STX18

Summary

STX18 (syntaxin 18, HGNC:15942) is a protein-coding gene on chromosome 4p16.3-p16.2, encoding Syntaxin-18 (Q9P2W9). Syntaxin that may be involved in targeting and fusion of Golgi-derived retrograde transport vesicles with the ER. It is a common-essential gene (DepMap: required in 97.5% of cancer cell lines).

This gene encodes a member of the syntaxin family of soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) which is part of a membrane tethering complex that includes other SNAREs and several peripheral membrane proteins, and is involved in vesicular transport between the endoplasmic reticulum (ER) and the Golgi complex. The encoded protein is important for the organization of the smooth, rough, and exit site ER subdomains. A pseudogene of this gene has been identified. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 53407 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 72 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_016930

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15942
Approved symbol	STX18
Name	syntaxin 18
Location	4p16.3-p16.2
Locus type	gene with protein product
Status	Approved
Aliases	Ufe1
Ensembl gene	ENSG00000168818
Ensembl biotype	protein_coding
OMIM	606046
Entrez	53407

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000306200, ENST00000502267, ENST00000503692, ENST00000503861, ENST00000505286, ENST00000507908, ENST00000510296, ENST00000512195, ENST00000512780, ENST00000515687, ENST00000889600, ENST00000889601, ENST00000889602, ENST00000889603, ENST00000963664, ENST00000963665

RefSeq mRNA: 4 — MANE Select: NM_016930 NM_001346281, NM_001346282, NM_001346300, NM_016930

CCDS: CCDS3377

Canonical transcript exons

ENST00000306200 — 11 exons

Exon	Start	End
ENSE00001161879	4425164	4425222
ENSE00001195927	4434770	4434858
ENSE00001195932	4438394	4438509
ENSE00001195938	4457191	4457257
ENSE00001195941	4457423	4457500
ENSE00001195956	4541797	4542048
ENSE00001217696	4418968	4420129
ENSE00003469150	4423518	4423587
ENSE00003487155	4420864	4420944
ENSE00003532603	4471639	4471706
ENSE00003649685	4459372	4459487

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3023 / max 281.4211, expressed in 1816 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51201	20.7028	1813
51202	6.4682	1751
51203	0.0671	26
51204	0.0643	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.85	gold quality
endocervix	UBERON:0000458	97.45	gold quality
endometrium	UBERON:0001295	95.77	gold quality
left testis	UBERON:0004533	95.66	gold quality
right testis	UBERON:0004534	95.58	gold quality
body of pancreas	UBERON:0001150	94.68	gold quality
ectocervix	UBERON:0012249	94.58	gold quality
metanephros cortex	UBERON:0010533	94.54	gold quality
sural nerve	UBERON:0015488	94.36	gold quality
adenohypophysis	UBERON:0002196	94.30	gold quality
body of uterus	UBERON:0009853	93.85	gold quality
testis	UBERON:0000473	93.62	gold quality
right adrenal gland cortex	UBERON:0035827	93.56	gold quality
calcaneal tendon	UBERON:0003701	93.46	gold quality
right adrenal gland	UBERON:0001233	93.31	gold quality
left ovary	UBERON:0002119	93.15	gold quality
left adrenal gland	UBERON:0001234	93.13	gold quality
right ovary	UBERON:0002118	92.99	gold quality
gall bladder	UBERON:0002110	92.95	gold quality
left adrenal gland cortex	UBERON:0035825	92.90	gold quality
rectum	UBERON:0001052	92.88	gold quality
pituitary gland	UBERON:0000007	92.73	gold quality
left uterine tube	UBERON:0001303	92.37	gold quality
granulocyte	CL:0000094	92.25	gold quality
body of stomach	UBERON:0001161	91.96	gold quality
mucosa of transverse colon	UBERON:0004991	91.90	gold quality
nerve	UBERON:0001021	91.87	gold quality
tibial nerve	UBERON:0001323	91.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.86	gold quality
adrenal gland	UBERON:0002369	91.80	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	422.00
E-MTAB-10283	no	412.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• RINT-1 coordinates the localization and function of ZW10 by serving as a link between ZW10 and the SNARE complex comprising syntaxin 18. (PMID:16571679)
• Stx18 in involved in growth of human breast cancer cells and may possibly be used as a prognostic marker and a molecular target in the treatment of breast cancer. (PMID:18722709)
• Suggest that syntaxin 18 has an important role in ER subdomain organization by mediating the fusion of retrograde membrane carriers with the ER membrane. (PMID:19401338)
• The SNP rs12644497 in the STX18 gene was associated with congenital heart diseases Chinese Han populations. (PMID:27816473)
• Syntaxin 18 Defects in Human and Zebrafish Unravel Key Roles in Early Cartilage and Bone Development. (PMID:37718532)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stx18	ENSDARG00000035763
mus_musculus	Stx18	ENSMUSG00000029125
rattus_norvegicus	Stx18	ENSRNOG00000006139
drosophila_melanogaster	Syx18	FBGN0039212
caenorhabditis_elegans		WBGENE00020425

Protein

Protein identifiers

Syntaxin-18 — Q9P2W9 (reviewed: Q9P2W9)

Alternative names: Cell growth-inhibiting gene 9 protein

All UniProt accessions (3): Q9P2W9, D6RC71, D6RF48

UniProt curated annotations — full annotation on UniProt →

Function. Syntaxin that may be involved in targeting and fusion of Golgi-derived retrograde transport vesicles with the ER.

Subunit / interactions. Component of a SNARE complex consisting of STX18, USE1L, BNIP1/SEC20L, and SEC22B. RINT1/TIP20L and ZW10 are associated with the complex through interaction with BNIP1/SEC20L. Interacts directly with USE1L and BNIP1/SEC20L.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Ubiquitous.

Similarity. Belongs to the syntaxin family.

RefSeq proteins (4): NP_001333210, NP_001333211, NP_001333229, NP_058626* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006012	Syntaxin/epimorphin_CS	Conserved_site
IPR019529	Syntaxin-18_N	Domain

Pfam: PF10496

UniProt features (13 total): sequence variant 3, topological domain 2, sequence conflict 2, compositionally biased region 2, chain 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P2W9-F1	73.01	0.24

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-199991	Membrane Trafficking
R-HSA-5653656	Vesicle-mediated transport
R-HSA-6811442	Intra-Golgi and retrograde Golgi-to-ER traffic
R-HSA-8856688	Golgi-to-ER retrograde transport

MSigDB gene sets: 186 (showing top): GOBP_REGULATION_OF_GOLGI_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_MEMBRANE_FUSION, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_TRANSPORT, MARTINEZ_RB1_TARGETS_UP, CEBP_Q2, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION

GO Biological Process (9): intracellular protein transport (GO:0006886), retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (GO:0006890), endoplasmic reticulum membrane organization (GO:0090158), positive regulation of organelle assembly (GO:1902117), positive regulation of ER to Golgi vesicle-mediated transport (GO:1902953), regulation of Golgi organization (GO:1903358), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), membrane fusion (GO:0061025)

GO Molecular Function (3): SNAP receptor activity (GO:0005484), protein domain specific binding (GO:0019904), protein binding (GO:0005515)

GO Cellular Component (6): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), SNARE complex (GO:0031201), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Golgi-to-ER retrograde transport	1
Vesicle-mediated transport	1
Membrane Trafficking	1
Intra-Golgi and retrograde Golgi-to-ER traffic	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
intracellular protein localization	2
membrane organization	2
transport	2
endomembrane system	2
intracellular membrane-bounded organelle	2
protein transport	1
intracellular transport	1
Golgi vesicle transport	1
endoplasmic reticulum organization	1
positive regulation of organelle organization	1
positive regulation of cellular component biogenesis	1
organelle assembly	1
regulation of organelle assembly	1
endoplasmic reticulum to Golgi vesicle-mediated transport	1
positive regulation of intracellular transport	1
regulation of ER to Golgi vesicle-mediated transport	1
Golgi organization	1
regulation of organelle organization	1
establishment of protein localization	1
cellular process	1
protein-macromolecule adaptor activity	1
membrane fusion	1
fusogenic activity	1
protein binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STX18	BNIP1	Q12981	984
STX18	SCFD1	Q8WVM8	980
STX18	SEC22B	O75396	977
STX18	USE1	Q9NZ43	931
STX18	NAPA	P54920	890
STX18	ZW10	O43264	873
STX18	RINT1	Q6NUQ1	839
STX18	NBAS	A2RRP1	829
STX18	STX5	Q13190	807
STX18	NSG1	P42857	806
STX18	ZNF787	Q6DD87	789
STX18	RAB18	Q9NP72	775
STX18	VAMP7	P51809	760
STX18	YKT6	O15498	735
STX18	EVC2	Q86UK5	701

IntAct

147 interactions, top by confidence:

A	B	Type	Score
ZWINT	NDC80	psi-mi:“MI:0914”(association)	0.940
USE1	STX18	psi-mi:“MI:0915”(physical association)	0.850
RINT1	NBAS	psi-mi:“MI:0914”(association)	0.830
STX18	SEC22B	psi-mi:“MI:0915”(physical association)	0.820
STX18	NBAS	psi-mi:“MI:0914”(association)	0.810
NAPA	SNAP23	psi-mi:“MI:0914”(association)	0.780
NBAS	ZW10	psi-mi:“MI:0914”(association)	0.720
ZW10	NBAS	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
NBAS	USE1	psi-mi:“MI:0914”(association)	0.640
IFT57	IFT56	psi-mi:“MI:0914”(association)	0.640
BNIP1	NBAS	psi-mi:“MI:0914”(association)	0.640

BioGRID (275): STX18 (Two-hybrid), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), STX18 (Affinity Capture-MS), SEC22B (Affinity Capture-MS), BNIP1 (Affinity Capture-MS), LDOC1L (Affinity Capture-MS), ZW10 (Affinity Capture-MS), NBAS (Affinity Capture-MS)

ESM2 similar proteins: O08522, O14662, O22151, O49160, O60499, O64791, O73787, O88384, O88630, O88983, O95249, P56962, P58200, Q08851, Q08DB5, Q13190, Q2KIU0, Q2TBU3, Q40554, Q4VBI7, Q5E9Y2, Q5RBL6, Q5REB4, Q62931, Q63635, Q68FW4, Q6DDF4, Q7ZTY7, Q8BVI5, Q8K1E0, Q8VDS8, Q944A9, Q946Y7, Q94KK7, Q9CQ56, Q9D0I4, Q9LMP7, Q9LNH6, Q9LRP1, Q9NZ43

Diamond homologs: Q4VBI7, Q5REB4, Q68FW4, Q8VDS8, Q9P2W9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 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	24.7×	3e-07
Retrograde transport at the Trans-Golgi-Network	5	13.1×	8e-04
COPII-mediated vesicle transport	6	11.7×	4e-04
COPI-dependent Golgi-to-ER retrograde traffic	8	10.6×	5e-05
Intra-Golgi and retrograde Golgi-to-ER traffic	8	10.0×	7e-05
ER to Golgi Anterograde Transport	5	7.9×	3e-03
Golgi-to-ER retrograde transport	5	7.9×	3e-03
Transport to the Golgi and subsequent modification	6	7.3×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
vesicle fusion	8	45.0×	5e-09
obsolete vesicle docking	6	43.0×	1e-06
membrane fusion	6	35.0×	3e-06
zinc ion transmembrane transport	5	32.8×	5e-05
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	8	25.2×	4e-07
intra-Golgi vesicle-mediated transport	5	24.6×	2e-04
endoplasmic reticulum to Golgi vesicle-mediated transport	7	8.9×	1e-03
MAPK cascade	6	8.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	54
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3062779	GRCh37/hg19 4p16.3-16.2(chr4:68345-4611819)x1	Pathogenic

SpliceAI

2974 predictions. Top by Δscore:

Variant	Effect	Δscore
4:4420941:CTTC:C	acceptor_gain	1.0000
4:4420942:TTC:T	acceptor_gain	1.0000
4:4420943:TC:T	acceptor_gain	1.0000
4:4420943:TCC:T	acceptor_loss	1.0000
4:4420944:CC:C	acceptor_gain	1.0000
4:4420944:CCT:C	acceptor_loss	1.0000
4:4420945:C:CC	acceptor_gain	1.0000
4:4420946:T:A	acceptor_loss	1.0000
4:4420947:G:GC	acceptor_gain	1.0000
4:4434764:CATTA:C	donor_loss	1.0000
4:4434765:ATTAC:A	donor_loss	1.0000
4:4434766:TTAC:T	donor_loss	1.0000
4:4434767:TACCA:T	donor_loss	1.0000
4:4434768:A:C	donor_loss	1.0000
4:4453538:G:C	donor_gain	1.0000
4:4457189:A:AC	donor_gain	1.0000
4:4457189:ACAAT:A	donor_gain	1.0000
4:4457190:C:CA	donor_gain	1.0000
4:4457190:CA:C	donor_gain	1.0000
4:4457190:CAA:C	donor_gain	1.0000
4:4457190:CAAT:C	donor_gain	1.0000
4:4457190:CAATC:C	donor_gain	1.0000
4:4457421:A:AC	donor_gain	1.0000
4:4457422:C:CC	donor_gain	1.0000
4:4459367:TTTA:T	donor_loss	1.0000
4:4459368:TTA:T	donor_loss	1.0000
4:4459369:TACCT:T	donor_loss	1.0000
4:4459370:ACCT:A	donor_loss	1.0000
4:4459371:C:A	donor_loss	1.0000
4:4459371:CCTT:C	donor_gain	1.0000

AlphaMissense

2220 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:4420075:A:G	C323R	1.000
4:4420129:C:G	A305P	1.000
4:4423552:A:G	L266P	1.000
4:4420053:A:G	L330P	0.999
4:4420871:A:T	I302K	0.999
4:4420884:C:G	G298R	0.999
4:4457221:C:G	R156P	0.999
4:4459446:C:G	R93P	0.999
4:4471675:A:G	L67P	0.999
4:4471687:A:G	L63P	0.999
4:4541927:A:T	V13D	0.999
4:4541938:G:C	F9L	0.999
4:4541938:G:T	F9L	0.999
4:4541939:A:G	F9S	0.999
4:4541940:A:G	F9L	0.999
4:4420059:A:G	L328P	0.998
4:4420092:A:G	L317P	0.998
4:4420871:A:C	I302R	0.998
4:4420883:C:T	G298D	0.998
4:4420905:C:G	A291P	0.998
4:4459383:A:G	L114P	0.998
4:4459426:C:G	A100P	0.998
4:4541948:G:A	T6M	0.998
4:4541955:C:G	D4H	0.998
4:4420048:A:G	W332R	0.997
4:4420048:A:T	W332R	0.997
4:4420053:A:T	L330H	0.997
4:4420077:A:T	M322K	0.997
4:4420092:A:T	L317H	0.997
4:4423528:A:T	V274D	0.997

dbSNP variants (sampled 300 via entrez): RS1000012244 (4:4448318 T>C), RS1000021155 (4:4422380 A>G), RS1000029740 (4:4484951 A>G), RS1000030408 (4:4530371 T>A), RS10000397 (4:4445337 T>A,C,G), RS1000050608 (4:4476474 A>G), RS1000064047 (4:4453053 T>C,G), RS1000100273 (4:4493403 A>C), RS1000152815 (4:4493052 T>C), RS1000156530 (4:4454588 T>C), RS10001717 (4:4461686 G>A), RS1000182384 (4:4485625 A>G), RS10002151 (4:4447901 C>A,T), RS1000225415 (4:4456167 C>T), RS1000236762 (4:4454367 A>G)

Disease associations

OMIM: gene MIM:606046 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002035_1	Congenital heart disease	3.000000e-10
GCST005038_36	Allergic disease (asthma, hay fever or eczema)	1.000000e-10
GCST012015_2	Chronic rhinosinusitis	2.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067125 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.74	Kd	18.4	nM	CHEMBL5653589
7.74	ED50	18.4	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149520: Binding affinity to human STX18 incubated for 45 mins by Kinobead based pull down assay	kd	0.0184	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	2
FR900359	decreases phosphorylation	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
ferrous chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Fulvestrant	affects cotreatment, increases methylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	decreases expression	1
Tamoxifen	decreases expression	1
Valproic Acid	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652562	Binding	Binding affinity to human STX18 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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