STX4

Summary

STX4 (syntaxin 4, HGNC:11439) is a protein-coding gene on chromosome 16p11.2, encoding Syntaxin-4 (Q12846). Plasma membrane t-SNARE that mediates docking of transport vesicles. It is a selective cancer dependency (DepMap: 30.4% of cell lines).

Enables sphingomyelin phosphodiesterase activator activity. Involved in several processes, including cornified envelope assembly; positive regulation of immune effector process; and positive regulation of protein localization. Located in several cellular components, including basolateral plasma membrane; cytoplasmic vesicle; and lamellipodium. Part of SNARE complex. Is active in glutamatergic synapse and postsynapse. Implicated in autosomal recessive nonsyndromic deafness.

Source: NCBI Gene 6810 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hearing loss, autosomal recessive 123 (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 37 total
• Phenotypes (HPO): 5
• Cancer dependency (DepMap): dependent in 30.4% of screened cell lines
• MANE Select transcript: NM_004604

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11439
Approved symbol	STX4
Name	syntaxin 4
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	p35-2
Ensembl gene	ENSG00000103496
Ensembl biotype	protein_coding
OMIM	186591
Entrez	6810

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 protein_coding, 8 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000313843, ENST00000394998, ENST00000457779, ENST00000460668, ENST00000461455, ENST00000468583, ENST00000475862, ENST00000478150, ENST00000486660, ENST00000487411, ENST00000493902, ENST00000496977, ENST00000503629, ENST00000564368, ENST00000565483, ENST00000566353, ENST00000613541, ENST00000851823, ENST00000851824, ENST00000851825, ENST00000927499, ENST00000950664

RefSeq mRNA: 3 — MANE Select: NM_004604 NM_001272095, NM_001272096, NM_004604

CCDS: CCDS10700, CCDS61916

Canonical transcript exons

ENST00000313843 — 11 exons

Exon	Start	End
ENSE00001953955	31033558	31033835
ENSE00003469279	31034013	31034114
ENSE00003502972	31034970	31035040
ENSE00003540616	31039723	31039818
ENSE00003553170	31034226	31034325
ENSE00003573048	31038114	31038190
ENSE00003599936	31034462	31034536
ENSE00003638418	31037926	31038034
ENSE00003659983	31039541	31039651
ENSE00003665148	31038510	31038647
ENSE00003841841	31039912	31040164

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7672 / max 605.2777, expressed in 1792 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153759	12.5560	1787
153758	2.4700	244
153760	0.3527	140
153761	0.2369	81
153762	0.1516	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	97.57	gold quality
granulocyte	CL:0000094	97.39	gold quality
skin of leg	UBERON:0001511	97.03	gold quality
skin of abdomen	UBERON:0001416	96.88	gold quality
upper lobe of left lung	UBERON:0008952	96.45	gold quality
omental fat pad	UBERON:0010414	96.34	gold quality
peritoneum	UBERON:0002358	96.33	gold quality
endocervix	UBERON:0000458	96.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.23	gold quality
lower esophagus mucosa	UBERON:0035834	96.17	gold quality
left uterine tube	UBERON:0001303	96.09	gold quality
right lung	UBERON:0002167	96.09	gold quality
sural nerve	UBERON:0015488	96.08	gold quality
spinal cord	UBERON:0002240	96.00	gold quality
left adrenal gland cortex	UBERON:0035825	95.98	gold quality
ectocervix	UBERON:0012249	95.97	gold quality
nerve	UBERON:0001021	95.96	gold quality
tibial nerve	UBERON:0001323	95.96	gold quality
apex of heart	UBERON:0002098	95.90	gold quality
spleen	UBERON:0002106	95.84	gold quality
right ovary	UBERON:0002118	95.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.79	gold quality
mucosa of stomach	UBERON:0001199	95.77	gold quality
transverse colon	UBERON:0001157	95.70	gold quality
left adrenal gland	UBERON:0001234	95.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.67	gold quality
right adrenal gland cortex	UBERON:0035827	95.67	gold quality
right adrenal gland	UBERON:0001233	95.62	gold quality
mucosa of transverse colon	UBERON:0004991	95.54	gold quality
upper lobe of lung	UBERON:0008948	95.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	17.80
E-GEOD-75367	no	115.15
E-MTAB-6524	no	103.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting STX4, 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-4775	99.98	75.00	6394
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-5189-3P	97.52	66.33	487
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-6765-5P	94.51	62.65	164
HSA-MIR-6789-5P	94.05	66.19	285

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 30.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 25)

• Syntaxin 4 and Synip (syntaxin 4 interacting protein) regulate insulin secretion in the pancreatic beta HC-9 cells (PMID:12855681)
• syntaxin 4 is involved in the intracellular transport of MT1-MMP toward the plasma membrane (PMID:15351710)
• Stx4 defines an exocytic zone that directs membrane fusion for postsynaptic plasticity, revealing a novel specialization for local membrane traffic in dendritic spines. (PMID:20434989)
• dysferlin and syntaxin-4 similarly transit a common endosomal pathway in skeletal muscle cells. (PMID:20595382)
• Syntaxin 4 is required for acid sphingomyelinase activity and apoptotic function. (PMID:20956541)
• Stx4 is an essential postsynaptic component for synaptic plasticity in hippocampal neurons. (PMID:20959521)
• Syntaxin 4 activation and insulin release in the absence of the glucose stimulus, consistent with nitrosative stress and dysfunctional exocytosis (PMID:21393240)
• siRNA knockdown (KD) of syntaxins 3 and 4 in HeLa cells reduced cell surface expression of alpha5beta1 and alpha3beta1 integrins (PMID:21720706)
• These results revealed, for the first time, the extracellular role of syntaxin4 and shed light on the division of the extracellular effects exerted by epimorphin and syntaxin4 on keratinocyte cornification. (PMID:22226963)
• Syntaxin-4 plays a vital role in exocytosis of IgE from plasma cells. Knock-down of syntaxin-4, but not VAMP3 dramatically reduced IgE secretion from U266 plasma cells causing it to accumulate in the cell. (PMID:24055037)
• STX4 is implicated in the antibody secretion. (PMID:24146186)
• upregulation of Syntaxin 4 is sufficient to significantly improve insulin secretory function to human type 2 diabetes islets retaining low levels of residual function (PMID:24552216)
• Increased level of SNAP23-Syntaxin4-VAMP7 interaction correlates with decreased Syntaxin4 phosphorylation and trafficking of MT1-MMP to invadopodia during cellular invasion. (PMID:24807903)
• When the expression of STX4 mRNA was inhibited with short or small interfering, or silencing, RNA in macrophages, the survival of Brucella melitensis was significantly reduced. (PMID:25673907)
• Syntaxin-4 has a role in mediating exocytosis of pre-docked and newcomer insulin granules underlying biphasic glucose-stimulated insulin secretion in human pancreatic beta cells (PMID:25762204)
• The analysis revealed three candidate genes GSK3B, PTPN1, STX4 that are differentially expressed in study subjects. GSK3B was highly significant in Ps-T2D (P=0.00018, FR=-26.6), followed by Ps (P=0.0028, FR=-14.5) and T2D groups (P=0.032, FR=-5.9). PTPN1 showed significant association only with PS-T2D (P=0.00027, FR=-8.5). STX4 showed significant association with both Ps (P=0.0002, FR=-20) and Ps-T2D (P=0.0016, FR=-11.2). (PMID:27530212)
• The authors found that activation of dendritic cells by bacterial lipopolysaccharide leads to increased Forster resonance energy transfer-fluorescence of fluorescently labeled syntaxin 4 with VAMP3 specifically at the plasma membrane, indicating increased SNARE complex formation, whereas FRET with other tested SNAREs was unaltered. (PMID:28524818)
• Confocal immunofluorescence microscopy revealed a colocalization of syntaxin 4 with a MVB-specific marker, exosomes and hepatitis C virus (HCV) core, which suggests a fraction of syntaxin 4 is associated with exosomes loaded with HCV. Altogether, it is assumed that syntaxin 4 is a novel essential cellular factor for the release of HCV. (PMID:28624237)
• Data suggest MUNC18C is required for STX4-mediated invadopodium formation and tumor invasion of extracellular matrix; N-terminal STX4 fragment binds to MUNC18C and inhibits interactions of STX4 with synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2). Fibrosarcoma/adenocarcinoma cell lines were used in these studies. (MUNC18C = syntaxin binding protein MUNC18C; STX4 = syntaxin 4) (PMID:28798239)
• 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)
• Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition. (PMID:29896202)
• Up-regulation expression and prognostic significance of Syntaxin4 in kidney renal clear cell carcinoma. (PMID:34482824)
• Syntaxin 4 is essential for hearing in human and zebrafish. (PMID:36355422)
• Syntaxin-4 and SNAP23 are involved in neutrophil degranulation, but not in the release of mitochondrial DNA during NET formation. (PMID:37885878)
• Phosphorylation of Syntaxin 4 by the Insulin Receptor Drives Exocytic SNARE Complex Formation to Deliver GLUT4 to the Cell Surface. (PMID:38136609)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	stx4	ENSDARG00000052518
mus_musculus	Stx4a	ENSMUSG00000030805
rattus_norvegicus	Stx4	ENSRNOG00000019302
drosophila_melanogaster	Syx1A	FBGN0013343
caenorhabditis_elegans		WBGENE00006798

Paralogs (12): STX7 (ENSG00000079950), STX1B (ENSG00000099365), STX1A (ENSG00000106089), STX2 (ENSG00000111450), STX12 (ENSG00000117758), STX16 (ENSG00000124222), STX11 (ENSG00000135604), STX17 (ENSG00000136874), STX5 (ENSG00000162236), STX3 (ENSG00000166900), TSNARE1 (ENSG00000171045), STX19 (ENSG00000178750)

Protein

Protein identifiers

Syntaxin-4 — Q12846 (reviewed: Q12846)

Alternative names: Renal carcinoma antigen NY-REN-31

All UniProt accessions (4): Q12846, A0A087WWW0, C9JFM5, H3BMK2

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane t-SNARE that mediates docking of transport vesicles. Necessary for the translocation of SLC2A4 from intracellular vesicles to the plasma membrane. In neurons, recruited at neurite tips to membrane domains rich in the phospholipid 1-oleoyl-2-palmitoyl-PC (OPPC) which promotes neurite tip surface expression of the dopamine transporter SLC6A3/DAT by facilitating fusion of SLC6A3-containing transport vesicles with the plasma membrane. Together with STXB3 and VAMP2, may also play a role in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes and in docking of synaptic vesicles at presynaptic active zones. Required for normal hearing.

Subunit / interactions. Component of the SNARE complex composed of STX4, SNAP23 and VAMP7 that interacts with SYT7 during lysosomal exocytosis. Found in a complex with VAMP8 and SNAP23. Detected in a complex with SNAP23 and STXBP4. Interacts with VAMP2. Interacts with SNAP23 and SNAPIN. Interacts with LLGL1. Interacts (via C-terminus) with CENPF. Interacts with DOC2B. Interacts with STXBP6. Interacts with STXBP3; excludes interaction with DOC2B and SNAP25. Interacts with STXBP4; excludes interaction with VAMP2. Interacts with STXBP5L. Interacts with FER1L6.

Subcellular location. Cell membrane. Cell projection. Neuron projection. Stereocilium. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed in neutrophils and neutrophil-differentiated HL-60 cells. Expression in neutrophils increases with differentiation.

Disease relevance. Deafness, autosomal recessive, 123 (DFNB123) [MIM:620745] A form of non-syndromic deafness characterized by bilateral, severe to profound sensorineural hearing loss with onset in the first decade of life. Sensorineural hearing loss results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the syntaxin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q12846-1	1	yes
Q12846-2	2

RefSeq proteins (3): NP_001259024, NP_001259025, NP_004595* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000727	T_SNARE_dom	Domain
IPR006011	Syntaxin_N	Domain
IPR006012	Syntaxin/epimorphin_CS	Conserved_site
IPR010989	SNARE	Homologous_superfamily
IPR045242	Syntaxin	Family

Pfam: PF00804, PF05739

UniProt features (20 total): modified residue 7, topological domain 2, sequence conflict 2, region of interest 2, chain 1, splice variant 1, transmembrane region 1, domain 1, coiled-coil region 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12846-F1	78.38	0.39

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 (1): 290 (required for neurite tip localization)

Post-translational modifications (7): 14, 15, 31, 36, 117, 208, 248

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-114516	Disinhibition of SNARE formation
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-199992	trans-Golgi Network Vesicle Budding
R-HSA-449836	Other interleukin signaling
R-HSA-109582	Hemostasis
R-HSA-1236975	Antigen processing-Cross presentation
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-449147	Signaling by Interleukins
R-HSA-5653656	Vesicle-mediated transport
R-HSA-76002	Platelet activation, signaling and aggregation
R-HSA-76005	Response to elevated platelet cytosolic Ca2+
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 414 (showing top): RNGTGGGC_UNKNOWN, CREL_01, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, KAAB_FAILED_HEART_ATRIUM_DN, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOBP_MEMBRANE_BIOGENESIS, GOCC_VACUOLAR_MEMBRANE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOCC_SECRETORY_GRANULE, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_DEGRANULATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_VESICLE_ORGANIZATION, GOBP_INSULIN_SECRETION

GO Biological Process (28): positive regulation of immunoglobulin production (GO:0002639), neurotransmitter transport (GO:0006836), intracellular protein transport (GO:0006886), exocytosis (GO:0006887), vesicle fusion (GO:0006906), sensory perception of sound (GO:0007605), positive regulation of cell population proliferation (GO:0008284), regulation of exocytosis (GO:0017157), positive regulation of cell migration (GO:0030335), protein localization to cell surface (GO:0034394), cellular response to oxidative stress (GO:0034599), SNARE complex assembly (GO:0035493), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), positive regulation of catalytic activity (GO:0043085), positive regulation of eosinophil degranulation (GO:0043311), positive regulation of cell adhesion (GO:0045785), obsolete vesicle docking (GO:0048278), organelle fusion (GO:0048284), positive regulation of chemotaxis (GO:0050921), long-term synaptic potentiation (GO:0060291), cellular response to type II interferon (GO:0071346), regulation of postsynaptic membrane neurotransmitter receptor levels (GO:0099072), regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902041), positive regulation of protein localization to plasma membrane (GO:1903078), cornified envelope assembly (GO:1903575), positive regulation of protein localization to cell surface (GO:2000010), vesicle-mediated transport (GO:0016192), membrane organization (GO:0061024)

GO Molecular Function (4): SNARE binding (GO:0000149), SNAP receptor activity (GO:0005484), sphingomyelin phosphodiesterase activator activity (GO:0016230), protein binding (GO:0005515)

GO Cellular Component (31): storage vacuole (GO:0000322), obsolete extracellular space (GO:0005615), endosome (GO:0005768), vacuole (GO:0005773), trans-Golgi network (GO:0005802), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), endomembrane system (GO:0012505), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), lamellipodium (GO:0030027), phagocytic vesicle membrane (GO:0030670), SNARE complex (GO:0031201), stereocilium (GO:0032420), neuron projection membrane (GO:0032589), myelin sheath adaxonal region (GO:0035749), somatodendritic compartment (GO:0036477), specific granule (GO:0042581), dendritic spine (GO:0043197), lateral loop (GO:0043219), synapse (GO:0045202), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), Schaffer collateral - CA1 synapse (GO:0098685), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), cell projection (GO:0042995), neuron projection (GO:0043005), phagocytic vesicle (GO:0045335)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Membrane Trafficking	2
Immune System	2
Response to elevated platelet cytosolic Ca2+	1
Antigen processing-Cross presentation	1
Signaling by Interleukins	1
Class I MHC mediated antigen processing & presentation	1
Vesicle-mediated transport	1
Cytokine Signaling in Immune system	1
Hemostasis	1
Platelet activation, signaling and aggregation	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	3
intracellular protein localization	2
vesicle-mediated transport	2
positive regulation of cellular process	2
vacuole	2
neuron projection	2
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
transport	1
protein transport	1
intracellular transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
vesicle organization	1
organelle membrane fusion	1
sensory perception of mechanical stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
response to oxidative stress	1
cellular response to chemical stress	1
vesicle fusion	1
protein-containing complex assembly	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
catalytic activity	1
positive regulation of molecular function	1
regulation of catalytic activity	1
positive regulation of myeloid leukocyte mediated immunity	1
positive regulation of leukocyte degranulation	1
eosinophil degranulation	1
regulation of eosinophil degranulation	1

Protein interactions and networks

STRING

1627 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STX4	VAMP3	Q15836	999
STX4	SNAP23	O00161	999
STX4	VAMP7	P51809	999
STX4	VAMP8	Q9BV40	999
STX4	STXBP3	O00186	999
STX4	VAMP2	P19065	999
STX4	SEC22B	O75396	990
STX4	STXBP4	Q6ZWJ1	955
STX4	SYT7	O43581	953
STX4	SNAP25	P13795	930
STX4	STX6	O43752	913
STX4	TXLNG	Q9NUQ3	904
STX4	STX8	Q9UNK0	863
STX4	VAMP1	P23763	858
STX4	STXBP6	Q8NFX7	857

IntAct

333 interactions, top by confidence:

A	B	Type	Score
STX4	VAMP3	psi-mi:“MI:0915”(physical association)	0.880
VAMP3	STX4	psi-mi:“MI:0915”(physical association)	0.880
STX4	STX6	psi-mi:“MI:0915”(physical association)	0.870
STX4	STX3	psi-mi:“MI:0915”(physical association)	0.870
STX12	STX4	psi-mi:“MI:0915”(physical association)	0.870
STX4	STX12	psi-mi:“MI:0915”(physical association)	0.870
STX3	STX4	psi-mi:“MI:0915”(physical association)	0.870
STX6	STX4	psi-mi:“MI:0915”(physical association)	0.870
TSPAN15	ADAM10	psi-mi:“MI:0914”(association)	0.840
STX7	STX4	psi-mi:“MI:0915”(physical association)	0.830
STX4	VAMP4	psi-mi:“MI:0915”(physical association)	0.830
VAMP5	STX4	psi-mi:“MI:0915”(physical association)	0.830
VAMP4	STX4	psi-mi:“MI:0915”(physical association)	0.830
STX4	STX7	psi-mi:“MI:0915”(physical association)	0.830

BioGRID (579): STX4 (Two-hybrid), STX4 (Two-hybrid), STX4 (Two-hybrid), STX5 (Two-hybrid), VAMP1 (Two-hybrid), VAMP2 (Two-hybrid), STX7 (Two-hybrid), VAMP4 (Two-hybrid), STX16 (Two-hybrid), VAMP3 (Two-hybrid), STX8 (Two-hybrid), GOSR2 (Two-hybrid), STX6 (Two-hybrid), BET1 (Two-hybrid), VTI1B (Two-hybrid)

ESM2 similar proteins: A8WVD0, O15400, O16000, O35526, O70257, O70439, P32850, P32851, P32856, P32867, P39926, P50279, P61264, P61265, P61266, P61267, P61268, P70452, Q00262, Q08849, Q08850, Q0VCI2, Q12846, Q13277, Q16623, Q16932, Q20024, Q24547, Q3SWZ3, Q3ZBT5, Q42374, Q59YF0, Q5R4L2, Q5R602, Q5TX47, Q64704, Q7XIE2, Q8N4C7, Q8R1Q0, Q8VZU2

Diamond homologs: A8WVD0, O16000, O35526, O75558, P32850, P32851, P32854, P32856, P50279, P61264, P61265, P61266, P61267, P61268, P70452, P91409, Q00262, Q08849, Q08850, Q12846, Q13277, Q16623, Q16932, Q20797, Q24547, Q3SWZ3, Q5R4L2, Q5TX47, Q64704, Q6F3B4, Q8R1Q0, Q9D3G5, G3V7P1, O14662, O15400, O64791, O65359, O70257, O70439, O94651

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
STXBP4	“up-regulates activity”	STX4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	5	48.5×	2e-06
Intra-Golgi traffic	7	37.1×	5e-08
Retrograde transport at the Trans-Golgi-Network	8	35.9×	1e-08
COPII-mediated vesicle transport	7	23.3×	8e-07
Intra-Golgi and retrograde Golgi-to-ER traffic	8	17.1×	8e-07
ER to Golgi Anterograde Transport	6	16.3×	5e-05
COPI-mediated anterograde transport	6	13.4×	1e-04
Transport to the Golgi and subsequent modification	6	12.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete vesicle docking	12	129.5×	2e-21
vesicle fusion	13	110.2×	7e-22
membrane fusion	6	52.7×	1e-07
retrograde transport, endosome to Golgi	6	17.4×	6e-05
exocytosis	8	17.1×	1e-06
intracellular protein transport	17	15.5×	7e-14
endoplasmic reticulum to Golgi vesicle-mediated transport	5	9.6×	4e-03
protein transport	10	6.2×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1501 predictions. Top by Δscore:

Variant	Effect	Δscore
16:31033594:G:T	donor_gain	1.0000
16:31034113:AGGTA:A	donor_loss	1.0000
16:31034114:GGTAA:G	donor_loss	1.0000
16:31034115:G:GC	donor_loss	1.0000
16:31034115:G:GG	donor_gain	1.0000
16:31034321:GGAGA:G	donor_gain	1.0000
16:31034322:GAGA:G	donor_gain	1.0000
16:31034322:GAGAG:G	donor_gain	1.0000
16:31034323:A:T	donor_gain	1.0000
16:31034324:GA:G	donor_gain	1.0000
16:31034326:G:GG	donor_gain	1.0000
16:31034535:GG:G	donor_gain	1.0000
16:31034535:GGGT:G	donor_loss	1.0000
16:31034536:GG:G	donor_gain	1.0000
16:31034536:GGT:G	donor_loss	1.0000
16:31034537:G:GG	donor_gain	1.0000
16:31034537:GTGAG:G	donor_loss	1.0000
16:31034968:A:AG	acceptor_gain	1.0000
16:31034969:G:GG	acceptor_gain	1.0000
16:31034969:GCC:G	acceptor_gain	1.0000
16:31034969:GCCAT:G	acceptor_gain	1.0000
16:31037923:TAG:T	acceptor_loss	1.0000
16:31037924:A:AG	acceptor_gain	1.0000
16:31037924:AGCAT:A	acceptor_gain	1.0000
16:31037925:G:GC	acceptor_gain	1.0000
16:31037925:GC:G	acceptor_gain	1.0000
16:31037925:GCA:G	acceptor_gain	1.0000
16:31037925:GCAT:G	acceptor_gain	1.0000
16:31037925:GCATG:G	acceptor_gain	1.0000
16:31038030:GATCA:G	donor_gain	1.0000

AlphaMissense

1963 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:31038026:T:C	L160P	0.998
16:31038179:T:C	F185L	0.998
16:31038181:T:A	F185L	0.998
16:31038181:T:G	F185L	0.998
16:31038583:T:C	L213P	0.998
16:31034531:T:C	L101P	0.997
16:31037993:G:C	R149P	0.997
16:31038011:G:C	R155P	0.997
16:31038180:T:G	F185C	0.997
16:31038604:T:C	L220P	0.997
16:31038627:G:C	A228P	0.997
16:31038562:G:C	R206P	0.996
16:31037936:T:C	L130P	0.995
16:31038615:T:C	F224L	0.995
16:31038617:C:A	F224L	0.995
16:31038617:C:G	F224L	0.995
16:31039557:G:C	R240P	0.995
16:31039622:G:C	A262P	0.994
16:31039580:T:C	S248P	0.993
16:31038180:T:C	F185S	0.992
16:31038540:G:C	A199P	0.992
16:31038625:T:C	L227P	0.992
16:31034477:T:C	L83P	0.991
16:31034489:G:C	R87P	0.991
16:31038565:A:C	H207P	0.991
16:31039601:G:T	G255W	0.990
16:31039744:T:C	C279R	0.990
16:31037938:T:C	S131P	0.989
16:31038558:G:C	A205P	0.989
16:31038574:T:C	I210T	0.989

dbSNP variants (sampled 300 via entrez): RS1000369536 (16:31037643 A>C,G), RS1000586302 (16:31033152 G>A), RS1000623305 (16:31032848 C>A), RS1000760768 (16:31032718 G>A), RS1000816221 (16:31032408 T>C), RS1001267287 (16:31031510 C>A,T), RS1001322275 (16:31038551 G>A,C), RS1001363633 (16:31037452 G>C), RS1001374257 (16:31038365 C>A,G), RS1001833010 (16:31037114 A>G), RS1002438998 (16:31038362 C>T), RS1002984032 (16:31032841 G>A), RS1002986357 (16:31040113 T>C), RS1003440192 (16:31035880 C>T), RS1003724936 (16:31034192 T>C)

Disease associations

OMIM: gene MIM:186591 | disease phenotypes: MIM:620745

GenCC curated gene-disease

Disease	Classification	Inheritance
hearing loss, autosomal recessive 123	Moderate	Autosomal recessive

Mondo (2): sensorineural hearing loss disorder (MONDO:0020678), hearing loss, autosomal recessive 123 (MONDO:0958277)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000256	Macrocephaly
HP:0000407	Sensorineural hearing impairment
HP:0001249	Intellectual disability
HP:0001751	Abnormal vestibular function

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003791_9	Response to metformin (IC50)	9.000000e-06
GCST010244_135	Triglyceride levels	7.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10871454	Dosage	3	warfarin
rs10871454	Dosage	3	phenprocoumon

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10871454	STX4	3	2.50	2	warfarin;phenprocoumon

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Etoposide	increases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Phenobarbital	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Sodium Chloride	affects cotreatment, affects localization, decreases expression, increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Thimerosal	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TR13	HAP1 STX4 (-) 1	Cancer cell line	Male
CVCL_TR14	HAP1 STX4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study
NCT02698787	Not specified	COMPLETED	Fundamental Asynchronous Stimulus Timing Sound Coding Study
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry