SYN1

Summary

SYN1 (synapsin I, HGNC:11494) is a protein-coding gene on chromosome Xp11.3-p11.23, encoding Synapsin-1 (P17600). Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 6853 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 705 total — 46 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 10
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006950

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11494
Approved symbol	SYN1
Name	synapsin I
Location	Xp11.3-p11.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000008056
Ensembl biotype	protein_coding
OMIM	313440
Entrez	6853

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000295987, ENST00000340666, ENST00000638337, ENST00000639776, ENST00000640721, ENST00000950906, ENST00000950907

RefSeq mRNA: 2 — MANE Select: NM_006950 NM_006950, NM_133499

CCDS: CCDS14280, CCDS35233

Canonical transcript exons

ENST00000295987 — 13 exons

Exon	Start	End
ENSE00000361448	47575128	47575274
ENSE00000669348	47574002	47574590
ENSE00000669350	47574688	47574775
ENSE00000669354	47576131	47576233
ENSE00000669361	47577439	47577501
ENSE00000867029	47604978	47605067
ENSE00000867030	47605223	47605379
ENSE00000867031	47606945	47607036
ENSE00000867032	47607141	47607198
ENSE00001368328	47619352	47619857
ENSE00001472563	47571901	47572999
ENSE00001601408	47576498	47576640
ENSE00001715201	47576332	47576406

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 99.08.

FANTOM5 (CAGE): breadth broad, TPM avg 9.4518 / max 584.3615, expressed in 724 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199128	8.2505	365
199104	0.4775	209
199106	0.2960	158
199129	0.1185	72
199127	0.0739	46
199131	0.0739	35
199130	0.0697	39
199132	0.0351	15
199103	0.0286	7
199105	0.0281	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.08	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.80	gold quality
prefrontal cortex	UBERON:0000451	98.61	gold quality
cerebellar hemisphere	UBERON:0002245	98.59	gold quality
cerebellar cortex	UBERON:0002129	98.55	gold quality
anterior cingulate cortex	UBERON:0009835	98.38	gold quality
cingulate cortex	UBERON:0003027	98.36	gold quality
frontal cortex	UBERON:0001870	98.29	gold quality
frontal lobe	UBERON:0016525	98.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.24	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.23	gold quality
cerebellum	UBERON:0002037	97.97	gold quality
postcentral gyrus	UBERON:0002581	97.76	gold quality
parietal lobe	UBERON:0001872	97.61	gold quality
neocortex	UBERON:0001950	97.59	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.54	gold quality
superior frontal gyrus	UBERON:0002661	97.52	gold quality
CA1 field of hippocampus	UBERON:0003881	97.50	gold quality
amygdala	UBERON:0001876	97.45	gold quality
cerebral cortex	UBERON:0000956	96.99	gold quality
temporal lobe	UBERON:0001871	96.87	gold quality
entorhinal cortex	UBERON:0002728	96.55	gold quality
hypothalamus	UBERON:0001898	96.49	gold quality
orbitofrontal cortex	UBERON:0004167	96.39	gold quality
nucleus accumbens	UBERON:0001882	96.36	gold quality
Ammon’s horn	UBERON:0001954	96.34	gold quality
telencephalon	UBERON:0001893	95.94	gold quality
forebrain	UBERON:0001890	95.31	gold quality
brain	UBERON:0000955	95.19	gold quality
cortical plate	UBERON:0005343	94.81	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	6.61
E-ANND-3	no	2.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR1, KDM5C, NRF1, POU2F2, REST, SP1

miRNA regulators (miRDB)

93 targeting SYN1, 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-4283	100.00	66.42	2097
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 26)

• The results showed that synapsin I was significantly decreased in the stratum radiatum of CA1 subfield and the molecular layer of DG in AD patients. (PMID:14673601)
• SYN1 nonsense mutation is the likely cause of epileptic and other phenotypes (PMID:14985377)
• Synapsins and S100A1 interact in nerve terminals where coexpresssed; S100A1 cannot bind SV-associated synapsin I and may function as a cytoplasmic store of monomeric synapsin I; synapsin dimerization and interaction with S100A1 are mutually exclusive (PMID:15147519)
• This study concluded that the human synapsin I gene is positively regulated by nuclear respiratory factor 1 and mediates the function of nuclear respiratory factor 1 in neurite outgrowth. (PMID:19301426)
• The authors propose claudin-2 and SYN1 work in concert to enhance microbial translocation across the intestinal epithelial barrier to contribute to chronic immune activation and CD4 T-cell depletion in HIV-1-infected patients. (PMID:20700059)
• the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia. (PMID:20921223)
• SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. (PMID:21441247)
• The histone modification marks were significantly increased in major depression and this effect was correlated with significant increases in SYN1b gene expression. (PMID:22571925)
• The allelic frequencies of SYN1 are associated with Korean female schizophrenia. (PMID:22807112)
• A conserved region of human and mouse SYN1 promoters contains cis-sites for the transcriptional activator Sp1 in close proximity to REST binding motifs. (PMID:23250796)
• Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity. (PMID:23406870)
• Data indicate that in patients carrying the W356x mutation the function of synapsin I is markedly impaired, and support the value of Syn1(-/-) mice as an experimental model mimicking the human pathology. (PMID:23818987)
• The implementation of the AlphaScreen pSYN1 assay and future development of additional primary neuronal HTS assays provides an attractive approach for discovery of novel classes of therapeutic candidates for a variety of CNS disorders. (PMID:24088370)
• these findings suggest PRICKLE1 mutations contribute to ASD by disrupting the interaction with SYN1 and regulation of synaptic vesicles. (PMID:24312498)
• Patterns of the immunoreactivity with antibodies to SNAP-25, synapsin-I and synaptophysin are completely appropriate to those of adult’s OB on the 38-40 weeks of the prenatal development. (PMID:26204769)
• Cerebral malaria causes pre-synaptic excitation and eventually activation of synapsin I, leading to increased neurotransmitter release. (PMID:26823711)
• These findings contribute to previous work showing dysregulation of Synapsins, particularly SYN2, in mood disorders and improve our understanding of the regulatory mechanisms that precipitate these changes likely leading to the BD or MDD phenotype. (PMID:27515700)
• Authors identified the c.236 C > G/p.S79W mutation in SYN1 as causative for the non-syndromic ID of the MRX50 family. Accordingly, the in vitro characterization of S79W SynI clearly indicates that the mutation does not interfere with neurodevelopmental aspects, but perturbs spontaneous SV exocytosis, SV clustering and SV lateral mobility along axons. (PMID:28973667)
• A surface-based group study using novel diffusion and quantitative multiparametric imaging on 13 SYN1Q555X mutation carriers and 13 age- and sex-matched controls. Results showed significant microstructural alterations in several regions usually involved in oral and written language as well as dyslexia. The most significant changes in these regions were lowered mean diffusivity and increased fractional anisotropy. (PMID:29671924)
• Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function. (PMID:31727880)
• Semaphorin 3A controls enteric neuron connectivity and is inversely associated with synapsin 1 expression in Hirschsprung disease. (PMID:32934297)
• Cooperative function of synaptophysin and synapsin in the generation of synaptic vesicle-like clusters in non-neuronal cells. (PMID:33431828)
• Synapsin Condensates Recruit alpha-Synuclein. (PMID:33774037)
• Familial SYN1 variants related neurodevelopmental disorders in Asian pediatric patients. (PMID:34243774)
• An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD. (PMID:35876881)
• Novel SYN1 Variant in Two Brothers with Focal Epilepsy and Their Prompt Response to Valproate. (PMID:36693418)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Syn1	ENSMUSG00000037217
rattus_norvegicus	Syn1	ENSRNOG00000010365
caenorhabditis_elegans		WBGENE00004913

Paralogs (2): SYN2 (ENSG00000157152), SYN3 (ENSG00000185666)

Protein

Protein identifiers

Synapsin-1 — P17600 (reviewed: P17600)

Alternative names: Brain protein 4.1, Synapsin I

All UniProt accessions (3): P17600, A0A1W2PS00, A0A1W2PSE9

UniProt curated annotations — full annotation on UniProt →

Function. Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton. Acts as a regulator of synaptic vesicles trafficking, involved in the control of neurotransmitter release at the pre-synaptic terminal. Also involved in the regulation of axon outgrowth and synaptogenesis. The complex formed with NOS1 and CAPON proteins is necessary for specific nitric-oxid functions at a presynaptic level.

Subunit / interactions. Homodimer. Can form oligomers with SYN2. Interacts with CAPON. Forms a ternary complex with NOS1. Isoform Ib interacts with PRNP.

Subcellular location. Synapse. Golgi apparatus. Presynapse. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle.

Post-translational modifications. Substrate of different protein kinases. Phosphorylated by CaMK2 and MAPK1. Phosphorylation, including phosphorylation at Ser-9, promotes synapsin-1 dissociation from synaptic vesicles, regulates its rate of dispersion, and controls the kinetics of vesicle pool turnover and neurotransmitter release.

Disease relevance. Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (EPILX1) [MIM:300491] A neurologic disorder characterized by variable combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behavior. The disease is caused by variants affecting the gene represented in this entry. Intellectual developmental disorder, X-linked 50 (XLID50) [MIM:300115] A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The A region binds phospholipids with a preference for negatively charged species.

Similarity. Belongs to the synapsin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P17600-1	IA	yes
P17600-2	IB

RefSeq proteins (2): NP_008881, NP_598006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001359	Synapsin	Family
IPR013815	ATP_grasp_subdomain_1	Homologous_superfamily
IPR016185	PreATP-grasp_dom_sf	Homologous_superfamily
IPR019735	Synapsin_CS	Conserved_site
IPR019736	Synapsin_P_site	PTM
IPR020897	Synapsin_pre-ATP-grasp_dom	Domain
IPR020898	Synapsin_ATP-bd_dom	Domain

Pfam: PF02078, PF02750, PF10581

UniProt features (57 total): modified residue 23, compositionally biased region 9, glycosylation site 9, region of interest 7, sequence variant 4, splice variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17600-F1	69.86	0.44

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 (23): 9, 39, 62, 67, 312, 427, 430, 432, 436, 438, 476, 534, 547, 551, 553, 556, 568, 605, 622, 663 …

Glycosylation sites (9): 55, 87, 96, 103, 261, 432, 526, 564, 578

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-181429	Serotonin Neurotransmitter Release Cycle
R-HSA-212676	Dopamine Neurotransmitter Release Cycle
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-112310	Neurotransmitter release cycle
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 208 (showing top): GOBP_SYNAPTIC_VESICLE_LOCALIZATION, MODULE_274, GOBP_VESICLE_LOCALIZATION, MODULE_563, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_EXOCYTOSIS, GOBP_CELL_JUNCTION_ORGANIZATION, GATA3_01, REACTOME_DOPAMINE_NEUROTRANSMITTER_RELEASE_CYCLE

GO Biological Process (10): chemical synaptic transmission (GO:0007268), neurotransmitter secretion (GO:0007269), regulation of neurotransmitter secretion (GO:0046928), neuron development (GO:0048666), synapse organization (GO:0050808), synaptic vesicle clustering (GO:0097091), regulation of synaptic vesicle cycle (GO:0098693), regulation of synaptic vesicle exocytosis (GO:2000300), modulation of chemical synaptic transmission (GO:0050804), synaptic vesicle cycle (GO:0099504)

GO Molecular Function (7): actin binding (GO:0003779), ATP binding (GO:0005524), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), calcium-dependent protein binding (GO:0048306), cytoskeletal protein-membrane anchor activity (GO:0106006), protein binding (GO:0005515)

GO Cellular Component (16): synaptonemal complex (GO:0000795), Golgi apparatus (GO:0005794), cytoskeleton (GO:0005856), synaptic vesicle (GO:0008021), postsynaptic density (GO:0014069), axon (GO:0030424), dendrite (GO:0030425), synaptic vesicle membrane (GO:0030672), cell body (GO:0044297), presynaptic active zone (GO:0048786), Schaffer collateral - CA1 synapse (GO:0098685), presynapse (GO:0098793), extrinsic component of synaptic vesicle membrane (GO:0098850), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Neurotransmitter release cycle	2
Sensory processing of sound	1
Transmission across Chemical Synapses	1
Neuronal System	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
presynapse	4
cellular anatomical structure	4
chemical synaptic transmission	2
establishment of localization in cell	2
synaptic vesicle cycle	2
protein binding	2
cytoplasm	2
neuron projection	2
synapse	2
anterograde trans-synaptic signaling	1
neurotransmitter transport	1
signal release from synapse	1
neurotransmitter secretion	1
modulation of chemical synaptic transmission	1
regulation of neurotransmitter transport	1
regulation of secretion by cell	1
neuron differentiation	1
cell development	1
cell junction organization	1
synaptic vesicle localization	1
regulation of vesicle-mediated transport	1
synaptic vesicle exocytosis	1
regulation of neurotransmitter secretion	1
regulation of regulated secretory pathway	1
regulation of trans-synaptic signaling	1
vesicle-mediated transport in synapse	1
cytoskeletal protein binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
calcium ion binding	1
cytoskeletal adaptor activity	1
lipid binding	1
protein-membrane adaptor activity	1
binding	1
synaptonemal structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
exocytic vesicle	1

Protein interactions and networks

STRING

3098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYN1	DLG4	P78352	951
SYN1	SYP	P08247	900
SYN1	SNAP25	P13795	886
SYN1	GAP43	P17677	886
SYN1	RIC8B	Q9NVN3	872
SYN1	SLC17A7	Q9P2U7	865
SYN1	SYT1	P21579	862
SYN1	VAMP2	P19065	836
SYN1	MARCKS	P29966	835
SYN1	MAPT	P10636	826
SYN1	CALM1	P02593	818
SYN1	RAB3A	P20336	817
SYN1	SLC32A1	Q9H598	816
SYN1	CALML4	Q96GE6	799
SYN1	GRIA1	P42261	793

IntAct

29 interactions, top by confidence:

A	B	Type	Score
EGFR	SYN1	psi-mi:“MI:0915”(physical association)	0.550
SYN1	EGFR	psi-mi:“MI:0915”(physical association)	0.550
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
NUFIP1	PDE2A	psi-mi:“MI:0914”(association)	0.530
SNCA	SYN1	psi-mi:“MI:2364”(proximity)	0.420
SNCA	SYN1	psi-mi:“MI:0914”(association)	0.420
RB1CC1	SYN1	psi-mi:“MI:0915”(physical association)	0.370
SYN1	LUC7L3	psi-mi:“MI:0914”(association)	0.350
MAPT	NCAN	psi-mi:“MI:0914”(association)	0.350
PRNP	SYNJ1	psi-mi:“MI:0914”(association)	0.350
PRNP	MBP	psi-mi:“MI:0914”(association)	0.350
SNAP25	STX7	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
GPM6A	KIF2A	psi-mi:“MI:0914”(association)	0.350
HAX1	DNM1L	psi-mi:“MI:0914”(association)	0.350
DNAAF2	DNM1L	psi-mi:“MI:0914”(association)	0.350
DGUOK	BIN1	psi-mi:“MI:0914”(association)	0.350
DUSP2	SYN3	psi-mi:“MI:0914”(association)	0.350
ARMC1	DCX	psi-mi:“MI:0914”(association)	0.350
VCP	FAM171A2	psi-mi:“MI:0914”(association)	0.350
MAPT	DCTN6	psi-mi:“MI:2364”(proximity)	0.270
SYN1	KAT5	psi-mi:“MI:0915”(physical association)	0.000
SYN1	SYN1	psi-mi:“MI:0915”(physical association)	0.000
SYN1	VIM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (61): SYN1 (Affinity Capture-MS), SYN1 (Affinity Capture-MS), SYN1 (Affinity Capture-MS), SYN1 (Affinity Capture-MS), SYN1 (Affinity Capture-MS), SYN1 (Two-hybrid), GTF3C2 (Affinity Capture-MS), PSMD2 (Affinity Capture-MS), VPS54 (Affinity Capture-MS), LUC7L3 (Affinity Capture-MS), DGCR8 (Affinity Capture-MS), ERGIC1 (Affinity Capture-MS), SAP130 (Affinity Capture-MS), ANTXR1 (Affinity Capture-MS), ERI1 (Affinity Capture-MS)

ESM2 similar proteins: A1L020, A8IH47, A8INQ0, A8JID5, D4P3R7, F1LP90, O49067, O88935, O96013, P09951, P17600, P53814, P83510, Q01JD1, Q05A36, Q10EL1, Q2QPW2, Q3UHD9, Q5QD03, Q5R8Z4, Q688R3, Q69T21, Q6C3D7, Q71FD5, Q75AS0, Q75DK7, Q7TSJ6, Q7XQN1, Q7XT42, Q80VW5, Q84SL2, Q8BTW9, Q8CGU4, Q8CI12, Q8N4C8, Q8NHG8, Q8TDN4, Q8VHH5, Q96G74, Q96KQ7

Diamond homologs: O14994, O62732, O70441, O88935, P09951, P17599, P17600, Q24546, Q63537, Q64332, Q6QM28, Q8JZP2, Q92777

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
SYN1	down-regulates	Synaptic_vesicle_exocytosis
PKA	“down-regulates activity”	SYN1	phosphorylation
“BHC complex”	“down-regulates quantity by repression”	SYN1	“transcriptional regulation”
SYN1	“up-regulates activity”	RAB3A	binding
SYN1	“up-regulates activity”	ACTB	binding
SYN1	“up-regulates activity”	Actin_cytoskeleton_reorganization	binding
CDK5	up-regulates	SYN1	phosphorylation
PRKAA1	“down-regulates activity”	SYN1	phosphorylation
UHMK1	unknown	SYN1	phosphorylation
KDM5C	“down-regulates quantity by repression”	SYN1	“transcriptional regulation”
PAK1	“up-regulates activity”	SYN1	phosphorylation
PAK2	unknown	SYN1	phosphorylation
PAK3	“up-regulates activity”	SYN1	phosphorylation
PAK	unknown	SYN1	phosphorylation
PRKACA	“down-regulates activity”	SYN1	phosphorylation
CAMK1	“down-regulates activity”	SYN1	phosphorylation
CAMK2G	unknown	SYN1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	18
Uncertain significance	308
Likely benign	223
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067772	NM_006950.3(SYN1):c.1941_1947dup (p.Ala650fs)	Pathogenic
1068662	NM_006950.3(SYN1):c.700C>T (p.Arg234Ter)	Pathogenic
1074864	NM_006950.3(SYN1):c.433_434del (p.Gln145fs)	Pathogenic
1301801	NM_006950.3(SYN1):c.1166dup (p.Ser390fs)	Pathogenic
1326265	NM_006950.3(SYN1):c.122del (p.Gly41fs)	Pathogenic
1451507	NM_006950.3(SYN1):c.1682dup (p.Gln562fs)	Pathogenic
1456713	NM_006950.3(SYN1):c.1258_1261dup (p.Gln421fs)	Pathogenic
1489277	NM_006950.3(SYN1):c.1385dup (p.Pro463fs)	Pathogenic
1700040	NM_006950.3(SYN1):c.39del (p.Phe13fs)	Pathogenic
1700042	NM_006950.3(SYN1):c.1258dup (p.Arg420fs)	Pathogenic
1700043	NM_006950.3(SYN1):c.980+43_981del	Pathogenic
1700045	NM_006950.3(SYN1):c.975del (p.Tyr326fs)	Pathogenic
1700046	NM_006950.3(SYN1):c.1729del (p.Ala577fs)	Pathogenic
1700047	NM_006950.3(SYN1):c.1794_1906del (p.Thr601fs)	Pathogenic
1700048	NM_006950.3(SYN1):c.1321dup (p.Ala441fs)	Pathogenic
1710316	NM_006950.3(SYN1):c.1444C>T (p.Gln482Ter)	Pathogenic
1710318	NM_006950.3(SYN1):c.527+1G>T	Pathogenic
1710320	NM_006950.3(SYN1):c.1406dup (p.Pro470fs)	Pathogenic
1710321	NM_006950.3(SYN1):c.1266del (p.Gln423fs)	Pathogenic
1879762	NM_006950.3(SYN1):c.691C>T (p.Gln231Ter)	Pathogenic
207469	NM_006950.3(SYN1):c.1264C>T (p.Arg422Ter)	Pathogenic
2133546	NM_006950.3(SYN1):c.1647_1650del (p.Ala550fs)	Pathogenic
2133935	NM_006950.3(SYN1):c.554_555insA (p.Arg186fs)	Pathogenic
2694635	NM_006950.3(SYN1):c.57_63del (p.Asn19fs)	Pathogenic
2714242	NM_006950.3(SYN1):c.1655del (p.Pro552fs)	Pathogenic
2766607	NM_006950.3(SYN1):c.98_114del (p.Pro33fs)	Pathogenic
2822546	NM_006950.3(SYN1):c.1287del (p.Arg430fs)	Pathogenic
282790	NM_006950.3(SYN1):c.377G>A (p.Trp126Ter)	Pathogenic
2834690	NM_006950.3(SYN1):c.1594C>T (p.Gln532Ter)	Pathogenic
2849297	NM_006950.3(SYN1):c.1208_1211del (p.Lys403fs)	Pathogenic

SpliceAI

2390 predictions. Top by Δscore:

Variant	Effect	Δscore
X:47574686:AC:A	donor_gain	1.0000
X:47574687:CC:C	donor_gain	1.0000
X:47575122:CCTGA:C	donor_loss	1.0000
X:47575123:CTGA:C	donor_loss	1.0000
X:47575124:TGAC:T	donor_loss	1.0000
X:47575125:GACCT:G	donor_loss	1.0000
X:47575126:A:AT	donor_loss	1.0000
X:47575127:C:CT	donor_loss	1.0000
X:47575159:T:TA	donor_gain	1.0000
X:47575196:TGTTG:T	donor_gain	1.0000
X:47575270:ACCAC:A	acceptor_gain	1.0000
X:47575271:CCAC:C	acceptor_gain	1.0000
X:47575271:CCACC:C	acceptor_gain	1.0000
X:47575272:CACC:C	acceptor_gain	1.0000
X:47575273:AC:A	acceptor_gain	1.0000
X:47575274:CC:C	acceptor_gain	1.0000
X:47575274:CCT:C	acceptor_loss	1.0000
X:47575275:C:CC	acceptor_gain	1.0000
X:47575275:CT:C	acceptor_loss	1.0000
X:47576128:TA:T	donor_loss	1.0000
X:47576129:A:C	donor_loss	1.0000
X:47576130:CCT:C	donor_gain	1.0000
X:47576229:TGTAT:T	acceptor_gain	1.0000
X:47576230:GTAT:G	acceptor_gain	1.0000
X:47576231:TAT:T	acceptor_gain	1.0000
X:47576232:AT:A	acceptor_gain	1.0000
X:47576232:ATC:A	acceptor_loss	1.0000
X:47576233:TCT:T	acceptor_loss	1.0000
X:47576234:C:CC	acceptor_gain	1.0000
X:47576234:C:CG	acceptor_loss	1.0000

AlphaMissense

4548 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:47572873:G:C	F703L	1.000
X:47572873:G:T	F703L	1.000
X:47572875:A:G	F703L	1.000
X:47572885:G:C	F699L	1.000
X:47572885:G:T	F699L	1.000
X:47572886:A:C	F699C	1.000
X:47572886:A:G	F699S	1.000
X:47572887:A:G	F699L	1.000
X:47572895:C:A	R696M	1.000
X:47576138:A:T	I384N	1.000
X:47576165:A:G	L375P	1.000
X:47576169:C:G	A374P	1.000
X:47576174:A:T	V372E	1.000
X:47576178:C:G	A371P	1.000
X:47576181:A:G	C370R	1.000
X:47576189:A:G	L367P	1.000
X:47576209:G:C	C360W	1.000
X:47576211:A:G	C360R	1.000
X:47576221:C:A	W356C	1.000
X:47576221:C:G	W356C	1.000
X:47576223:A:G	W356R	1.000
X:47576223:A:T	W356R	1.000
X:47576356:A:G	L344P	1.000
X:47576379:C:A	K336N	1.000
X:47576379:C:G	K336N	1.000
X:47576380:T:G	K336T	1.000
X:47576381:T:C	K336E	1.000
X:47576382:C:A	W335C	1.000
X:47576382:C:G	W335C	1.000
X:47576383:C:A	W335L	1.000

dbSNP variants (sampled 300 via entrez): RS1000047738 (X:47597200 T>C), RS1000082751 (X:47586417 C>G), RS1000133980 (X:47579179 C>T), RS1000144047 (X:47573115 G>C), RS1000196781 (X:47572463 T>C), RS1000398847 (X:47597637 G>A), RS1000632535 (X:47610520 C>T), RS1000649794 (X:47596578 T>A), RS1000920962 (X:47618471 C>G,T), RS1000930549 (X:47572048 C>T), RS1001002728 (X:47599811 C>T), RS1001077846 (X:47583197 CAAT>C), RS1001096299 (X:47581904 C>T), RS1001108183 (X:47608972 G>A), RS1001190153 (X:47573380 G>T)

Disease associations

OMIM: gene MIM:313440 | disease phenotypes: MIM:300491, MIM:300115

GenCC curated gene-disease

Disease	Classification	Inheritance
epilepsy, X-linked 1, with variable learning disabilities and behavior disorders	Strong	X-linked
intellectual disability, X-linked 50	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (7): epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (MONDO:0010339), intellectual disability, X-linked 50 (MONDO:0010251), epilepsy (MONDO:0005027), neurodevelopmental disorder (MONDO:0700092), X-linked complex neurodevelopmental disorder (MONDO:0100148), Klinefelter syndrome (MONDO:0006823), intellectual disability (MONDO:0001071)

Orphanet (3): X-linked epilepsy-learning disabilities-behavior disorders syndrome (Orphanet:85294), X-linked non-syndromic intellectual disability (Orphanet:777), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000256	Macrocephaly
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001328	Specific learning disability
HP:0001417	X-linked inheritance
HP:0001419	X-linked recessive inheritance
HP:0001423	X-linked dominant inheritance
HP:0007359	Focal-onset seizure

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007713	Klinefelter Syndrome	C12.050.351.875.253.795.500; C12.200.706.316.795.500; C12.800.316.795.500; C16.131.260.830.835.500; C16.131.939.316.795.500; C16.320.180.830.835.500; C19.391.119.795.500; C19.391.482.629
D065886	Neurodevelopmental Disorders	F03.625
C564505	Epilepsy, X-Linked, with Variable Learning Disabilities and Behavior Disorders (supp.)
C564713	Mental Retardation, X-Linked 50 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	decreases expression, decreases reaction	3
Acetylcysteine	decreases reaction, decreases expression	2
Glutathione	decreases expression, decreases reaction	2
Lead	decreases expression, decreases reaction, increases abundance, affects expression	2
dicrotophos	increases expression	1
methylmercuric chloride	increases expression	1
mipafox	decreases expression	1
lead acetate	decreases expression, decreases reaction, increases abundance	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
ethyl-p-hydroxybenzoate	decreases expression	1
cypermethrin	decreases expression	1
aluminum sulfate	decreases expression	1
cyfluthrin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
(+)-JQ1 compound	increases expression	1
Aripiprazole	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	decreases expression, decreases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Colforsin	increases expression	1
Hemin	decreases expression, decreases reaction, increases abundance	1
Ivermectin	decreases expression	1
Paraoxon	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
S-Adenosylmethionine	decreases expression, decreases reaction	1
Trichlorfon	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1HU	Abcam A-549 SYN1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients
NCT01118455	PHASE4	TERMINATED	Trial to Assess Vagus Nerve Stimulation Therapy vs. Anti-Epileptic Drug (AED) Treatment in Children With Refractory Seizures
NCT01127165	PHASE4	COMPLETED	Low and High Dose Zonisamide in Children as Monotherapy
NCT01127256	PHASE4	COMPLETED	Comparative Study of Zonisamide and Carbamazepine as an Initial Monotherapy: Efficacy and Safety Evaluation
NCT01140867	PHASE4	COMPLETED	Open-label, Multi-center Trial of Zonisamide as Adjunctive Therapy in Patients With Uncontrolled Partial Epilepsy
NCT01175954	PHASE4	COMPLETED	Cognitive and Behavioral Effects of Lacosamide
NCT01229735	PHASE4	COMPLETED	Levetiracetam Versus Topiramate as Adjunctive Therapy to Evaluate Efficacy and Safety in Subjects With Refractory Partial Onset Seizures
NCT01244724	PHASE4	TERMINATED	Lexapro for Major Depression in Patients With Epilepsy