SYP

Summary

SYP (synaptophysin, HGNC:11506) is a protein-coding gene on chromosome Xp11.23, encoding Synaptophysin (P08247). Possibly involved in structural functions as organizing other membrane components or in targeting the vesicles to the plasma membrane.

This gene encodes an integral membrane protein of small synaptic vesicles in brain and endocrine cells. The protein also binds cholesterol and is thought to direct targeting of vesicle-associated membrane protein 2 (synaptobrevin) to intracellular compartments. Mutations in this gene are associated with an X-linked form of cognitive disability.

Source: NCBI Gene 6855 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, X-linked 96 (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 118 total — 4 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 3
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003179

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11506
Approved symbol	SYP
Name	synaptophysin
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	MRX96
Ensembl gene	ENSG00000102003
Ensembl biotype	protein_coding
OMIM	313475
Entrez	6855

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 5 protein_coding, 5 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263233, ENST00000376303, ENST00000466635, ENST00000469389, ENST00000472598, ENST00000472737, ENST00000479808, ENST00000494396, ENST00000689634, ENST00000691258, ENST00000692723, ENST00000920145, ENST00000968645

RefSeq mRNA: 1 — MANE Select: NM_003179 NM_003179

CCDS: CCDS14321

Canonical transcript exons

ENST00000263233 — 7 exons

Exon	Start	End
ENSE00001094897	49197715	49197839
ENSE00001829082	49187815	49189282
ENSE00003520347	49198968	49199033
ENSE00003582502	49193272	49193463
ENSE00003605272	49194166	49194361
ENSE00003607525	49191433	49191763
ENSE00003930664	49200151	49200193

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 99.14.

FANTOM5 (CAGE): breadth broad, TPM avg 35.5449 / max 2985.5518, expressed in 725 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199259	34.0155	713
199255	0.8357	87
199256	0.1639	41
199254	0.1358	36
199257	0.1137	33
199260	0.0874	47
199248	0.0808	38
199261	0.0584	18
199258	0.0537	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.14	gold quality
cerebellar hemisphere	UBERON:0002245	99.12	gold quality
cerebellar cortex	UBERON:0002129	99.10	gold quality
right frontal lobe	UBERON:0002810	99.04	gold quality
prefrontal cortex	UBERON:0000451	98.97	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.15	gold quality
anterior cingulate cortex	UBERON:0009835	98.12	gold quality
cingulate cortex	UBERON:0003027	98.11	gold quality
cerebellum	UBERON:0002037	97.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.66	gold quality
frontal cortex	UBERON:0001870	97.52	gold quality
frontal lobe	UBERON:0016525	97.51	gold quality
amygdala	UBERON:0001876	97.22	gold quality
cortical plate	UBERON:0005343	97.04	gold quality
neocortex	UBERON:0001950	96.91	gold quality
adenohypophysis	UBERON:0002196	96.89	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.74	gold quality
nucleus accumbens	UBERON:0001882	96.45	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	96.33	gold quality
islet of Langerhans	UBERON:0000006	96.12	gold quality
pituitary gland	UBERON:0000007	96.02	gold quality
cerebral cortex	UBERON:0000956	95.89	gold quality
hypothalamus	UBERON:0001898	95.84	gold quality
telencephalon	UBERON:0001893	95.60	gold quality
forebrain	UBERON:0001890	95.56	gold quality
brain	UBERON:0000955	95.48	gold quality
central nervous system	UBERON:0001017	95.44	gold quality
putamen	UBERON:0001874	95.37	gold quality
caudate nucleus	UBERON:0001873	95.31	gold quality
parietal lobe	UBERON:0001872	94.87	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	48.43
E-HCAD-5	yes	46.40
E-GEOD-137537	yes	18.64
E-GEOD-84465	yes	7.12
E-ANND-3	yes	3.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, NR1I2, PKNOX1, REST, SP1

miRNA regulators (miRDB)

112 targeting SYP, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3681-5P	99.82	66.88	387
HSA-MIR-6756-5P	99.82	67.97	2466

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• during prenatal development synaptophysin expression increased gradually in the red nucleus (PMID:12077483)
• we have identified a functional binding site for REST in the first intron of the human synaptophysin gene indicating that REST blocks human synaptophysin gene transcription through an intronic neuron-specific silencer element. (PMID:12492469)
• AP180 had an overall expression similar to synaptophysin, the immunoreactivity for the two proteins did not always co-localize. (PMID:12493563)
• This protein was found in cells of adrenal cortical neoplasms. (PMID:12575533)
• expression and localization of chromogranin A (CgA), chromogranin B (CgB), synaptophysin, and insulin were ultrastructurally studied with the immunogold technique in porcine and human pancreatic islet neuroendocrine cells (PMID:12826904)
• Synaptophysin immunoreactivity was significantly reduced in both the inner and outer molecular layers of the dentate gyrus (both p<0.01 by paired t-test), but not in the hilus. In contrast to patients with schizophrenia. (PMID:15694236)
• Synaptophysin was absent near neurons bearing clusters of oligomer Abeta, suggesting that accumulated oligomer Abeta, but not fibrillar Abeta, is closely associated with synaptic failure, a major cause of cognitive dysfunction. (PMID:16721760)
• Results describe patterns of synaptophysin protein and mRNA expression in the human hippocampal formation from birth to old age. (PMID:16807900)
• Synaptophysin regulates micro-opioid receptor trafficking and signaling. (PMID:17005904)
• 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 Synaptophysin is associated with squamous carcinoma and adenocarcinoma of the lung (PMID:17724707)
• synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10 then decrease until the adult level was reached by age 16 (PMID:17916412)
• Synaptophysin(SYN) was correlated with mini-mental status examination scores. Frontal cortex SYN protein levels may protect neuronal function in oldest-old individuals and reflect compensatory responses that may be involved with maintaining cognition. (PMID:18006193)
• Chromogranin A-, serotonin-, synaptophysin- and vascular endothelial growth factor-positive endocrine cells and the prognosis of colorectal cancer: an immunohistochemical and ultrastructural study. (PMID:18771509)
• Additional immunohistochemical detection of neuroendocrine differentiation (chromogranin-A, synaptophysin, and neural-cell adhesion molecule) in non-small cell lung cancer is presently not of prognostic importance. (PMID:19652998)
• Chromogranin A, synaptophysin and CK 20 were not expressed in any basal cell carcinoma (PMID:19724850)
• Significant decreases in synaptophysin levels are observed in hippocampal neurons from Alzheimer’s disease patients. (PMID:20847448)
• Prescence of of APOEepsilon4 allele and MAPT H2 haplotype in frontotemporal lobar degeneration had a significant influence on the expression of synaptophysin and SNAP-25 (PMID:21073671)
• This is the first report of immunoreactivity for inhibin-alpha and synaptophysin in synovial sarcoma (PMID:22055401)
• The expression of synaptophysin and GAD67 was downregulated in the basolateral nucleus of schizophrenics. (PMID:22099865)
• Finding that synaptophysin is produced by Paneth cells adds new information which might help to unravel the riddle of the ultimate biological significance of these puzzling cells. (PMID:22210727)
• The data of this study suggested that the common polymorphisms of the SYP gene appear not to play a major role in conferring susceptibility to schizophrenia. (PMID:22348818)
• NCAM1, SYPT and CGA expressions are differently regulated by neuroendocrine phenotype-specific transcription factors in lung cancer cells. (PMID:22449227)
• Normal goblet cells found in duodenal adenomas express synaptophysin. (PMID:22843923)
• Depressed patients showed significant decreases in synaptophysin (SYN) and VGLUT1 expression. (PMID:23022470)
• Lower levels of synaptophysin were found in the visual cortex of dementia with Lewy bodies patients compared to controls. (PMID:23242284)
• the author showed that, in cutaneous basal cell carcinoma, the expression of NCAM and c-KIT was high, PDGFRA was intermediate, and chromogranin A and synaptophysin was relatively low (PMID:23292839)
• Data suggest that multi-antibody assay of TTF1, Vimentin, p63 CD56, chromogranin and synaptophysin may be of special value, especially in diagnosing small biopsies. (PMID:23418554)
• The results of this study suggested that SYP may be primarily associated with ADHD-I and its genetic mechanism may be gender-specific. (PMID:23726717)
• The paucity or absence of synaptophysin-positive cells in all three phenotypes of Barrett’s mucosa might mirror a sequela of chronic inflammation caused by the particular pathogenic bacteria present in the immediate oesophageal microenvironment. (PMID:23763443)
• This study demonstrated that synaptophysin was significantly lower in Down syndrome with Alzheimer disease compared with Down syndrome alone and similar to sporadic Alzheimer disease. (PMID:24927707)
• Docosahexaenoic acid-containing phosphatidylcholines and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer’s disease. (PMID:25410733)
• Anomalous expression of all intermediate filament proteins and synaptophysin was found in significant subsets of malignant melanoma. (PMID:26022451)
• 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)
• Study reveals the presence of two selected neuronal markers, MAP-2 and SYP mRNAs and protein expression, in eutopic endometrium and in endometriotic lesions. (PMID:26604067)
• The expression of MAP2 and SYP proved most relevant to neurocognitive functioning in HIV-infected patients. (PMID:26637429)
• High synaptophysin expression is associated with neuroendocrine differentiation in colorectal cancer. (PMID:28351413)
• Synaptophysin-positive epithelial proliferations suggest breast neoplasms. (PMID:28630050)
• Suggest that INSM1 is valuable for identification of the high-grade thoracic neuroendocrine carcinomas that are sometimes negative for synaptophysin, chromogranin, and CD56. (PMID:28719469)
• Report of a novel SYP mutation identified in a patient with a severe neurodevelopmental disorder. Mutation does not impact on synaptic vesicles endocytosis or trafficking of common cargoes. However it is unable to support sybII retrieval in synaptophysin knockout neurons. It fully restores plasma membrane levels of sybII, suggesting that activity-dependent trafficking of sybII is specifically affected by this mutation. (PMID:28887151)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sypb	ENSDARG00000002230
danio_rerio	sypa	ENSDARG00000110528
mus_musculus	Syp	ENSMUSG00000031144
rattus_norvegicus	Syp	ENSRNOG00000059720
caenorhabditis_elegans		WBGENE00004979

Paralogs (3): SYPL1 (ENSG00000008282), SYPL2 (ENSG00000143028), SYNPR (ENSG00000163630)

Protein

Protein identifiers

Synaptophysin — P08247 (reviewed: P08247)

Alternative names: Major synaptic vesicle protein p38

All UniProt accessions (4): P08247, F2Z3E1, G5E9A2, H7C4W3

UniProt curated annotations — full annotation on UniProt →

Function. Possibly involved in structural functions as organizing other membrane components or in targeting the vesicles to the plasma membrane. Involved in the regulation of short-term and long-term synaptic plasticity.

Subunit / interactions. Homohexamer or homotetramer. Interacts with SRCIN1. Interacts with VAMP2; the interaction is inhibited by interaction of VAPM2 with SEPT8.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Synapse. Synaptosome.

Tissue specificity. Expressed in the brain, with expression in the hippocampus, the neuropil in the dentate gyrus, where expression is higher in the outer half of the molecular layer than in the inner half, and in the neuropil of CA4 and CA3. Expressed in the putamen (at protein level).

Post-translational modifications. Ubiquitinated; mediated by SIAH1 or SIAH2 and leading to its subsequent proteasomal degradation. Phosphorylated by SRC.

Disease relevance. Intellectual developmental disorder, X-linked 96 (XLID96) [MIM:300802] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The calcium-binding activity is thought to be localized in the cytoplasmic tail of the protein.

Similarity. Belongs to the synaptophysin/synaptobrevin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P08247-1	1	yes
P08247-2	2

RefSeq proteins (1): NP_003170* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001285	Synaptophysin/porin	Family
IPR008253	Marvel	Domain

Pfam: PF01284

UniProt features (28 total): sequence variant 8, topological domain 5, transmembrane region 4, compositionally biased region 3, region of interest 2, chain 1, domain 1, modified residue 1, glycosylation site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08247-F1	77.92	0.42

Functional residue map

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

Post-translational modifications (1): 81

Glycosylation sites (1): 59

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9659379	Sensory processing of sound
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 204 (showing top): GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_VESICLE_ORGANIZATION, GOBP_REGULATION_OF_SHORT_TERM_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_CELL_SIGNALING, GOBP_EXOCYTOSIS, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, GOMF_SH2_DOMAIN_BINDING, CCTGTGA_MIR513, BACH2_01, GOBP_SECRETION, GOBP_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, TGANTCA_AP1_C

GO Biological Process (9): endocytosis (GO:0006897), regulation of synaptic vesicle priming (GO:0010807), synaptic vesicle maturation (GO:0016188), regulation of neuronal synaptic plasticity (GO:0048168), regulation of long-term neuronal synaptic plasticity (GO:0048169), regulation of short-term neuronal synaptic plasticity (GO:0048172), synaptic vesicle membrane organization (GO:0048499), regulation of opioid receptor signaling pathway (GO:2000474), modulation of chemical synaptic transmission (GO:0050804)

GO Molecular Function (4): cholesterol binding (GO:0015485), SH2 domain binding (GO:0042169), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (16): synaptic vesicle (GO:0008021), synaptic vesicle membrane (GO:0030672), neuromuscular junction (GO:0031594), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), terminal bouton (GO:0043195), perinuclear region of cytoplasm (GO:0048471), presynaptic active zone (GO:0048786), excitatory synapse (GO:0060076), Schaffer collateral - CA1 synapse (GO:0098685), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), neuron projection terminus (GO:0044306), synapse (GO:0045202), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory processing of sound	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
presynapse	4
synapse	4
regulation of neuronal synaptic plasticity	2
cytoplasm	2
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
synaptic vesicle priming	1
regulation of protein-containing complex assembly	1
vesicle organization	1
developmental maturation	1
regulation of synaptic plasticity	1
endomembrane system organization	1
membrane organization	1
regulation of G protein-coupled receptor signaling pathway	1
G protein-coupled opioid receptor signaling pathway	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
sterol binding	1
alcohol binding	1
protein domain specific binding	1
protein binding	1
binding	1
exocytic vesicle	1
synaptic vesicle	1
exocytic vesicle membrane	1
synaptic membrane	1
plasma membrane bounded cell projection	1
axon terminus	1
vacuole	1
plasma membrane	1
intracellular vesicle	1
neuron projection	1
cell junction	1

Protein interactions and networks

STRING

3346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SYP	VAMP2	P19065	997
SYP	SV2A	Q7L0J3	975
SYP	SNAP25	P13795	933
SYP	SYT1	P21579	926
SYP	RAB3A	P20336	922
SYP	CHGA	P10645	918
SYP	APP	P05067	916
SYP	ENO2	P09104	906
SYP	SYN1	P17600	900
SYP	DLG4	P78352	889
SYP	NCAM1	P13591	880
SYP	KRT20	P35900	870
SYP	MAP2	P11137	861
SYP	SLC17A7	Q9P2U7	860
SYP	GAP43	P17677	854

IntAct

154 interactions, top by confidence:

A	B	Type	Score
SYP	SH3GLB1	psi-mi:“MI:0915”(physical association)	0.720
SYP	HTT	psi-mi:“MI:0915”(physical association)	0.670
DIABLO	SYP	psi-mi:“MI:0915”(physical association)	0.560
MIEF2	SYP	psi-mi:“MI:0915”(physical association)	0.560
SYP	SNX1	psi-mi:“MI:0915”(physical association)	0.560
SYP	MTERF3	psi-mi:“MI:0915”(physical association)	0.560
SYP	NDRG4	psi-mi:“MI:0915”(physical association)	0.560
SYP	PBX3	psi-mi:“MI:0915”(physical association)	0.560
SYP	PPIF	psi-mi:“MI:0915”(physical association)	0.560
SYP	MIEF1	psi-mi:“MI:0915”(physical association)	0.560
SYP	MRRF	psi-mi:“MI:0915”(physical association)	0.560
SYP	LNPK	psi-mi:“MI:0915”(physical association)	0.560
CD160	SYP	psi-mi:“MI:0915”(physical association)	0.560
SYP	MYG1	psi-mi:“MI:0915”(physical association)	0.560
SYP	JOSD2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (155): SYP (Biochemical Activity), SYP (Affinity Capture-MS), SYP (Affinity Capture-MS), SYP (Affinity Capture-MS), SYP (Affinity Capture-MS), SYP (Affinity Capture-MS), AP1G1 (Two-hybrid), TMEM183A (Affinity Capture-MS), PTS (Affinity Capture-MS), SYP (Affinity Capture-MS), SYP (Affinity Capture-MS), SLC25A23 (Affinity Capture-MS), MRS2 (Affinity Capture-MS), SLC35B2 (Affinity Capture-MS), SFXN3 (Affinity Capture-MS)

ESM2 similar proteins: A2VE58, A3KQ86, A6H7B0, A7E3W5, A8MWL6, B2RZ87, O43759, O43760, O43761, O54980, O55100, O55101, O76735, O95473, P07825, P08247, P0DI73, P20488, P22831, P47987, P79826, Q08AU7, Q08DL4, Q28793, Q2YDD6, Q5EBF8, Q5R703, Q5RER2, Q5XGR0, Q5XIT3, Q5YJC1, Q62277, Q62876, Q642A2, Q6RW13, Q7JYV2, Q7TQJ1, Q8BGN8, Q8R191, Q8TBG9

Diamond homologs: O09117, O62646, O89104, P07825, P08247, P20488, P22831, Q16563, Q5VXT5, Q5YJC1, Q62277, Q8BGN8, Q8TBG9

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PKNOX1	“up-regulates quantity by expression”	SYP	“transcriptional regulation”
SYP	“up-regulates quantity”	VAMP2	binding
SYP	up-regulates	Synaptic_vesicle_recycling
DNM1	“up-regulates activity”	SYP	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	7
Uncertain significance	56
Likely benign	15
Benign	2

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
3393445	NM_003179.3(SYP):c.583_584del (p.Asp195fs)	Pathogenic
9863	NM_003179.3(SYP):c.274dup (p.Thr92fs)	Pathogenic
9864	NM_003179.3(SYP):c.177_178delinsGT (p.Asn59_Lys60delinsLysTer)	Pathogenic
9866	NM_003179.3(SYP):c.649G>C (p.Gly217Arg)	Pathogenic
1700130	NM_003179.3(SYP):c.684G>A (p.Trp228Ter)	Likely pathogenic
3024328	NM_003179.3(SYP):c.615+2T>C	Likely pathogenic
4085523	NM_003179.3(SYP):c.726del (p.Lys242fs)	Likely pathogenic
4527018	NM_003179.3(SYP):c.874C>T (p.Gln292Ter)	Likely pathogenic
4531323	NM_003179.3(SYP):c.103-1G>A	Likely pathogenic
4819717	NM_003179.3(SYP):c.277A>T (p.Lys93Ter)	Likely pathogenic
987397	NM_003179.3(SYP):c.829_832del (p.Asp277fs)	Likely pathogenic

SpliceAI

816 predictions. Top by Δscore:

Variant	Effect	Δscore
X:49193271:CCA:C	donor_gain	1.0000
X:49194159:GACTC:G	donor_loss	1.0000
X:49194164:A:AC	donor_gain	1.0000
X:49194164:ACC:A	donor_loss	1.0000
X:49194165:C:CC	donor_gain	1.0000
X:49194165:CCAG:C	donor_gain	1.0000
X:49194357:GCAGC:G	acceptor_gain	1.0000
X:49194358:CAGC:C	acceptor_gain	1.0000
X:49194358:CAGCC:C	acceptor_gain	1.0000
X:49194359:AGC:A	acceptor_gain	1.0000
X:49194360:GCCTG:G	acceptor_loss	1.0000
X:49194362:C:CC	acceptor_gain	1.0000
X:49197847:A:T	acceptor_gain	1.0000
X:49198966:AC:A	donor_gain	1.0000
X:49198967:CC:C	donor_gain	1.0000
X:49200147:GTACC:G	donor_loss	1.0000
X:49200148:TA:T	donor_loss	1.0000
X:49193265:GGCTT:G	donor_loss	0.9900
X:49193266:GCTTA:G	donor_loss	0.9900
X:49193268:TTA:T	donor_loss	0.9900
X:49193269:TA:T	donor_loss	0.9900
X:49193270:A:C	donor_loss	0.9900
X:49193462:TC:T	acceptor_gain	0.9900
X:49193462:TCCTA:T	acceptor_loss	0.9900
X:49193463:CC:C	acceptor_gain	0.9900
X:49193464:C:CC	acceptor_gain	0.9900
X:49193464:C:CG	acceptor_loss	0.9900
X:49193465:T:G	acceptor_loss	0.9900
X:49193470:C:CT	acceptor_gain	0.9900
X:49193471:A:T	acceptor_gain	0.9900

AlphaMissense

2034 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:49191707:C:A	K224N	1.000
X:49191707:C:G	K224N	1.000
X:49191736:A:G	W215R	1.000
X:49191736:A:T	W215R	1.000
X:49191738:A:T	L214H	1.000
X:49193409:A:G	W160R	1.000
X:49193409:A:T	W160R	1.000
X:49193430:A:G	W153R	1.000
X:49193430:A:T	W153R	1.000
X:49191716:G:C	F221L	0.999
X:49191716:G:T	F221L	0.999
X:49191717:A:G	F221S	0.999
X:49191718:A:G	F221L	0.999
X:49191721:A:G	W220R	0.999
X:49191721:A:T	W220R	0.999
X:49191725:G:C	N218K	0.999
X:49191725:G:T	N218K	0.999
X:49191729:C:T	G217D	0.999
X:49191730:C:G	G217R	0.999
X:49191746:G:C	N211K	0.999
X:49191746:G:T	N211K	0.999
X:49191756:C:T	G208D	0.999
X:49191757:C:G	G208R	0.999
X:49193276:G:C	S204W	0.999
X:49193285:A:T	L201H	0.999
X:49193396:A:G	L164P	0.999
X:49193407:C:A	W160C	0.999
X:49193407:C:G	W160C	0.999
X:49193419:G:C	S156R	0.999
X:49193419:G:T	S156R	0.999

dbSNP variants (sampled 300 via entrez): RS1000128761 (X:49190271 C>T), RS1000479443 (X:49190749 G>A,C), RS1000851398 (X:49200717 T>A), RS1000905120 (X:49200346 T>C), RS1001760182 (X:49192314 C>T), RS1002146304 (X:49194209 A>G), RS1002206048 (X:49192077 A>G), RS1003559312 (X:49187715 G>A), RS1003765181 (X:49197235 G>A), RS1004152553 (X:49199472 G>C), RS1005551491 (X:49191869 G>C), RS1005751765 (X:49201693 T>A), RS1005759095 (X:49201327 G>A), RS1006446173 (X:49192956 T>G), RS1007713250 (X:49195461 C>T)

Disease associations

OMIM: gene MIM:313475 | disease phenotypes: MIM:300802, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 96	Definitive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
non-syndromic X-linked intellectual disability	Moderate	XL

Mondo (3): intellectual disability, X-linked 96 (MONDO:0010429), Charcot-Marie-Tooth disease (MONDO:0015626), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (2): X-linked non-syndromic intellectual disability (Orphanet:777), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001419	X-linked recessive inheritance

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases expression, affects cotreatment, increases expression	3
methylmercuric chloride	decreases expression	2
bisphenol A	decreases methylation, increases expression	2
Resveratrol	decreases reaction, increases expression	2
Lead	affects cotreatment, decreases expression, increases abundance, increases reaction, affects expression	2
Valproic Acid	affects cotreatment, increases expression	2
Yindan Xinnaotong	increases expression	1
mipafox	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	decreases reaction, increases expression	1
lead acetate	increases abundance, increases reaction, affects cotreatment, decreases expression	1
terbufos	increases methylation	1
dimethylselenide	increases expression, increases oxidation	1
fisetin	decreases expression, decreases reaction	1
sodium arsenite	increases expression	1
pyrrolidine dithiocarbamic acid	decreases reaction, increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
naphthalene	decreases reaction, increases expression	1
aluminum sulfate	decreases expression	1
amyloid beta-protein (1-42)	decreases expression, decreases reaction	1
CGP 52608	increases reaction, affects binding	1
deguelin	decreases expression	1
pyrimidifen	decreases expression	1
naphthol AS-E phosphate	decreases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Alitretinoin	decreases expression	1
Acetaminophen	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3IU	Abcam HEK293T SYP KO 1	Transformed cell line	Female
CVCL_B3IV	Abcam HEK293T SYP KO 2	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT