eqtl	1.7e-32	-0.35	4:786919:G:T
Artery Tibial	eqtl	2.1e-32	-0.28	4:763198:T:C
Adipose Visceral Omentum	eqtl	2.3e-32	-0.36	4:762257:T:C
Esophagus Muscularis	eqtl	1.1e-30	-0.38	4:766470:G:T
Breast Mammary Tissue	eqtl	6.7e-30	-0.48	4:786919:G:T
Colon Transverse	eqtl	2.3e-27	-0.49	4:774061:CTG:C
Esophagus Mucosa	eqtl	7.5e-26	-0.31	4:786919:G:T
Lung	eqtl	1.0e-25	-0.33	4:787733:G:C
Muscle Skeletal	eqtl	6.6e-24	-0.35	4:766470:G:T
Skin Sun Exposed Lower leg	eqtl	4.3e-21	-0.25	4:774504:G:A
Skin Not Sun Exposed Suprapubic	eqtl	2.9e-20	-0.24	4:779262:G:A
Heart Left Ventricle	eqtl	7.7e-20	-0.40	4:786919:G:T
Prostate	eqtl	4.0e-19	-0.56	4:789840:G:T
Pituitary	eqtl	4.6e-19	-0.46	4:790354:C:G
Heart Atrial Appendage	eqtl	1.1e-15	+0.40	4:833210:G:A
Esophagus Gastroesophageal Junction	eqtl	1.3e-15	-0.33	4:789248:C:G
Ovary	eqtl	2.4e-15	-0.74	4:802102:G:A
Adrenal Gland	eqtl	5.7e-15	-0.43	4:777799:A:G

FANTOM5 promoters

showing 10 of 12 alternative TSS:

Promoter ID	TPM avg	Samples expressed
51019	6.9332	411
51018	2.4362	175
51008	0.5382	182
51020	0.1492	73
203085	0.1007	61
51012	0.0843	40
51011	0.0797	33
51017	0.0779	44
51009	0.0673	41
51013	0.0493	32

Top tissues by expression

showing 100 of 251 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	99.72	gold quality
lateral globus pallidus	UBERON:0002476	99.00	gold quality
postcentral gyrus	UBERON:0002581	98.87	gold quality
parietal lobe	UBERON:0001872	98.83	gold quality
pons	UBERON:0000988	98.64	gold quality
superior frontal gyrus	UBERON:0002661	98.60	gold quality
right frontal lobe	UBERON:0002810	98.48	gold quality
putamen	UBERON:0001874	98.47	gold quality
primary visual cortex	UBERON:0002436	98.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.24	gold quality
caudate nucleus	UBERON:0001873	98.00	gold quality
occipital lobe	UBERON:0002021	97.99	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.94	gold quality
cerebellar cortex	UBERON:0002129	97.90	gold quality
cerebellar hemisphere	UBERON:0002245	97.89	gold quality
cerebellum	UBERON:0002037	97.83	gold quality
cerebellar vermis	UBERON:0004720	97.83	gold quality
nucleus accumbens	UBERON:0001882	97.69	gold quality
anterior cingulate cortex	UBERON:0009835	97.46	gold quality
frontal cortex	UBERON:0001870	97.07	gold quality
entorhinal cortex	UBERON:0002728	96.81	gold quality
neocortex	UBERON:0001950	96.31	gold quality
prefrontal cortex	UBERON:0000451	96.08	gold quality
cerebral cortex	UBERON:0000956	95.93	gold quality
temporal lobe	UBERON:0001871	95.49	gold quality
middle temporal gyrus	UBERON:0002771	95.38	gold quality
substantia nigra pars compacta	UBERON:0001965	95.13	gold quality
medulla oblongata	UBERON:0001896	95.00	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.89	gold quality
amygdala	UBERON:0001876	94.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.74	gold quality
Ammon’s horn	UBERON:0001954	94.64	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.57	gold quality
ventral tegmental area	UBERON:0002691	94.54	gold quality
superior vestibular nucleus	UBERON:0007227	94.52	gold quality
brain	UBERON:0000955	94.41	gold quality
dorsal root ganglion	UBERON:0000044	94.21	gold quality
forebrain	UBERON:0001890	94.13	gold quality
substantia nigra	UBERON:0002038	93.59	gold quality
midbrain	UBERON:0001891	93.57	gold quality
hypothalamus	UBERON:0001898	91.57	gold quality
trigeminal ganglion	UBERON:0001675	89.35	gold quality
adult organism	UBERON:0007023	88.93	gold quality
spinal cord	UBERON:0002240	88.26	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.24	gold quality
dorsal plus ventral thalamus	UBERON:0001897	87.86	gold quality
apex of heart	UBERON:0002098	87.06	gold quality
spleen	UBERON:0002106	83.49	gold quality
omental fat pad	UBERON:0010414	83.41	gold quality
peritoneum	UBERON:0002358	83.29	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.73	gold quality
endocervix	UBERON:0000458	81.92	gold quality
inferior vagus X ganglion	UBERON:0005363	81.67	gold quality
body of uterus	UBERON:0009853	81.65	gold quality
cortical plate	UBERON:0005343	81.38	gold quality
left uterine tube	UBERON:0001303	81.21	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.90	gold quality
right adrenal gland cortex	UBERON:0035827	80.81	gold quality
right adrenal gland	UBERON:0001233	80.71	gold quality
left adrenal gland	UBERON:0001234	80.52	gold quality
left adrenal gland cortex	UBERON:0035825	80.14	gold quality
adrenal cortex	UBERON:0001235	80.00	gold quality
pituitary gland	UBERON:0000007	79.84	gold quality
adenohypophysis	UBERON:0002196	79.62	gold quality
globus pallidus	UBERON:0001875	78.87	gold quality
adrenal gland	UBERON:0002369	78.82	gold quality
ectocervix	UBERON:0012249	78.61	gold quality
right atrium auricular region	UBERON:0006631	78.34	gold quality
cardiac atrium	UBERON:0002081	78.02	gold quality
minor salivary gland	UBERON:0001830	77.66	gold quality
adipose tissue	UBERON:0001013	77.64	gold quality
subthalamic nucleus	UBERON:0001906	77.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	77.48	gold quality
lower esophagus	UBERON:0013473	77.44	gold quality
right lobe of liver	UBERON:0001114	77.43	gold quality
heart left ventricle	UBERON:0002084	77.11	gold quality
mucosa of stomach	UBERON:0001199	77.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	76.63	gold quality
cardiac ventricle	UBERON:0002082	76.48	gold quality
right ovary	UBERON:0002118	76.41	gold quality
cardiac muscle of right atrium	UBERON:0003379	76.26	gold quality
left ovary	UBERON:0002119	76.13	gold quality
right uterine tube	UBERON:0001302	76.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.79	silver quality
left coronary artery	UBERON:0001626	75.78	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.62	gold quality
left ventricle myocardium	UBERON:0006566	75.53	gold quality
coronary artery	UBERON:0001621	75.43	gold quality
tibial nerve	UBERON:0001323	75.26	gold quality
uterine cervix	UBERON:0000002	75.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.17	gold quality
right lung	UBERON:0002167	75.16	gold quality
right lobe of thyroid gland	UBERON:0001119	75.12	gold quality
thymus	UBERON:0002370	75.01	gold quality
cortex of kidney	UBERON:0001225	74.86	gold quality
medial globus pallidus	UBERON:0002477	74.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.32	gold quality
heart	UBERON:0000948	74.22	gold quality
myometrium	UBERON:0001296	73.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	10.36
E-ANND-3	yes	4.07

HPA expression

RNA tissue specificity: Tissue enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	729.5
Frontal cortex	tissue	633.8
Caudate putamen	tissue	503.1
Superior colliculi	tissue	467.3
Cerebral cortex	tissue	453.6	high
Occipital cortex	tissue	453.6
Somatosensory cortex	tissue	439.9
Olfactory bulb	tissue	343.2
Thalamus	tissue	316.7
Pons	tissue	300.8
Motor cortex	tissue	273.1
Midbrain	tissue	253.9
Medulla oblongata	tissue	246.1
Retrosplenial cortex	tissue	228.5
Retrosplenial and cingulate cortex	tissue	220.8
Temporal cortex	tissue	209.8
Hippocampal formation	tissue	191.3
Entorhinal cortex	tissue	191.3
Prefrontal cortex	tissue	182.4
Nucleus accumbens	tissue	181.5
Putamen	tissue	159.1
Spinal cord	tissue	156.1
Ventral forebrain	tissue	145.4
Insular cortex	tissue	143.9
Hippocampus	tissue	122.9	medium
Cerebellum	tissue	110.3	high
Substantia nigra	tissue	108.6
Basal ganglia	tissue	100.8	medium
Septum	tissue	90.7
Locus coeruleus	tissue	89.8
Amygdala	tissue	79.6
Periaqueductal gray	tissue	75.4
Hypothalamus	tissue	49.6
Corpus callosum	tissue	20.0
Choroid plexus	tissue	13.1
Vagina	tissue	12.7	not detected
Pituitary gland	tissue	12.2
Retina	tissue	5.3
Adipose tissue	tissue	4.6	not detected
Adrenal gland	tissue	3.3	high
Thymus	tissue	3.3
Spleen	tissue	3.0	not detected
Testis	tissue	2.3	medium
Skeletal muscle	tissue	2.3	not detected
Prostate	tissue	2.1	not detected
Salivary gland	tissue	2.0	not detected
Endometrium 1	tissue	1.9	not detected
Parathyroid gland	tissue	1.3	not detected
Stomach 1	tissue	1.2	low
Heart muscle	tissue	1.2	not detected
Skin 1	tissue	1.1	not detected
Appendix	tissue	1.1	not detected
Pancreas	tissue	1.0	medium
Ovary	tissue	0.9	not detected
Lung	tissue	0.9	not detected
Duodenum	tissue	0.9	not detected
Colon	tissue	0.8	low
Small intestine	tissue	0.8	not detected
Lymph node	tissue	0.7	not detected
Seminal vesicle	tissue	0.7	not detected

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Precentral gyrus (773.3), Supplementary motor cortex (518.7), Nucleus raphe magnus (487.9), Nuclei of the trapezoid body (472.6), Lateral geniculate body (463.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CPLX1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 74 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
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-3065-5P	99.97	71.56	3281
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-765	99.84	68.24	2442
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-548A-3P	99.76	70.58	3524
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-5580-5P	99.38	66.96	1139

Functional genomics

gnomAD constraint: pLI 0.436, LOEUF 0.756, missense Z -1.21 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000304062 — one region, missense o/e 1.28.

Literature-anchored findings (GeneRIF, showing 16)

• role in synaptic vesicle exocytosis (PMID:12058476)
• altered immunoreactivity of this protein in prefrontal cortex in severe mental illness (PMID:12082566)
• description of what may represent a basic principle of the coupling mechanism in SNARE dependent exocytosis: a reversible clamping protein, complexin, that can freeze the SNAREpin, an assembled fusion-competent intermediate en route to fusion (PMID:16794037)
• CX1 level increased progressively across development (PMID:18240322)
• The crystal structure of complexin bound to a prefusion SNAREpin mimetic shows that the accessory helix extends away from the SNAREpin in an ‘open’ conformation, binding another SNAREpin and inhibiting its assembly, to clamp fusion. (PMID:21785412)
• The ‘central helix’ of complexin is anchored to one SNARE complex, while its ‘accessory helix’ extends away at ~45 degrees and bridges to a second complex, occupying the vacant v-SNARE binding site to inhibit fusion. (PMID:21785414)
• Together with synaptotagmin 1, complexin synchronizes and stimulates rapid fusion of accumulated docked vesicles in response to physiological Ca(2+) concentrations. (PMID:22705946)
• Data support the the trans insertion model for complexin clamping. (PMID:25831964)
• Studies indicate the role of the small regulatory factor complexin in Ca(2+)-dependent vesicle fusion and exocytosis. (PMID:26245303)
• Study showed for the first time that neuro-Behcet’s disease and Behcet’s disease patients are inclined to display the GG genotype of the CPLX1 rs936551 polymorphism and to exhibit increased CPLX1 expression levels (PMID:26577184)
• Collectively these results demonstrate that CPX-1 is a secreted collagen-binding glycoprotein and provide a foundation for future studies investigating the function of CPX-1. (PMID:26603934)
• This study demonstrated that complexin-I influence cognitive function in early and late stages of Alzheimer’s disease. (PMID:27866231)
• data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction (PMID:28108469)
• Homozygous CPLX1 variants were identified in three patients with severe infantile myoclonic epilepsy and ID. (PMID:28422131)
• Findings do not support microRNA137 (MIR137) and complexin 1 (CPLX1) conferring susceptibility to schizophrenia in Han Chinese. (PMID:29118371)
• Synergistic roles of Synaptotagmin-1 and complexin in calcium-regulated neuronal exocytosis. (PMID:32401194)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	cplx2a	ENSDARG00000018997
danio_rerio	cplx1	ENSDARG00000111920
mus_musculus	Cplx1	ENSMUSG00000033615
rattus_norvegicus	Cplx1	ENSRNOG00000090522
drosophila_melanogaster	cpx	FBGN0041605
caenorhabditis_elegans		WBGENE00010520
caenorhabditis_elegans	cpx-1	WBGENE00022271

Paralogs (3): CPLX2 (ENSG00000145920), CPLX4 (ENSG00000166569), CPLX3 (ENSG00000213578)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:104727) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired acrosome reaction	2
impaired fertilization	1
sporadic seizures	1
decreased body size	1
ataxia	1
infertility	1
male infertility	1
premature death	1
abnormal sexual interaction	1
asthenozoospermia	1
abnormal paired-pulse inhibition	1
abnormal neuron physiology	1
abnormal hearing electrophysiology	1
decreased excitatory postsynaptic current amplitude	1
increased or absent threshold for auditory brainstem response	1
decreased miniature excitatory postsynaptic current frequency	1
increased auditory brainstem response wave peak latency	1
decreased auditory brainstem response wave amplitude	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	P84088	100.0%	Diamond
Macaca fascicularis	Q4R4N1	99.3%	Diamond
Caenorhabditis briggsae	Q60PP8	96.5%	Diamond
Narke japonica	O42105	90.3%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
PCGF3	protein-coding	10336
CPLX1-AS1	ncRNA	105374339
PCGF3-AS1	ncRNA	100129917
SLC49A3-AS1	ncRNA	124900643
PCGF3-AS2	ncRNA	138842257
MYL5	protein-coding	4636
SLC49A3	protein-coding	84179
GAK-AS1	protein-coding	105374341
GAK	protein-coding	2580
TMEM175	protein-coding	84286
DGKQ	protein-coding	1609

Protein

Protein identifiers

Complexin-1 — O14810 (reviewed: O14810)

Alternative names: Complexin I, Synaphin-2

All UniProt accessions (3): D6RAG3, D6RI11, O14810

UniProt curated annotations — full annotation on UniProt →

Function. Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles. Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse. Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior.

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

Subcellular location. Cytoplasm. Cytosol. Perikaryon. Presynapse.

Tissue specificity. Nervous system. In hippocampus and cerebellum, expressed mainly by inhibitory neurons. Overexpressed in substantia nigra from patients with Parkinson disease.

Disease relevance. Developmental and epileptic encephalopathy 63 (DEE63) [MIM:617976] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE63 is an autosomal recessive disease with onset in infancy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the complexin/synaphin family.

RefSeq proteins (1): NP_006642* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008849	Synaphin	Family

Pfam: PF05835

UniProt features (10 total): region of interest 3, sequence variant 3, chain 1, coiled-coil region 1, compositionally biased region 1, helix 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
3RK3	Truncated SNARE complex with complexin	X-RAY DIFFRACTION	3.5
3RL0	Truncated SNARE complex with complexin (P1)	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14810-F1	72.31	0.22

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Other congenital disorders, Chromosomal abnormalities, Epilepsy

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles

Antibody reliability (HPA): IH supported · IF uncertain

Function

Pathways and Gene Ontology

Reactome pathways

6 curated (TAS) of 9; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

9 pathways:

ID	Pathway	Evidence
R-HSA-264642	Acetylcholine Neurotransmitter Release Cycle	curated
R-HSA-212676	Dopamine Neurotransmitter Release Cycle	curated
R-HSA-888590	GABA synthesis, release, reuptake and degradation	curated
R-HSA-210500	Glutamate Neurotransmitter Release Cycle	curated
R-HSA-181430	Norepinephrine Neurotransmitter Release Cycle	curated
R-HSA-181429	Serotonin Neurotransmitter Release Cycle	curated
R-HSA-112316	Neuronal System	—
R-HSA-112310	Neurotransmitter release cycle	—
R-HSA-112315	Transmission across Chemical Synapses	—

MSigDB gene sets: 541 (showing top): GOBP_REGULATION_OF_VESICLE_FUSION, GOBP_VESICLE_ORGANIZATION, GOBP_INSULIN_SECRETION, AAGCCAT_MIR135A_MIR135B, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_HORMONE_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_VESICLE_FUSION_TO_PLASMA_MEMBRANE

GO Biological Process (9): exocytosis (GO:0006887), chemical synaptic transmission (GO:0007268), synaptic vesicle exocytosis (GO:0016079), regulation of exocytosis (GO:0017157), insulin secretion (GO:0030073), regulation of synaptic vesicle fusion to presynaptic active zone membrane (GO:0031630), modulation of chemical synaptic transmission (GO:0050804), regulation of exocytic insertion of neurotransmitter receptor to postsynaptic membrane (GO:0099145), neurotransmitter transport (GO:0006836)

GO Molecular Function (4): SNARE binding (GO:0000149), syntaxin-1 binding (GO:0017075), protein binding (GO:0005515), syntaxin binding (GO:0019905)

GO Cellular Component (15): 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 I complex (GO:0070032), synaptobrevin 2-SNAP-25-syntaxin-3-complexin complex (GO:0070554), Schaffer collateral - CA1 synapse (GO:0098685), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), protein-containing complex (GO:0032991), neuronal cell body (GO:0043025), synapse (GO:0045202), presynapse (GO:0098793)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Neurotransmitter release cycle	6
Transmission across Chemical Synapses	1
Neuronal System	1

GO top-level categories

46 GO namespaces:

Category	Terms
cellular anatomical structure	4
synapse	4
presynapse	2
cytoplasm	2
axon terminus	2
SNARE complex	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
anterograde trans-synaptic signaling	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
protein secretion	1
peptide hormone secretion	1
regulation of vesicle fusion	1
synaptic vesicle fusion to presynaptic active zone membrane	1
regulation of synaptic vesicle membrane organization	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
regulation of exocytosis	1
regulation of protein transport	1
regulation of biological quality	1
exocytic insertion of neurotransmitter receptor to postsynaptic membrane	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
transport	1
protein binding	1
syntaxin binding	1
binding	1
SNARE binding	1
neuron projection	1
dendritic tree	1
membrane protein complex	1
neuronal cell body	1
cellular_component	1
somatodendritic compartment	1
cell body	1
cell junction	1

Protein interactions and networks

STRING

showing 15 of 1,434 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CPLX1	SYT1	P21579	929
CPLX1	STX1A	Q16623	902
CPLX1	VAMP2	P19065	899
CPLX1	SYT7	O43581	825
CPLX1	SYT4	Q9H2B2	818
CPLX1	SYT2	Q8N9I0	713
CPLX1	CPLX3	Q8WVH0	651
CPLX1	CPLX4	Q7Z7G2	645
CPLX1	STXBP1	P61764	599
CPLX1	SNAP25	P13795	598
CPLX1	RNF212	Q495C1	579
CPLX1	NAPA	P54920	524
CPLX1	SLC49A3	Q6UXD7	515
CPLX1	SNCB	Q16143	509
CPLX1	UNC13B	O14795	497

IntAct

Human interaction partners of CPLX1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
SNAP25	direct interaction	0.730	3
CPLX2	association	0.530	1
VAMP3	association	0.530	1
AGTRAP	physical association	0.370	1
CMTM5	physical association	0.370	1
OPRM1	physical association	0.370	1
HSPA8	association	0.350	1
RXRB	physical association	0.000	1

BioGRID (50 interactions; top human partners by supporting records): CPLX2 (Affinity Capture-MS; 3 records), STX1A (Affinity Capture-Western; 3 records), GYPB (Affinity Capture-MS; 2 records), SNAP25 (Co-crystal Structure; 2 records), VAMP3 (Affinity Capture-MS; 2 records), AGTRAP (Two-hybrid), CMTM5 (Two-hybrid), DBN1 (Cross-Linking-MS (XL-MS)), DPY30 (Co-fractionation), FLNA (Co-fractionation), GGA2 (Co-fractionation), GINS3 (Co-fractionation), GLO1 (Co-fractionation), HBS1L (Co-fractionation), HN1 (Co-fractionation)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ SNARE complex (CPLX1, SNAP25, STX1A, VAMP2)	4	SNAP25, STX1A, VAMP2, CPLX1

Disease & clinical

Genetic variants

Variant evidence for CPLX1: 94 ClinVar records (3 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	46
Likely benign	35
Benign	2

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
402136	NM_006651.4(CPLX1):c.322G>T (p.Glu108Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1705441	NM_006651.4(CPLX1):c.66_75del (p.Asp23fs)	Likely pathogenic	criteria provided, single submitter	1
3062796	GRCh37/hg19 4p16.3(chr4:769757-2009467)x3	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CPLX1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 830):

Position(s)	Effect	Δscore	Sites
4:786699–786700	acceptor_loss	0.9900	5
4:792431–792432	donor_loss	0.9900	5
4:822919	donor_gain	0.9900
4:824490–824491	donor_loss	0.9900	5
4:824602–824603	acceptor_loss	0.9900	6
4:826048	donor_gain	0.9900
4:786699	acceptor_loss	0.9800
4:792609–792610	acceptor_loss	0.9800	6
4:824490	donor_loss	0.9800
4:826044–826045	donor_loss	0.9800	4

AlphaMissense

365 missense substitutions predicted likely pathogenic (of 885 scored), across 103 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
F3	8	0.931	0.997
D15	8	0.920	0.974
E56	7	0.884	0.947
E60	7	0.874	0.936
M19	7	0.841	0.962
Q7	7	0.829	0.912
C105	7	0.798	0.909
D27	7	0.743	0.842
R59	6	0.955	0.993
K6	6	0.953	0.988
R63	6	0.953	0.994
Y70	6	0.909	0.979
M5	6	0.900	0.913
G11	6	0.898	0.968
K69	6	0.898	0.982
R48	6	0.886	0.992
P125	6	0.884	0.929
G92	6	0.880	0.964
G17	6	0.864	0.950
K98	6	0.861	0.977

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Kidney Chromophobe)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	2.55e-05

Disease associations

OMIM: gene MIM:605032 | disease phenotypes: MIM:617976

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
developmental and epileptic encephalopathy, 63	Strong	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Early onset or syndromic epilepsy	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (1): developmental and epileptic encephalopathy, 63 (MONDO:0033372)

HPO phenotypes

showing 60 of 194 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000077	Abnormality of the kidney
HP:0000078	Abnormality of the genital system
HP:0000079	Abnormality of the urinary system
HP:0000119	Abnormality of the genitourinary system
HP:0000151	Aplasia of the uterus
HP:0000153	Abnormality of the mouth
HP:0000159	Abnormal lip morphology
HP:0000175	Cleft palate
HP:0000188	Short upper lip
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000288	Abnormality of the philtrum
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000389	Chronic otitis media
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000465	Webbed neck
HP:0000485	Megalocornea
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000558	Rieger anomaly
HP:0000574	Thick eyebrow
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000643	Blepharospasm
HP:0000647	Sclerocornea
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000718	Aggressive behavior
HP:0000733	Motor stereotypy
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000765	Abnormal thorax morphology

GWAS associations

2 associations:

Study	Trait	p-value
GCST006979_65	Heel bone mineral density	2e-9
GCST012073_14	Behcet’s disease	2e-6

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Cyclosporine	decreases expression, increases expression	2
methyleugenol	decreases expression	1
bisphenol A	decreases methylation, affects cotreatment	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cylindrospermopsin	increases expression	1
MRK 003	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Azacitidine	increases expression	1
Cadmium	increases abundance, increases expression	1
Bucladesine	affects cotreatment, increases expression	1
Estradiol	increases expression, affects cotreatment	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Medroxyprogesterone Acetate	affects cotreatment, increases expression	1
Asbestos, Serpentine	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D0H2	KAIMRCi003-A	Induced pluripotent stem cell	Female
CVCL_D0H3	KAIMRCi003-B	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

1 trials:

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford