VAMP2

Summary

VAMP2 (vesicle associated membrane protein 2, HGNC:12643) is a protein-coding gene on chromosome 17p13.1, encoding Vesicle-associated membrane protein 2 (P63027). Involved in the targeting and/or fusion of transport vesicles to their target membrane.

The protein encoded by this gene is a member of the vesicle-associated membrane protein (VAMP)/synaptobrevin family. Synaptobrevins/VAMPs, syntaxins, and the 25-kD synaptosomal-associated protein SNAP25 are the main components of a protein complex involved in the docking and/or fusion of synaptic vesicles with the presynaptic membrane. This gene is thought to participate in neurotransmitter release at a step between docking and fusion. The protein forms a stable complex with syntaxin, synaptosomal-associated protein, 25 kD, and synaptotagmin. It also forms a distinct complex with synaptophysin. It is a likely candidate gene for familial infantile myasthenia (FIMG) because of its map location and because it encodes a synaptic vesicle protein of the type that has been implicated in the pathogenesis of FIMG.

Source: NCBI Gene 6844 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (Strong, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 44 total — 8 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_014232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12643
Approved symbol	VAMP2
Name	vesicle associated membrane protein 2
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	VAMP-2
Ensembl gene	ENSG00000220205
Ensembl biotype	protein_coding
OMIM	185881
Entrez	6844

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

ENST00000316509, ENST00000404970, ENST00000481878, ENST00000488857, ENST00000711100, ENST00000870910

RefSeq mRNA: 2 — MANE Select: NM_014232 NM_001330125, NM_014232

CCDS: CCDS32561, CCDS82064

Canonical transcript exons

ENST00000316509 — 5 exons

Exon	Start	End
ENSE00001483806	8159149	8160871
ENSE00001888549	8162878	8162948
ENSE00003464967	8161608	8161766
ENSE00003535503	8162249	8162369
ENSE00003545133	8161473	8161524

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 99.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 109.3625 / max 2827.6620, expressed in 1821 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164406	102.2726	1820
164394	5.2015	1111
164404	1.1547	448
164408	0.2988	134
164405	0.2910	113
164407	0.1440	69

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 10	UBERON:0013541	99.80	gold quality
frontal pole	UBERON:0002795	99.61	gold quality
paraflocculus	UBERON:0005351	99.56	gold quality
prefrontal cortex	UBERON:0000451	99.53	gold quality
right frontal lobe	UBERON:0002810	99.52	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.49	gold quality
cerebellar cortex	UBERON:0002129	99.47	gold quality
cerebellar hemisphere	UBERON:0002245	99.47	gold quality
cingulate cortex	UBERON:0003027	99.42	gold quality
anterior cingulate cortex	UBERON:0009835	99.42	gold quality
cerebellum	UBERON:0002037	99.22	gold quality
amygdala	UBERON:0001876	99.12	gold quality
nucleus accumbens	UBERON:0001882	99.03	gold quality
adenohypophysis	UBERON:0002196	99.02	gold quality
middle frontal gyrus	UBERON:0002702	99.00	gold quality
cortical plate	UBERON:0005343	99.00	gold quality
cerebellar vermis	UBERON:0004720	98.90	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.89	gold quality
frontal cortex	UBERON:0001870	98.86	gold quality
hypothalamus	UBERON:0001898	98.73	gold quality
pituitary gland	UBERON:0000007	98.71	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.68	gold quality
caudate nucleus	UBERON:0001873	98.65	gold quality
neocortex	UBERON:0001950	98.54	gold quality
left ovary	UBERON:0002119	98.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.45	gold quality
superior vestibular nucleus	UBERON:0007227	98.44	gold quality
putamen	UBERON:0001874	98.34	gold quality
ventral tegmental area	UBERON:0002691	98.23	gold quality
brain	UBERON:0000955	98.22	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	1586.95
E-GEOD-93593	yes	606.84
E-HCAD-35	yes	53.75
E-HCAD-10	yes	18.84
E-GEOD-137537	yes	18.19
E-GEOD-135922	yes	11.28
E-GEOD-125970	yes	8.31
E-GEOD-84465	yes	7.23
E-MTAB-9154	no	2210.87
E-MTAB-10485	no	1028.56
E-MTAB-7303	no	883.25
E-MTAB-6108	no	367.20
E-MTAB-7316	no	40.12
E-HCAD-8	no	23.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, HSF1, MYC, SP1

Literature-anchored findings (GeneRIF, showing 40)

• SNAP-23 and syntaxin-4 are expressed in human eosinophils and are likely candidates for association with VAMP-2 during docking, which is followed by exocytosis (PMID:11842301)
• VAMP-2 mediates exocytosis of specific and tertiary granules of neutrophils through its interaction with Q-SNARE/R-SNARE complexes located at the neutrophil plasma membrane. (PMID:12517971)
• VAMP-2 can be one of the v-SNAREs for constitutive exocytosis (PMID:16195891)
• addition of PIP2 to Stx4/SNAP23 vesicles inhibited the fusion reaction, and its addition to VAMP2 vesicles was stimulatory (PMID:17001002)
• The vesicular distribution may be attributed in part to the direct interaction between PKD3 and vesicle-associated membrane protein VAMP2, through which PKD3 may regulate VAMP2 vesicle trafficking by facilitating its recruitment to the target membrane. (PMID:17196367)
• VAMP2 can be phosphorylated by activated PKCzeta in vitro and the presence of ProF increases the PKCzeta-dependent phosphorylation of VAMP2 in vitro (PMID:17313651)
• Results indicate that the sorting determinants of synaptic vesicle proteins can operate independently of a neuronal context and implicate the association of VAMP2 with synaptophysin I in the specification of the pathway of synaptic vesicle biogenesis. (PMID:17331077)
• Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. (PMID:18182011)
• BoNT/B and TeNT possess similar organization but have unique residues to recognize and cleave VAMP-2 (PMID:18511417)
• analysis of the substrate recognition mechanism of VAMP/synaptobrevin-cleaving clostridial neurotoxins (PMID:18511418)
• SNARE complex-related genes STX1A, VAMP2 and SNAP25 do not play a major role in susceptibility to schizophrenia in the Japanese population (PMID:18512733)
• These results do not suggest that a common genetic variant at VAMP2 or VAMP3 contributes to the development of bipolar affective disorder in German patients. (PMID:18628682)
• VAMP2 mediates the trafficking of alpha5beta1 integrin to the plasma membrane and VAMP2-dependent integrin trafficking is critical in cell adhesion, migration and survival. (PMID:19822142)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• unique mechanism of SNARE motif-dependent endocytic sorting and identify the ANTH domain proteins AP180 and CALM as cargo-specific adaptors for synaptobrevin 2 endocytosis (PMID:21808019)
• BoNT/F5 cleaves substrate synaptobrevin-2 in a different location than the other BoNT/F subtypes, between (54)L and (55)E. (PMID:22172278)
• The genetic variations of VAMP2, Synaptotagmin XI might be indication of the relationship between these genes and idiopathic generalized epilepsy (PMID:24164654)
• SNARE complex genes and their interactions may play a significant role in susceptibility and working memory of ADHD. (PMID:25445064)
• miR-206 regulates lung surfactant secretion by limiting the availability of VAMP-2 protein. (PMID:25481410)
• VAMP2-NRG1 is a novel oncogenic fusion gene representing a new addition to the list of NRG1 fusion genes, which together may form an important diagnostic and clinical category of lung adenocarcinoma cases (PMID:26134228)
• A large vesicular pool of VAMP2 maintained by AP180 is crucial to sustain efficient neurotransmission. (PMID:26412491)
• VAMP2 is involved in Porphyromonas gingivalis recycling pathway.VAMP2 is localized in early endosomes in gingival epithelial cells. (PMID:26617273)
• This study showed that decreased Levels of VAMP2 correlate with Duration of Dementia. (PMID:26639969)
• The present study addressed for the first time the unique substrate recognition mechanism of LC/F5 substrate cleavage of VAMP-2 by Botulinum Neurotoxin subtype F5. (PMID:26794648)
• VAMP2 is a promising new plasma cell marker (PMID:27247366)
• A significant interactive two-locus model of STX1A_rs4363087|VAMP2_rs2278637 (presynaptic genes) was observed among SVC variants in all epilepsy cases. (PMID:27458546)
• these findings implicate VAMP2 as the main VAMP isoform functionally involved in antibody secretion. (PMID:27616736)
• Data suggest that A-syn (alpha-synuclein) promotes SNARE-dependent vesicle docking; phosphatidylserine (PS) removal from t-SNARE-bearing vesicles causes A-syn to inhibit vesicle docking; PS removal from v-SNARE-bearing vesicles promotes vesicle docking; the C-terminal 45 residues of A-syn are required for promotion of vesicle docking. (Here, t-SNARE is SNAP-25; v-SNARE is VAMP2.) (PMID:28495859)
• these results indicate that the activation of beta-ARs induces secretory granules and cell membrane fusion via the interaction of VAMP-2 and syntaxin-4 in a PKA- and F-actin-dependent manner in human submandibular gland. Up-regulated beta-ARs might participate in altering protein secretion in transplanted submandibular gland by promoting the interaction of VAMP-2 with syntaxin-4. (PMID:29358308)
• To investigate the possible roles of selected synaptic and presynaptic membrane protein genetic polymorphisms (VAMP2, SNAP-25, synaptotagmin, and syntaxin 1A) in patients with multiple sclerosis (PMID:30582321)
• miR-185 inhibited osteosarcoma (OS) cell proliferation, migration and invasion. VAMP2 was validated as a direct target of miR-185. Study in human OS tissues confirm that decreased expression of miR-185 might be regarded as a tumor marker for the early diagnosis of OS, by manipulating of its interactive factors with VAMP2, to provide an effective novel therapeutic target for treatment of the OS tumor. (PMID:30721745)
• analysis of five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features (PMID:30929742)
• alpha-syn-VAMP2 interactions are necessary for alpha-syn-induced synaptic attenuation. (PMID:31110017)
• the present results indicated that circFAM53B could be a competing endogenous RNA (ceRNA) to competitively sponge miR646 and miR647 to upregulate VAMP2 and MDM2 expression at the posttranscriptional level, thus mediating the cellular behaviors of Ovarian cancer cells (PMID:31638250)
• Ceramide induces a multicomponent intracellular calcium increase triggering the acrosome secretion in human sperm. (PMID:32194132)
• Dlg4 and Vamp2 are involved in comorbid epilepsy and attention-deficit hyperactivity disorder: A microarray data study. (PMID:32580088)
• Amyloid-beta Peptides Disrupt Interactions Between VAMP-2 and SNAP-25 in Neuronal Cells as Determined by FRET/FLIM. (PMID:32675412)
• Oligomeric alpha-Syn and SNARE complex proteins in peripheral extracellular vesicles of neural origin are biomarkers for Parkinson’s disease. (PMID:33217562)
• VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome. (PMID:34183050)
• The neuronal calcium sensor Synaptotagmin-1 and SNARE proteins cooperate to dilate fusion pores. (PMID:34190041)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Vamp2	ENSMUSG00000020894
rattus_norvegicus	Vamp2	ENSRNOG00000006989
caenorhabditis_elegans		WBGENE00004897

Paralogs (10): VAMP3 (ENSG00000049245), SEC22C (ENSG00000093183), YKT6 (ENSG00000106636), VAMP4 (ENSG00000117533), VAMP8 (ENSG00000118640), SEC22A (ENSG00000121542), VAMP7 (ENSG00000124333), VAMP1 (ENSG00000139190), VAMP5 (ENSG00000168899), SEC22B (ENSG00000265808)

Protein

Protein identifiers

Vesicle-associated membrane protein 2 — P63027 (reviewed: P63027)

Alternative names: Synaptobrevin-2

All UniProt accessions (5): A0AA34QW14, P63027, F8WCA0, J3QRU4, K7ENK9

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the targeting and/or fusion of transport vesicles to their target membrane. Major SNARE protein of synaptic vesicles which mediates fusion of synaptic vesicles to release neurotransmitters. Essential for fast vesicular exocytosis and activity-dependent neurotransmitter release as well as fast endocytosis that mediates rapid reuse of synaptic vesicles. Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.

Subunit / interactions. Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A; this complex constitutes the basic catalytic machinery of the complex neurotransmitter release apparatus. Recruited to the SNARE complex following binding of the SNARE complex component STX1A to STXBP1. This complex binds to CPLX1. Interacts with POPDC1 and STX4. Interacts with VAPA and VAPB. Interacts with WDFY2, PRKCZ and PRKCI. Forms a complex with WDFY2 and PRKCZ. Interacts (via N-terminus) with KCNB1 (via N-terminus and C-terminus); stimulates the channel inactivation rate of KCNB1. Interacts with SEPT8; the interaction inhibits interaction of VAMP2 with SYP. Interacts with SYP; the interaction is inhibited by interaction with SEPT8. Interacts with PICALM. Interacts with alpha-synuclein/SNCA. Interacts with STX3.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Cell membrane.

Tissue specificity. Nervous system and skeletal muscle.

Post-translational modifications. Phosphorylated by PRKCZ in vitro and this phosphorylation is increased in the presence of WDFY2. (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release. (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which probably hydrolyzes the 59-Lys-|-Leu-60 bond and inhibits neurotransmitter release. Note that humans are not known to be infected by C.botulinum type D. (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 58-Gln-|-Lys-59 bond and probably inhibits neurotransmitter release. (Microbial infection) Targeted and hydrolyzed by C.tetani tetanus toxin (tetX) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release.

Disease relevance. Neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (NEDHAHM) [MIM:618760] An autosomal dominant disorder characterized by axial hypotonia apparent at birth, global developmental delay, intellectual disability, seizures, and autistic features. Involuntary hyperkinetic movements are present in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the synaptobrevin family.

RefSeq proteins (2): NP_001317054, NP_055047* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001388	Synaptobrevin-like	Family
IPR016444	Synaptobrevin/VAMP	Family
IPR042855	V_SNARE_CC	Domain

Pfam: PF00957

UniProt features (35 total): mutagenesis site 9, sequence variant 5, strand 4, helix 4, site 3, topological domain 2, region of interest 2, initiator methionine 1, chain 1, modified residue 1, sequence conflict 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9CKX	X-RAY DIFFRACTION	1.98
3FIE	X-RAY DIFFRACTION	2.1
3FII	X-RAY DIFFRACTION	2.17
3RK2	X-RAY DIFFRACTION	2.2
3RK3	X-RAY DIFFRACTION	3.5
7UDC	ELECTRON MICROSCOPY	3.7
3RL0	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63027-F1	79.34	0.30

Functional residue map

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

Catalytic / active sites (3): 76–77 ((microbial infection) cleavage; by c.tetani toxin (tetx)); 58–59 ((microbial infection) cleavage; by c.botulinum neurotoxin type f (bont/f, botf)); 76–77 ((microbial infection) cleavage; by c.botulinum neurotoxin type d (bont/d, botd))

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (9):

Position	Phenotype
28	significant loss of phosphorylation; when associated with a-61, a-75 and a-80.
41	70% reduction in cleavage by c.botulinum neurotoxin type f (bont/f, botf).
50	65% reduction in cleavage by bont/f.
53–54	98% reduction in cleavage by bont/f.
53	wild-type cleavage by bont/f.
53	90% reduction in cleavage by bont/f.
61	significant loss of phosphorylation; when associated with a-28, a-75 and a-80.
75	significant loss of phosphorylation; when associated with a-28, a-61 and a-80.
80	significant loss of phosphorylation; when associated with a-28, a-61 and a-75.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-181429	Serotonin Neurotransmitter Release Cycle
R-HSA-181430	Norepinephrine Neurotransmitter Release Cycle
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-212676	Dopamine Neurotransmitter Release Cycle
R-HSA-264642	Acetylcholine Neurotransmitter Release Cycle
R-HSA-264876	Insulin processing
R-HSA-422356	Regulation of insulin secretion
R-HSA-432720	Lysosome Vesicle Biogenesis
R-HSA-432722	Golgi Associated Vesicle Biogenesis
R-HSA-449836	Other interleukin signaling
R-HSA-5250955	Toxicity of botulinum toxin type D (botD)
R-HSA-5250958	Toxicity of botulinum toxin type B (botB)
R-HSA-5250981	Toxicity of botulinum toxin type F (botF)
R-HSA-5250982	Toxicity of tetanus toxin (tetX)
R-HSA-5250989	Toxicity of botulinum toxin type G (botG)
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-888590	GABA synthesis, release, reuptake and degradation
R-HSA-9609523	Insertion of tail-anchored proteins into the endoplasmic reticulum membrane
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea

MSigDB gene sets: 475 (showing top): FXR_IR1_Q6, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MODY_HIPPOCAMPUS_POSTNATAL, MYOGENIN_Q6, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, RORA1_01, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, TTTGTAG_MIR520D, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_MEMBRANE_FUSION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_EXOCYTOSIS

GO Biological Process (19): exocytosis (GO:0006887), vesicle fusion (GO:0006906), response to glucose (GO:0009749), protein transport (GO:0015031), synaptic vesicle exocytosis (GO:0016079), vesicle-mediated transport (GO:0016192), calcium-ion regulated exocytosis (GO:0017156), regulation of exocytosis (GO:0017157), cellular response to insulin stimulus (GO:0032869), SNARE complex assembly (GO:0035493), Golgi to plasma membrane protein transport (GO:0043001), eosinophil degranulation (GO:0043308), synaptic vesicle endocytosis (GO:0048488), long-term synaptic potentiation (GO:0060291), regulation of vesicle-mediated transport (GO:0060627), membrane fusion (GO:0061025), protein-containing complex assembly (GO:0065003), positive regulation of intracellular protein transport (GO:0090316), regulation of delayed rectifier potassium channel activity (GO:1902259)

GO Molecular Function (8): SNARE binding (GO:0000149), SNAP receptor activity (GO:0005484), calmodulin binding (GO:0005516), phospholipid binding (GO:0005543), syntaxin-1 binding (GO:0017075), syntaxin binding (GO:0019905), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515)

GO Cellular Component (27): trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), membrane (GO:0016020), clathrin-coated vesicle (GO:0030136), secretory granule (GO:0030141), secretory granule membrane (GO:0030667), clathrin-coated endocytic vesicle membrane (GO:0030669), synaptic vesicle membrane (GO:0030672), SNARE complex (GO:0031201), cytoplasmic vesicle (GO:0031410), vesicle (GO:0031982), zymogen granule membrane (GO:0042589), neuron projection (GO:0043005), neuron projection terminus (GO:0044306), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), clathrin-sculpted glutamate transport vesicle membrane (GO:0060203), clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane (GO:0061202), synaptobrevin 2-SNAP-25-syntaxin-1a-complexin I complex (GO:0070032), synaptobrevin 2-SNAP-25-syntaxin-1a-complexin II complex (GO:0070033), synaptobrevin 2-SNAP-25-syntaxin-1a complex (GO:0070044), clathrin-sculpted monoamine transport vesicle membrane (GO:0070083), voltage-gated potassium channel complex (GO:0008076), endomembrane system (GO:0012505), transport vesicle (GO:0030133)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Neurotransmitter release cycle	6
Neurotoxicity of clostridium toxins	5
Membrane Trafficking	3
trans-Golgi Network Vesicle Budding	2
Peptide hormone metabolism	1
Integration of energy metabolism	1
Signaling by Interleukins	1
Clathrin-mediated endocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
cellular anatomical structure	4
vesicle-mediated transport	3
protein binding	3
clathrin-coated vesicle membrane	3
transport	2
regulated exocytosis	2
presynapse	2
secretion by cell	1
vesicle fusion to plasma membrane	1
vesicle organization	1
organelle membrane fusion	1
response to hexose	1
intracellular protein localization	1
establishment of protein localization	1
neurotransmitter secretion	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
cellular process	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
response to insulin	1
cellular response to peptide hormone stimulus	1
vesicle fusion	1
protein-containing complex assembly	1
Golgi to plasma membrane transport	1
protein transport	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
eosinophil activation involved in immune response	1
eosinophil mediated immunity	1
leukocyte degranulation	1
synaptic vesicle recycling	1
presynaptic endocytosis	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
regulation of cellular process	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

197 interactions, top by confidence:

A	B	Type	Score
SNAP25	VAMP2	psi-mi:“MI:0914”(association)	0.760
VAMP2	SNAP25	psi-mi:“MI:0914”(association)	0.760
SNAP25	VAMP2	psi-mi:“MI:0915”(physical association)	0.760
SNAP25	Stx1a	psi-mi:“MI:0915”(physical association)	0.740
STX4	VAMP2	psi-mi:“MI:0915”(physical association)	0.720
VAMP2	STX4	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
VAMP2	SNAP29	psi-mi:“MI:0915”(physical association)	0.670
SNAP29	VAMP2	psi-mi:“MI:0915”(physical association)	0.670
VAMP2	STX1A	psi-mi:“MI:0915”(physical association)	0.670
VAMP2	VCP	psi-mi:“MI:0915”(physical association)	0.670
STX6	GOSR2	psi-mi:“MI:0914”(association)	0.670
CPLX1	Stx1a	psi-mi:“MI:0915”(physical association)	0.660
STX1B	VAMP2	psi-mi:“MI:0915”(physical association)	0.660
STX1B	VAMP2	psi-mi:“MI:2364”(proximity)	0.660
STX3	SNAP23	psi-mi:“MI:0914”(association)	0.660
STX7	SNAP23	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
VAMP2	SNCA	psi-mi:“MI:0915”(physical association)	0.630
VAMP2	SNCA	psi-mi:“MI:0914”(association)	0.630

BioGRID (280): VAMP2 (Two-hybrid), SNAP29 (Two-hybrid), EXOC3 (Reconstituted Complex), VAMP2 (Affinity Capture-MS), VAMP2 (Affinity Capture-MS), VAMP2 (Affinity Capture-MS), VAMP2 (Affinity Capture-MS), VAMP2 (Affinity Capture-MS), VAMP2 (Affinity Capture-MS), VAMP2 (Affinity Capture-MS), STX7 (Co-fractionation), VAMP2 (Proximity Label-MS), VAMP2 (Proximity Label-MS), VAMP2 (Proximity Label-MS), VAMP2 (Affinity Capture-MS)

ESM2 similar proteins: O02495, O15155, O23429, O35623, O94651, O95183, P13701, P18489, P23763, P32867, P34351, P35589, P47192, P47193, P47194, P63024, P63025, P63026, P63027, P63044, P63045, P78768, P93654, Q04338, Q09730, Q0V7N0, Q15836, Q20574, Q27236, Q2KJD2, Q4R8T0, Q54GB3, Q5RBX2, Q60WU2, Q62442, Q62896, Q63666, Q6TMJ9, Q7XIE2, Q8VXX9

Diamond homologs: O02495, O48850, O49377, O70404, O70480, O75379, O95183, P13701, P18489, P23763, P31109, P33328, P34351, P35589, P47192, P47193, P47194, P63024, P63025, P63026, P63027, P63044, P63045, Q0V7N0, Q12255, Q15836, Q27236, Q2KHY2, Q2KJD2, Q32L97, Q3T0Y8, Q4R8T0, Q5REQ5, Q60WU2, Q62442, Q63666, Q6TMJ9, Q92356, Q9BV40, Q9FMR5

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
VAMP2	“form complex”	SNARE_complex	binding
SYP	“up-regulates quantity”	VAMP2	binding
VAMP2	up-regulates	Synaptic_vesicle_exocytosis
SNCA	“down-regulates quantity”	VAMP2	binding
SNAP91	“up-regulates quantity”	VAMP2	binding
STON2	“up-regulates quantity”	VAMP2	binding
CADPS	“up-regulates activity”	VAMP2	binding
CADPS2	“up-regulates activity”	VAMP2	binding
MYO5A	“up-regulates activity”	VAMP2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 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
Intra-Golgi traffic	8	24.4×	4e-07
trans-Golgi Network Vesicle Budding	6	17.9×	7e-05
NCAM signaling for neurite out-growth	5	16.0×	4e-04
Retrograde transport at the Trans-Golgi-Network	6	15.5×	1e-04
Intra-Golgi and retrograde Golgi-to-ER traffic	7	8.6×	4e-04
Membrane Trafficking	12	5.2×	1e-04
Vesicle-mediated transport	12	4.9×	2e-04
Neutrophil degranulation	11	3.0×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
obsolete vesicle docking	12	82.8×	2e-18
vesicle fusion	10	54.2×	5e-13
regulation of long-term neuronal synaptic plasticity	5	44.6×	9e-06
synaptic vesicle priming	5	36.1×	3e-05
synaptic vesicle exocytosis	5	34.5×	3e-05
membrane fusion	5	28.1×	7e-05
insulin secretion	5	19.5×	4e-04
exocytosis	13	17.8×	8e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	5
Uncertain significance	16
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
4055786	NM_014232.3(VAMP2):c.197G>C (p.Arg66Pro)	Pathogenic
666257	NM_014232.3(VAMP2):c.128_130del	Pathogenic
810675	NM_014232.3(VAMP2):c.223T>C (p.Ser75Pro)	Pathogenic
810676	NM_014232.3(VAMP2):c.233A>C (p.Glu78Ala)	Pathogenic
810677	NM_014232.3(VAMP2):c.230T>C (p.Phe77Ser)	Pathogenic
810679	NM_014232.3(VAMP2):c.132CAT[1] (p.Ile45del)	Pathogenic
929460	NM_014232.3(VAMP2):c.166C>T (p.Arg56Ter)	Pathogenic
929462	NM_014232.3(VAMP2):c.1A>G (p.Met1Val)	Pathogenic
3068556	NM_014232.3(VAMP2):c.226C>T (p.Gln76Ter)	Likely pathogenic
4528360	NM_014232.3(VAMP2):c.148G>A (p.Val50Met)	Likely pathogenic
929461	NM_014232.3(VAMP2):c.217G>T (p.Gly73Trp)	Likely pathogenic
929463	NM_014232.3(VAMP2):c.167G>T (p.Arg56Leu)	Likely pathogenic
929464	NM_014232.3(VAMP2):c.337_341del (p.Tyr113fs)	Likely pathogenic

SpliceAI

461 predictions. Top by Δscore:

Variant	Effect	Δscore
17:8161470:CA:C	donor_loss	1.0000
17:8161471:A:AC	donor_gain	1.0000
17:8161472:C:A	donor_loss	1.0000
17:8161472:C:CC	donor_gain	1.0000
17:8161472:CCT:C	donor_gain	1.0000
17:8161520:ATCAT:A	acceptor_gain	1.0000
17:8161521:TCAT:T	acceptor_gain	1.0000
17:8161522:CAT:C	acceptor_gain	1.0000
17:8161522:CATC:C	acceptor_gain	1.0000
17:8161523:ATC:A	acceptor_loss	1.0000
17:8161524:TC:T	acceptor_loss	1.0000
17:8161524:TCTG:T	acceptor_loss	1.0000
17:8161525:C:A	acceptor_loss	1.0000
17:8161525:C:CC	acceptor_gain	1.0000
17:8161526:T:G	acceptor_loss	1.0000
17:8161531:G:GC	acceptor_gain	1.0000
17:8161604:TTAC:T	donor_loss	1.0000
17:8161605:TACC:T	donor_loss	1.0000
17:8161605:TACCT:T	donor_loss	1.0000
17:8161607:C:CA	donor_loss	1.0000
17:8161620:C:CT	donor_gain	1.0000
17:8161763:CCAC:C	acceptor_gain	1.0000
17:8161764:CAC:C	acceptor_gain	1.0000
17:8161764:CACC:C	acceptor_gain	1.0000
17:8161765:AC:A	acceptor_gain	1.0000
17:8161765:ACC:A	acceptor_loss	1.0000
17:8161766:CC:C	acceptor_gain	1.0000
17:8161767:C:CA	acceptor_loss	1.0000
17:8162245:TCA:T	donor_loss	1.0000
17:8162876:A:AC	donor_gain	1.0000

AlphaMissense

757 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8161509:C:G	G100R	1.000
17:8161509:C:T	G100R	1.000
17:8161639:A:G	L84P	1.000
17:8161659:A:C	F77L	1.000
17:8161659:A:T	F77L	1.000
17:8161660:A:C	F77C	1.000
17:8161660:A:G	F77S	1.000
17:8161661:A:G	F77L	1.000
17:8161681:A:G	L70P	1.000
17:8161681:A:T	L70H	1.000
17:8161685:C:G	A69P	1.000
17:8161691:C:G	A67P	1.000
17:8161702:A:G	L63P	1.000
17:8161711:A:G	L60P	1.000
17:8161500:A:G	C103R	0.999
17:8161508:C:T	G100E	0.999
17:8161639:A:T	L84H	0.999
17:8161649:C:G	A81P	0.999
17:8161667:A:G	S75P	0.999
17:8161669:G:T	A74D	0.999
17:8161670:C:G	A74P	0.999
17:8161676:C:G	A72P	0.999
17:8161678:T:G	Q71P	0.999
17:8161693:C:G	R66P	0.999
17:8161720:T:A	D57V	0.999
17:8161723:C:G	R56P	0.999
17:8161729:A:G	L54P	0.999
17:8161743:G:C	N49K	0.999
17:8161743:G:T	N49K	0.999
17:8161753:A:T	M46K	0.999

dbSNP variants (sampled 300 via entrez): RS1000312665 (17:8164382 C>G), RS1001101161 (17:8162659 G>A,T), RS1001201123 (17:8163277 T>A), RS1002560384 (17:8162656 A>G), RS1002614996 (17:8159498 C>A), RS1002904084 (17:8161951 C>T), RS1003191189 (17:8160725 G>A,T), RS1003652978 (17:8160395 T>G), RS1003707866 (17:8162155 G>T), RS1003876364 (17:8163793 G>C,T), RS1004415872 (17:8163649 A>G), RS1004611108 (17:8163195 C>A,T), RS1004757873 (17:8162824 A>C,G), RS1005551848 (17:8159479 G>C), RS1006171245 (17:8163911 AAAG>A)

Disease associations

OMIM: gene MIM:185881 | disease phenotypes: MIM:618760

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements	Strong	Autosomal dominant

Mondo (1): neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements (MONDO:0032900)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002072	Chorea
HP:0002079	Hypoplasia of the corpus callosum
HP:0002353	EEG abnormality
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0007359	Focal-onset seizure
HP:0008936	Axial hypotonia
HP:0012171	Stereotypical hand wringing
HP:0032660	Convulsive status epilepticus
HP:0100704	Cerebral visual impairment
HP:0100716	Self-injurious behavior

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST006190_14	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	7.000000e-18
GCST006190_56	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-21
GCST006192_58	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-12
GCST006192_85	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-07
GCST006193_47	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-18
GCST006193_85	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-20
GCST006195_36	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	4.000000e-07
GCST006195_77	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	2.000000e-12
GCST007565_93	Morning person	2.000000e-23
GCST007576_293	Chronotype	2.000000e-23

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364160 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, increases expression, affects methylation	2
cobaltous chloride	decreases expression	2
Diethylhexyl Phthalate	decreases expression, decreases methylation, increases abundance	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
methylparaben	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
sodium arsenite	affects cotreatment, increases expression	1
rimabotulinumtoxinB	increases cleavage, increases degradation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol S	increases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenicals	decreases methylation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1DN	Ubigene THP-1 VAMP2 KO	Cancer cell line	Male
CVCL_E8EB	SiMa APEX2-VAMP2	Cancer cell line	Male
CVCL_E8EC	SiMa NanoLuc-VAMP2	Cancer cell line	Male
CVCL_RG05	SiMa GFP-VAMP2	Cancer cell line	Male

Clinical trials (associated diseases)

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