STX3

Summary

STX3 (syntaxin 3, HGNC:11438) is a protein-coding gene on chromosome 11q12.1, encoding Syntaxin-3 (Q13277). Potentially involved in docking of synaptic vesicles at presynaptic active zones.

The gene is a member of the syntaxin family. The encoded protein is targeted to the apical membrane of epithelial cells where it forms clusters and is important in establishing and maintaining polarity necessary for protein trafficking involving vesicle fusion and exocytosis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 6809 — RefSeq curated summary.

At a glance

• Gene–disease (curated): retinal dystrophy and microvillus inclusion disease (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 240 total — 11 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_004177

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11438
Approved symbol	STX3
Name	syntaxin 3
Location	11q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166900
Ensembl biotype	protein_coding
OMIM	600876
Entrez	6809

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 13 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000337979, ENST00000528805, ENST00000529177, ENST00000530221, ENST00000530498, ENST00000533637, ENST00000633708, ENST00000641815, ENST00000887353, ENST00000887354, ENST00000887355, ENST00000887356, ENST00000928727, ENST00000928728, ENST00000955060

RefSeq mRNA: 2 — MANE Select: NM_004177 NM_001178040, NM_004177

CCDS: CCDS53637, CCDS7975

Canonical transcript exons

ENST00000337979 — 11 exons

Exon	Start	End
ENSE00001107601	59795372	59795482
ENSE00001170551	59797283	59797396
ENSE00002142855	59800855	59805878
ENSE00003468330	59793380	59793514
ENSE00003480029	59792107	59792215
ENSE00003515243	59793099	59793172
ENSE00003625903	59788873	59788947
ENSE00003642980	59787037	59787136
ENSE00003674811	59790519	59790586
ENSE00004283334	59773211	59773294
ENSE00004283335	59755376	59755635

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 95.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4181 / max 905.9944, expressed in 1778 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114417	13.2469	1723
114419	3.1520	1138
114418	1.9658	972
114420	1.0730	190
114416	0.7726	477
114415	0.6104	250
114422	0.2922	127
114414	0.1356	41
114410	0.0629	6
114409	0.0617	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	95.84	gold quality
right lung	UBERON:0002167	95.63	gold quality
blood	UBERON:0000178	95.61	gold quality
islet of Langerhans	UBERON:0000006	94.96	gold quality
upper lobe of left lung	UBERON:0008952	94.76	gold quality
duodenum	UBERON:0002114	94.65	gold quality
upper lobe of lung	UBERON:0008948	94.42	gold quality
gall bladder	UBERON:0002110	94.32	gold quality
jejunal mucosa	UBERON:0000399	94.01	gold quality
colonic mucosa	UBERON:0000317	93.76	gold quality
metanephros cortex	UBERON:0010533	93.71	gold quality
secondary oocyte	CL:0000655	93.62	gold quality
oocyte	CL:0000023	93.50	gold quality
mucosa of transverse colon	UBERON:0004991	93.47	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.38	gold quality
monocyte	CL:0000576	93.19	gold quality
endometrium epithelium	UBERON:0004811	92.81	gold quality
mononuclear cell	CL:0000842	92.72	gold quality
leukocyte	CL:0000738	92.62	gold quality
transverse colon	UBERON:0001157	92.06	gold quality
bone marrow	UBERON:0002371	91.92	gold quality
adult mammalian kidney	UBERON:0000082	91.89	gold quality
pancreas	UBERON:0001264	91.80	gold quality
body of pancreas	UBERON:0001150	91.79	gold quality
body of stomach	UBERON:0001161	91.62	gold quality
minor salivary gland	UBERON:0001830	91.37	gold quality
right adrenal gland cortex	UBERON:0035827	91.11	gold quality
body of uterus	UBERON:0009853	90.74	gold quality
lung	UBERON:0002048	90.65	gold quality
right adrenal gland	UBERON:0001233	90.64	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	15.25
E-MTAB-9067	yes	12.41
E-CURD-112	yes	11.68
E-ANND-3	yes	10.75
E-GEOD-135922	yes	8.14
E-MTAB-6524	no	89.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

160 targeting STX3, 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-3120-5P	100.00	65.56	965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-150-5P	99.99	66.69	1976
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-1297	99.91	73.41	3162

Literature-anchored findings (GeneRIF, showing 22)

• Munc18b binds to syntaxins 1A, 2, and 3 and regulates vesicle transport to the apical plasma membrane (PMID:12198139)
• Data show that the BCG phagosome is relatively depleted in LAMP-2, NPC1, flotillin-1, vATPase, and syntaxin 3. (PMID:19815536)
• Munc18b is functionally coupled to the assembly of exocytic SNARE complexes and increases exocytosis by interacting with the N-peptide and closed-conformation C-terminus of Stx3, thereby neutralizing the secretion-inhibitory effect of this SNARE. (PMID:20695848)
• syntaxin 3 interacts with CFTR in vivo. (PMID:20844248)
• These results demonstrate a function for STX3 in human cytomegalovirus morphogenesis, and unravel a new role for this SNARE protein in late endosomes/lysosomes compartments. (PMID:21371234)
• siRNA knockdown (KD) of syntaxins 3 and 4 in HeLa cells reduced cell surface expression of alpha5beta1 and alpha3beta1 integrins (PMID:21720706)
• STX-3 and SNAP-23 are crucial for the release of all chemokines in mature human mast cells (PMID:21981832)
• In insulin secretion, SYN-3 plays a role in the mediation of newcomer SG exocytosis and SG-SG fusion that contributes to biphasic GSIS. (PMID:23132338)
• syntaxin3 has a latent prosurvival function and is involved in maintenance of homeostasis in epidermal keratinocytes (PMID:24171760)
• loss of STX3 function causes variant microvillus inclusion disease (PMID:24726755)
• we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability. (PMID:25358429)
• the secretion of IL-1alpha, IL-1beta, IL-12b, and CCL4 occurs during gelatinase degranulation, a process controlled by STX3. (PMID:25548252)
• hcmv-miR-US33-5p-mediated inhibition of HCMV DNA synthesis and of viral replication are specifically mediated by down-regulation of STX3 expression. (PMID:25583387)
• The results showed that there was reduction in aggregation propensity of syntaxin-3 with point mutation at Val286. (PMID:25630102)
• Rab11a-knockdown cells displayed mislocalization of STX3 and the presentation of microvilli in the basolateral compartment (PMID:25673875)
• GLUT5 required an interaction cascade of Rab11, Myo5B, Slp4a, Munc18-2, and Vamp7 with Stx3. (PMID:26553929)
• mechanism study shows that STX3 binds to PTEN and increases PTEN ubiquitination and degradation, thus leading to activation of the PI3K-Akt-mTOR signaling. Therefore, STX3 promotes the growth of breast cancer cells by regulating the PTEN-PI3K-Akt-mTOR signaling. (PMID:29408595)
• Stx3S is differentially expressed in normal human tissues, during epithelial cell polarization, and in breast cancer versus normal breast tissue. Inhibition of endogenous Stx3S expression alters the expression of cancer-associated genes and promotes cell proliferation. (PMID:29475951)
• Syntaxin-3 is a novel Weibel-Palade body-associated SNARE protein that controls WPB von Willebrand factor exocytosis. (PMID:29880488)
• Interaction networks of Weibel-Palade body regulators syntaxin-3 and syntaxin binding protein 5 in endothelial cells. (PMID:31201948)
• Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects. (PMID:33974130)
• Increased STX3 transcript and protein levels were associated with poor prognosis in two independent cohorts of esophageal squamous cell carcinoma patients. (PMID:38014487)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	stx3b	ENSDARG00000001880
danio_rerio	stx3a	ENSDARG00000051981
mus_musculus	Stx3	ENSMUSG00000041488
rattus_norvegicus	Stx3	ENSRNOG00000021013
drosophila_melanogaster	Syx1A	FBGN0013343
caenorhabditis_elegans		WBGENE00006798

Paralogs (12): STX7 (ENSG00000079950), STX1B (ENSG00000099365), STX4 (ENSG00000103496), STX1A (ENSG00000106089), STX2 (ENSG00000111450), STX12 (ENSG00000117758), STX16 (ENSG00000124222), STX11 (ENSG00000135604), STX17 (ENSG00000136874), STX5 (ENSG00000162236), TSNARE1 (ENSG00000171045), STX19 (ENSG00000178750)

Protein

Protein identifiers

Syntaxin-3 — Q13277 (reviewed: Q13277)

All UniProt accessions (7): Q13277, A0A0C4DGE4, A0A0J9YW33, A0A286YF28, E9PN33, E9PQJ8, Q53YE2

UniProt curated annotations — full annotation on UniProt →

Function. Potentially involved in docking of synaptic vesicles at presynaptic active zones. Apical receptor involved in membrane fusion of apical vesicles. Essential for survival of retinal photoreceetors. Functions as a regulator of gene expression.

Subunit / interactions. Interacts with REEP6. Interacts with PRPH2 in rod and cone photoreceptors. Interacts with ROM1. Interacts with SNAP25. Interacts with VAMP2. Interacts with IPO5.

Subcellular location. Apical cell membrane Nucleus.

Tissue specificity. Expressed in small intestine, kidney, pancreas, placenta as well as in retina. Weaker expression in lung, liver and heart. Not expressed in brain and skeletal muscle. Expressed only in the retina. Ubiquitously expressed.

Disease relevance. Retinal dystrophy and microvillus inclusion disease (RDMVID) [MIM:619446] An autosomal recessive disease characterized by early-onset, severe retinal dystrophy associated with intractable congenital diarrhea. Intestinal biopsies show loss of microvilli, microvillus inclusions, and accumulation of subapical vesicles in villus enterocytes. The disease is caused by variants affecting the gene represented in this entry. Diarrhea 12, with microvillus atrophy (DIAR12) [MIM:619445] An autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea, resulting in severe dehydration and metabolic acidosis. DIAR12 can be diagnosed based on variable loss of brush-border microvilli, microvillus inclusions, and accumulation of subapical vesicles in villus enterocytes. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the syntaxin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13277-1	A	yes
Q13277-2	B
Q13277-3	3, S, Non-membrane-anchored form

RefSeq proteins (2): NP_001171511, NP_004168* (*=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
IPR031186	STX3_SNARE	Domain
IPR045242	Syntaxin	Family

Pfam: PF00804, PF05739

UniProt features (17 total): sequence variant 5, sequence conflict 4, topological domain 2, splice variant 2, chain 1, transmembrane region 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13277-F1	83.60	0.47

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-449836	Other interleukin signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-449147	Signaling by Interleukins

MSigDB gene sets: 399 (showing top): ELVIDGE_HYPOXIA_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MEMBRANE_FUSION, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_SURFACE, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (19): neurotransmitter transport (GO:0006836), intracellular protein transport (GO:0006886), vesicle fusion (GO:0006906), positive regulation of cell population proliferation (GO:0008284), regulation of gene expression (GO:0010468), neuron projection development (GO:0031175), positive regulation of cell adhesion (GO:0045785), obsolete vesicle docking (GO:0048278), positive regulation of chemotaxis (GO:0050921), long-term synaptic potentiation (GO:0060291), organelle membrane fusion (GO:0090174), exocytic insertion of neurotransmitter receptor to postsynaptic membrane (GO:0098967), vesicle-mediated transport in synapse (GO:0099003), positive regulation of protein localization to plasma membrane (GO:1903078), positive regulation of protein localization to cell surface (GO:2000010), exocytosis (GO:0006887), vesicle-mediated transport (GO:0016192), modulation of chemical synaptic transmission (GO:0050804), membrane fusion (GO:0061025)

GO Molecular Function (4): SNARE binding (GO:0000149), SNAP receptor activity (GO:0005484), arachidonate binding (GO:0050544), protein binding (GO:0005515)

GO Cellular Component (26): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), nucleus (GO:0005634), vacuole (GO:0005773), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), endomembrane system (GO:0012505), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), dendrite (GO:0030425), growth cone (GO:0030426), SNARE complex (GO:0031201), melanosome (GO:0042470), specific granule (GO:0042581), azurophil granule (GO:0042582), zymogen granule membrane (GO:0042589), neuron projection (GO:0043005), extracellular exosome (GO:0070062), Schaffer collateral - CA1 synapse (GO:0098685), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), membrane (GO:0016020), secretory granule (GO:0030141), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Interleukins	1
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
vesicle-mediated transport	3
synapse	3
transport	2
positive regulation of cellular process	2
membrane fusion	2
intracellular membrane-bounded organelle	2
cytoplasm	2
plasma membrane bounded cell projection	2
secretory granule	2
intracellular protein localization	1
protein transport	1
intracellular transport	1
vesicle organization	1
organelle membrane fusion	1
cell population proliferation	1
regulation of cell population proliferation	1
gene expression	1
regulation of macromolecule biosynthetic process	1
neuron development	1
plasma membrane bounded cell projection organization	1
cell adhesion	1
regulation of cell adhesion	1
chemotaxis	1
positive regulation of response to external stimulus	1
positive regulation of locomotion	1
regulation of chemotaxis	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
organelle fusion	1
exocytosis	1
neurotransmitter receptor transport to postsynaptic membrane	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
positive regulation of protein localization to cell periphery	1
positive regulation of protein localization to membrane	1
protein localization to cell surface	1
positive regulation of protein localization	1
regulation of protein localization to cell surface	1

Protein interactions and networks

STRING

1431 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STX3	SNAP23	O00161	999
STX3	VAMP8	Q9BV40	994
STX3	VAMP2	P19065	981
STX3	VAMP3	Q15836	961
STX3	VAMP7	P51809	953
STX3	SNAP29	O95721	935
STX3	SEC22B	O75396	918
STX3	STX6	O43752	909
STX3	SNAP25	P13795	903
STX3	STX8	Q9UNK0	886
STX3	STXBP3	O00186	811
STX3	SNAP47	Q5SQN1	797
STX3	TXLNA	P40222	795
STX3	VAMP1	P23763	792
STX3	STXBP2	Q15833	787

IntAct

171 interactions, top by confidence:

A	B	Type	Score
STX4	STX3	psi-mi:“MI:0915”(physical association)	0.870
NAPB	STX3	psi-mi:“MI:0915”(physical association)	0.870
STX3	NAPB	psi-mi:“MI:0915”(physical association)	0.870
STX3	STX4	psi-mi:“MI:0915”(physical association)	0.870
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
SNAP29	STX3	psi-mi:“MI:0915”(physical association)	0.740
STX5	STX3	psi-mi:“MI:0915”(physical association)	0.740
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CEP20	OFD1	psi-mi:“MI:0914”(association)	0.710
SNAP23	STX3	psi-mi:“MI:0915”(physical association)	0.660
STX3	SNAP23	psi-mi:“MI:0914”(association)	0.660
STX7	SNAP23	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
ZFYVE9	STX3	psi-mi:“MI:0403”(colocalization)	0.570
STX3	ZFYVE9	psi-mi:“MI:0407”(direct interaction)	0.570
STX3	ZFYVE9	psi-mi:“MI:0915”(physical association)	0.570
STX3	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
STX3	PGRMC2	psi-mi:“MI:0915”(physical association)	0.560
STX3	TMX2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (267): STX4 (Two-hybrid), NAPB (Two-hybrid), STX3 (Affinity Capture-MS), STX3 (Affinity Capture-Western), STXBP1 (Affinity Capture-Western), STX3 (Affinity Capture-MS), STX3 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), STXBP2 (Affinity Capture-MS), TXLNA (Affinity Capture-MS), GOSR1 (Affinity Capture-MS), SLMAP (Affinity Capture-MS), STX5 (Affinity Capture-MS), STXBP5 (Affinity Capture-MS), YKT6 (Affinity Capture-MS)

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

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 96 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	6	26.4×	1e-05
COPII-mediated vesicle transport	5	13.8×	6e-04
RHOG GTPase cycle	5	12.6×	6e-04
COPI-mediated anterograde transport	5	9.3×	1e-03
Intra-Golgi and retrograde Golgi-to-ER traffic	5	8.9×	1e-03
RHOA GTPase cycle	6	7.6×	1e-03
Vesicle-mediated transport	9	5.3×	6e-04
Membrane Trafficking	8	5.0×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
obsolete vesicle docking	8	73.8×	4e-11
vesicle fusion	8	58.0×	2e-10
exocytosis	7	12.8×	1e-04
intracellular protein transport	11	8.6×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	2
Uncertain significance	88
Likely benign	117
Benign	8

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1069027	NM_004177.5(STX3):c.739C>T (p.Arg247Ter)	Pathogenic
1070995	NM_004177.5(STX3):c.177_178del (p.Tyr60fs)	Pathogenic
1184254	NM_004177.5(STX3):c.372_373dup (p.Arg125fs)	Pathogenic
1184255	NM_004177.5(STX3):c.363_366delinsGA (p.Val122fs)	Pathogenic
1184256	NM_004177.5(STX3):c.115-2A>G	Pathogenic
2162523	NM_004177.5(STX3):c.442C>T (p.Arg148Ter)	Pathogenic
2703993	NM_004177.5(STX3):c.718_725del (p.Val240fs)	Pathogenic
2884036	NM_004177.5(STX3):c.424C>T (p.Arg142Ter)	Pathogenic
3244754	NC_000011.9:g.(?59523079)(59540787_?)del	Pathogenic
3655238	NM_004177.5(STX3):c.756del (p.Ala253fs)	Pathogenic
4730894	NM_004177.5(STX3):c.438del (p.Arg148fs)	Pathogenic
1506068	NM_004177.5(STX3):c.30+1G>T	Likely pathogenic
4718357	NM_004177.5(STX3):c.541-2A>G	Likely pathogenic

SpliceAI

2126 predictions. Top by Δscore:

Variant	Effect	Δscore
11:59755633:GCC:G	donor_gain	1.0000
11:59773199:T:TA	acceptor_gain	1.0000
11:59773206:T:A	acceptor_gain	1.0000
11:59773206:TGCA:T	acceptor_loss	1.0000
11:59773208:CA:C	acceptor_loss	1.0000
11:59773209:A:AG	acceptor_gain	1.0000
11:59773209:A:C	acceptor_loss	1.0000
11:59773210:G:GT	acceptor_gain	1.0000
11:59773210:GA:G	acceptor_gain	1.0000
11:59773210:GAA:G	acceptor_gain	1.0000
11:59773210:GAAGC:G	acceptor_gain	1.0000
11:59773292:GAG:G	donor_gain	1.0000
11:59773293:AG:A	donor_gain	1.0000
11:59773293:AGG:A	donor_loss	1.0000
11:59773294:GG:G	donor_gain	1.0000
11:59773295:G:GG	donor_gain	1.0000
11:59787132:GCCAA:G	donor_gain	1.0000
11:59787137:G:GG	donor_gain	1.0000
11:59788943:GAAGA:G	donor_gain	1.0000
11:59788946:GA:G	donor_gain	1.0000
11:59788948:G:GG	donor_gain	1.0000
11:59789042:G:GT	donor_gain	1.0000
11:59790515:TTA:T	acceptor_loss	1.0000
11:59790516:TAGGC:T	acceptor_loss	1.0000
11:59790517:A:AG	acceptor_gain	1.0000
11:59790517:AG:A	acceptor_gain	1.0000
11:59790518:G:A	acceptor_gain	1.0000
11:59790518:G:GT	acceptor_gain	1.0000
11:59790518:GGC:G	acceptor_gain	1.0000
11:59790518:GGCAT:G	acceptor_gain	1.0000

AlphaMissense

1933 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:59788942:T:C	L95P	0.999
11:59792174:G:C	R142P	0.999
11:59792201:G:C	R151P	0.999
11:59792207:T:C	L153P	0.999
11:59793450:T:C	L204P	0.999
11:59793471:T:C	L211P	0.999
11:59788920:G:C	A88P	0.998
11:59792192:G:C	R148P	0.998
11:59793161:T:C	F177L	0.998
11:59793163:C:A	F177L	0.998
11:59793163:C:G	F177L	0.998
11:59793429:G:C	R197P	0.998
11:59793482:T:C	F215L	0.998
11:59793484:T:A	F215L	0.998
11:59793484:T:G	F215L	0.998
11:59793494:G:C	A219P	0.998
11:59795432:G:C	A246P	0.998
11:59795453:G:C	A253P	0.998
11:59788933:G:C	R92P	0.997
11:59790573:T:C	I115T	0.997
11:59790576:G:C	R116P	0.997
11:59792117:T:C	L123P	0.997
11:59792158:G:C	A137P	0.997
11:59792180:G:C	R144P	0.997
11:59793162:T:C	F177S	0.997
11:59788888:T:C	L77P	0.996
11:59790570:G:C	R114P	0.996
11:59792170:T:C	F141L	0.996
11:59792172:C:A	F141L	0.996
11:59792172:C:G	F141L	0.996

dbSNP variants (sampled 300 via entrez): RS1000052273 (11:59774237 A>G,T), RS1000128950 (11:59764391 G>C), RS1000162081 (11:59791460 C>A,G,T), RS1000207020 (11:59805730 C>A), RS1000224861 (11:59799038 C>T), RS1000357133 (11:59778405 T>C), RS1000452053 (11:59778644 T>C), RS1000498907 (11:59789987 T>G), RS1000511807 (11:59760845 C>T), RS1000610697 (11:59763440 G>A,T), RS1000652747 (11:59783513 C>T), RS1000689350 (11:59776848 A>G), RS1000717485 (11:59784991 G>A,C), RS1000730486 (11:59806013 G>A), RS1000785381 (11:59777165 G>A)

Disease associations

OMIM: gene MIM:600876 | disease phenotypes: MIM:619445, MIM:619446

GenCC curated gene-disease

Disease	Classification	Inheritance
retinal dystrophy and microvillus inclusion disease	Strong	Autosomal recessive
diarrhea 12, with microvillus atrophy	Strong	Autosomal recessive
microvillus inclusion disease	Moderate	Autosomal recessive

Mondo (3): diarrhea 12, with microvillus atrophy (MONDO:0030335), retinal dystrophy and microvillus inclusion disease (MONDO:0859170), microvillus inclusion disease (MONDO:0009635)

Orphanet (0):

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000938	Osteopenia
HP:0000989	Pruritus
HP:0001141	Severely reduced visual acuity
HP:0001263	Global developmental delay
HP:0001522	Death in infancy
HP:0001942	Metabolic acidosis
HP:0001944	Dehydration
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002028	Chronic diarrhea
HP:0002110	Bronchiectasis
HP:0002783	Recurrent lower respiratory tract infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0003270	Abdominal distention
HP:0003623	Neonatal onset
HP:0005208	Secretory diarrhea
HP:0011106	Hypovolemia
HP:0011472	Abnormal small intestinal villus morphology
HP:0011473	Villous atrophy
HP:0011947	Respiratory tract infection
HP:0012211	Abnormal renal physiology
HP:0033994	Dependency on parenteral nutrition
HP:0033995	Microvillus inclusions
HP:0033996	Microvillar PAS-positive secretory granules

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008943_2	High chromosomal aberration frequency (chromosome type)	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009861	chromosome-type aberration frequency

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	increases expression, affects expression	2
mercuric bromide	increases expression, affects cotreatment	2
Arsenic	increases abundance, increases expression, affects methylation	2
Benzo(a)pyrene	increases expression	2
Cisplatin	affects expression, increases expression	2
Copper	affects binding, decreases expression, increases expression	2
Ozone	increases abundance, affects cotreatment, decreases expression, affects expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Potassium Dichromate	increases expression	2
Tunicamycin	increases expression	2
Valproic Acid	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
FR900359	decreases phosphorylation	1
selenomethylselenocysteine	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	increases expression, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
boron nitride	increases expression	1
sodium arsenite	increases expression	1
nickel chloride	increases expression	1
ferrous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
methacrylaldehyde	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06721871	PHASE2	RECRUITING	Ascending Doses of Crofelemer Powder for Oral Solution in Pediatric Microvillus Inclusion Disease (MVID)