STT3A

Summary

STT3A (STT3 oligosaccharyltransferase complex catalytic subunit A, HGNC:6172) is a protein-coding gene on chromosome 11q24.2, encoding Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A (P46977). Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nasce…. It is a selective cancer dependency (DepMap: 19.0% of cell lines).

The protein encoded by this gene is a catalytic subunit of the N-oligosaccharyltransferase (OST) complex, which functions in the endoplasmic reticulum to transfer glycan chains to asparagine residues of target proteins. A separate complex containing a similar catalytic subunit with an overlapping function also exists. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3703 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital disorder of glycosylation, type Iw, autosomal dominant (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 287 total — 4 likely-pathogenic
• Phenotypes (HPO): 44
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 19.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_152713

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6172
Approved symbol	STT3A
Name	STT3 oligosaccharyltransferase complex catalytic subunit A
Location	11q24.2
Locus type	gene with protein product
Status	Approved
Aliases	TMC, MGC9042, STT3-A
Ensembl gene	ENSG00000134910
Ensembl biotype	protein_coding
OMIM	601134
Entrez	3703

Gene structure

Transcript identifiers

Ensembl transcripts: 41 — 32 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000392708, ENST00000524639, ENST00000525431, ENST00000525652, ENST00000525946, ENST00000526213, ENST00000526364, ENST00000526726, ENST00000527456, ENST00000527606, ENST00000529196, ENST00000529886, ENST00000531001, ENST00000531491, ENST00000531599, ENST00000534472, ENST00000649491, ENST00000905685, ENST00000905686, ENST00000905687, ENST00000905688, ENST00000905689, ENST00000905690, ENST00000905691, ENST00000905692, ENST00000905693, ENST00000905694, ENST00000905695, ENST00000905696, ENST00000936150, ENST00000936151, ENST00000936152, ENST00000936153, ENST00000936154, ENST00000936155, ENST00000936156, ENST00000960416, ENST00000960417, ENST00000960418, ENST00000960419, ENST00000960420

RefSeq mRNA: 3 — MANE Select: NM_152713 NM_001278503, NM_001278504, NM_152713

CCDS: CCDS60998, CCDS8458

Canonical transcript exons

ENST00000392708 — 18 exons

Exon	Start	End
ENSE00000991169	125612989	125613177
ENSE00000991170	125614087	125614203
ENSE00001512833	125620772	125623091
ENSE00002196304	125592852	125592918
ENSE00003459288	125595881	125596003
ENSE00003469505	125614324	125614426
ENSE00003492299	125612592	125612747
ENSE00003511748	125602803	125602948
ENSE00003516584	125609434	125609589
ENSE00003532255	125597059	125597119
ENSE00003539604	125602303	125602424
ENSE00003540957	125608109	125608289
ENSE00003548597	125611428	125611519
ENSE00003562087	125620011	125620126
ENSE00003570150	125604157	125604247
ENSE00003592429	125606301	125606465
ENSE00003613374	125605629	125605735
ENSE00003633229	125618373	125618561

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 99.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 126.5720 / max 975.8683, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117447	115.7826	1825
117448	10.2236	1709
117445	0.4650	158
117446	0.0802	38
117449	0.0104	7
117450	0.0102	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.34	gold quality
body of pancreas	UBERON:0001150	98.62	gold quality
islet of Langerhans	UBERON:0000006	98.04	gold quality
endocervix	UBERON:0000458	97.82	gold quality
rectum	UBERON:0001052	97.81	gold quality
calcaneal tendon	UBERON:0003701	97.71	gold quality
adrenal tissue	UBERON:0018303	97.67	gold quality
right ovary	UBERON:0002118	97.56	gold quality
colonic epithelium	UBERON:0000397	97.50	gold quality
ventricular zone	UBERON:0003053	97.38	gold quality
left ovary	UBERON:0002119	97.35	gold quality
gall bladder	UBERON:0002110	97.30	gold quality
pancreas	UBERON:0001264	97.27	gold quality
body of uterus	UBERON:0009853	97.22	gold quality
right lobe of thyroid gland	UBERON:0001119	96.94	gold quality
ectocervix	UBERON:0012249	96.89	gold quality
left uterine tube	UBERON:0001303	96.65	gold quality
minor salivary gland	UBERON:0001830	96.63	gold quality
left lobe of thyroid gland	UBERON:0001120	96.53	gold quality
right coronary artery	UBERON:0001625	96.52	gold quality
ascending aorta	UBERON:0001496	96.46	gold quality
thoracic aorta	UBERON:0001515	96.43	gold quality
adenohypophysis	UBERON:0002196	96.25	gold quality
body of stomach	UBERON:0001161	96.22	gold quality
mucosa of transverse colon	UBERON:0004991	96.21	gold quality
upper lobe of left lung	UBERON:0008952	96.18	gold quality
corpus epididymis	UBERON:0004359	96.11	gold quality
left coronary artery	UBERON:0001626	96.04	gold quality
aorta	UBERON:0000947	96.00	gold quality
left adrenal gland	UBERON:0001234	95.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	20.36
E-GEOD-93593	yes	7.70
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

99 targeting STT3A, 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-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 19.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 12)

• The STT3A OST isoform is primarily responsible for cotranslational glycosylation of the nascent polypeptide as it enters the lumen of the endoplasmic reticulum. (PMID:19167329)
• Gene-expression data suggest a difference in expression between STT3A, Clorf24, and TFF3 in FAs versus carcinomas that may be detected from an FNA sample. Findings must be validated from preoperative FNAs in larger numbers (PMID:21520112)
• DDIT3, STT3A, ARG2 and FAM129A immunohistochemistry does not appear to be useful in the diagnosis of thyroid follicular neoplasias, as they do not reliably distinguish follicular thyroid carcinoma from follicular thyroid adenoma. (PMID:22157935)
• Results show homozygous mutation in STT3A and in STT3B causes congenital disorders of glycosylation. (PMID:23842455)
• Consensus sites containing large hydrophobic and negatively charged middle residues are frequently skipped by STT3A during protein translation. (PMID:25029371)
• This study showed that Congenital Disorder of Glycosylation Caused by Mutations in STT3A. (PMID:28424003)
• DC2 and KCP2 mediate the interaction between the oligosaccharyltransferase STT3A and the endoplasmic reticulum translocon. (PMID:28860277)
• Study reports that STT3B-oligosaccharyltransferase, but not STT3A-oligosaccharyltransferase, is a lipid-linked oligosaccharide hydrolase. (PMID:30181269)
• Analysis of site occupancy data disclosed several new classes of STT3A-dependent acceptor sites including those with suboptimal flanking sequences and sites located within cysteine-rich protein domains. (PMID:31296534)
• Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings. (PMID:34653363)
• Proteome and Glycoproteome Analyses Reveal the Protein N-Linked Glycosylation Specificity of STT3A and STT3B. (PMID:36139350)
• STT3A-mediated viral N-glycosylation underlies the tumor selectivity of oncolytic virus M1. (PMID:37864032)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	stt3a	ENSDARG00000104953
mus_musculus	Stt3a	ENSMUSG00000032116
rattus_norvegicus	Chek1	ENSRNOG00000031896
drosophila_melanogaster	Stt3A	FBGN0031149

Paralogs (2): RPL35 (ENSG00000136942), STT3B (ENSG00000163527)

Protein

Protein identifiers

Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A — P46977 (reviewed: P46977)

Alternative names: B5, Integral membrane protein 1, Transmembrane protein TMC

All UniProt accessions (5): A0A0C4DH80, E9PI32, E9PN73, P46977, H0YET6

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation. N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. This subunit contains the active site and the acceptor peptide and donor lipid-linked oligosaccharide (LLO) binding pockets. STT3A is present in the majority of OST complexes and mediates cotranslational N-glycosylation of most sites on target proteins, while STT3B-containing complexes are required for efficient post-translational glycosylation and mediate glycosylation of sites that have been skipped by STT3A. STT3A-containing OST-A complex is also required to prevent hyperglycosylation of some target proteins by preventing glycosylation of facultative sites before folding of target proteins is completed.

Subunit / interactions. Component of the oligosaccharyltransferase (OST) complex. There are 2 OST complexes, OST-A and OST-B, which contain STT3A or STT3B as catalytic subunit, respectively. OST-A and OST-B contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, and OST-A contains DC2/OSTC and KRTCAP2/KCP2 specific accessory subunits. OST-A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the OST-A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The OST-A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes.

Subcellular location. Endoplasmic reticulum. Endoplasmic reticulum membrane.

Tissue specificity. Expressed at high levels in placenta, liver, muscle and pancreas, and at very low levels in brain, lung and kidney. Expressed in skin fibroblasts (at protein level).

Disease relevance. Congenital disorder of glycosylation 1W, autosomal recessive (CDG1WAR) [MIM:615596] A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The disease is caused by variants affecting the gene represented in this entry. Congenital disorder of glycosylation 1W, autosomal dominant (CDG1WAD) [MIM:619714] A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. CDG1WAD patients show variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features. Some have impaired intellectual development. Additional features include increased muscle tone and muscle cramps. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. STT3A, but not STT3B, is specifically inhibited by the N-glycosylation inhibitor NGI-235, which prevents productive binding pose of the glycan donor in the active site of STT3A.

Domain organisation. Despite low primary sequence conservation between eukaryotic catalytic subunits and bacterial and archaeal single subunit OSTs (ssOST), structural comparison revealed several common motifs at spatially equivalent positions, like the DXD motif 1 on the external loop 1 and the DXD motif 2 on the external loop 2 involved in binding of the metal ion cofactor and the carboxamide group of the acceptor asparagine, the conserved Glu residue of the TIXE/SVSE motif on the external loop 5 involved in catalysis, as well as the WWDYG and the DK/MI motifs in the globular domain that define the binding pocket for the +2 Ser/Thr of the acceptor sequon. In bacterial ssOSTs, an Arg residue was found to interact with a negatively charged side chain at the -2 position of the sequon. This Arg is conserved in bacterial enzymes and correlates with an extended sequon requirement (Asp-X-Asn-X-Ser/Thr) for bacterial N-glycosylation.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the STT3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P46977-1	1	yes
P46977-2	2

RefSeq proteins (3): NP_001265432, NP_001265433, NP_689926* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003674	Oligo_trans_STT3	Family
IPR048307	STT3_N	Domain
IPR054479	AglB-like_core	Domain

Pfam: PF02516, PF22627

Enzyme classification (BRENDA):

• EC 2.4.99.18 — dolichyl-diphosphooligosaccharide-protein glycotransferase (BRENDA: 84 organisms, 135 substrates, 28 inhibitors, 38 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

29 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TYR-ASN-LEU-THR-SER-VAL	0.05–0.6	3
ACETYL-ASN-ALA-THR	0.08–0.143	2
ALA-LEU-GLN-ASN-ALA-THR-ARG	0.3–0.358	2
ASN-ALA-THR	0.56–2.09	2
DIPHENYL-ALA-LEU-GLU-ASN-ALA-THR-ARG-NH2	0.072–0.23	2
TYR-GLN-SER-ASN-SER-THR-MET	0.08–0.127	2
AC-ASN-ALA-THR-NH2	2	1
AC-ASN-LEU-THR-NH2	1	1
ACETYL-ASN-LYS-THR	0.278	1
ACETYL-DFNAT-(4-NITROPHENYLALANINE)-NH2	0.0009	1
ACETYL-DFNVT-(4-NITROPHENYLALANINE)-NH2	0.0012	1
ACETYL-DQNAT-(4-NITROPHENYLALANINE)-NH2	0.0008	1
ACETYL-DVNAS-(4-NITROPHENYLALANINE)-NH2	0.003	1
ACETYL-DVNAT-(4-NITROPHENYLALANINE)-NH2	0.0011	1
ACETYL-DVNVT-(4-NITROPHENYLALANINE)-NH2	0.0014	1

Catalyzed reactions (Rhea), 1 shown:

• a di-trans,poly-cis-dolichyl diphosphooligosaccharide + L-asparaginyl-[protein] = N(4)-(oligosaccharide-(1->4)-N-acetyl-beta-D-glucosaminyl-(1->4)-N-acetyl-beta-D-glucosaminyl)-L-asparaginyl-[protein] + a di-trans,poly-cis-dolichyl diphosphate + H(+) (RHEA:22980)

UniProt features (130 total): helix 35, topological domain 14, strand 14, transmembrane region 13, sequence conflict 10, turn 8, sequence variant 8, mutagenesis site 8, short sequence motif 5, binding site 5, site 4, glycosylation site 3, chain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9N9J	ELECTRON MICROSCOPY	3.2
6S7O	ELECTRON MICROSCOPY	3.5
8PN9	ELECTRON MICROSCOPY	3.61
9YGY	ELECTRON MICROSCOPY	4.1
8B6L	ELECTRON MICROSCOPY	7.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46977-F1	88.44	0.65

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 (4): 49 (interacts with target acceptor peptide in protein substrate); 160 (important for catalytic activity); 351 (interacts with target acceptor peptide in protein substrate); 595 (interacts with target acceptor peptide in protein substrate)

Ligand- & substrate-binding residues (5): 49; 167; 169; 405; 530

Glycosylation sites (3): 537, 544, 548

Mutagenesis-validated functional residues (8):

Position	Phenotype
209	in llo mutant; abolished oligosaccharyl transferase activity due to defects in binding lipid-linked oligosaccharide; whe
256	confers resistance to inhibitor n-glycosylation inhibitor ngi-1.
260	confers resistance to inhibitor n-glycosylation inhibitor ngi-1.
266	confers resistance to inhibitor n-glycosylation inhibitor ngi-1.
331	confers resistance to inhibitor n-glycosylation inhibitor ngi-1.
405	in llo mutant; abolished oligosaccharyl transferase activity due to defects in binding lipid-linked oligosaccharide; whe
525–527	impaired ability to prevent hyperglycosylation of target proteins.
530	in llo mutant; abolished oligosaccharyl transferase activity due to defects in binding lipid-linked oligosaccharide; whe

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-9694548	Maturation of spike protein
R-HSA-9768727	Regulation of CDH1 posttranslational processing and trafficking to plasma membrane
R-HSA-9918432	Maturation of DENV proteins
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane
R-HSA-1643685	Disease
R-HSA-392499	Metabolism of proteins
R-HSA-5663205	Infectious disease
R-HSA-597592	Post-translational protein modification
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9694635	Translation of Structural Proteins
R-HSA-9772573	Late SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 290 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GCANCTGNY_MYOD_Q6, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, KEGG_N_GLYCAN_BIOSYNTHESIS, ATGCAGT_MIR217, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, E4F1_Q6, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, HTF_01, SCHLOSSER_SERUM_RESPONSE_DN, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP

GO Biological Process (5): protein N-linked glycosylation (GO:0006487), obsolete protein N-linked glycosylation via asparagine (GO:0018279), post-translational protein modification (GO:0043687), obsolete protein glycosylation (GO:0006486), obsolete co-translational protein modification (GO:0043686)

GO Molecular Function (6): dolichyl-diphosphooligosaccharide-protein glycotransferase activity (GO:0004579), metal ion binding (GO:0046872), oligosaccharyl transferase activity (GO:0004576), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), oligosaccharyltransferase complex (GO:0008250), membrane (GO:0016020), oligosaccharyltransferase complex A (GO:0160226), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Post-translational protein modification	1
Translation of Structural Proteins	1
Regulation of CDH1 Expression and Function	1
Dengue Virus Genome Translation and Replication	1
Regulation of PD-L1(CD274) Post-translational modification	1
Disease	1
Metabolism of proteins	1
Viral Infection Pathways	1
SARS-CoV Infections	1
Late SARS-CoV-2 Infection Events	1
SARS-CoV-2 Infection	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycoprotein biosynthetic process	1
protein modification process	1
oligosaccharyl transferase activity	1
cation binding	1
hexosyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
cellular anatomical structure	1
oligosaccharyltransferase complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1782 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STT3A	DDOST	P39656	996
STT3A	DAD1	P46966	995
STT3A	RPN1	P04843	993
STT3A	RPN2	P04844	982
STT3A	OST4	P0C6T2	982
STT3A	TMEM258	P61165	958
STT3A	STT3B	Q8TCJ2	921
STT3A	MAGT1	Q9H0U3	891
STT3A	KRTCAP2	Q8N6L1	831
STT3A	SEC61A1	P38378	807
STT3A	OSTC	Q9NRP0	769
STT3A	TUSC3	Q13454	749
STT3A	TMC2	Q8TDI7	717
STT3A	ALG6	Q9Y672	646
STT3A	ALG12	Q9BV10	639

IntAct

189 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
STT3A		psi-mi:“MI:0915”(physical association)	0.620
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
STT3A	RPN1	psi-mi:“MI:0915”(physical association)	0.560
STT3A	PECAM1	psi-mi:“MI:0915”(physical association)	0.560
STT3A	TGFBR2	psi-mi:“MI:0915”(physical association)	0.560
STT3A	WFS1	psi-mi:“MI:0915”(physical association)	0.560
STT3A	VCP	psi-mi:“MI:0915”(physical association)	0.560
STT3A	RPN1	psi-mi:“MI:0914”(association)	0.560
	XPO1	psi-mi:“MI:0914”(association)	0.530
CEP78	CEP43	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
	SCD	psi-mi:“MI:0914”(association)	0.500

BioGRID (295): STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-Western), STT3A (Synthetic Lethality), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS), STT3A (Affinity Capture-MS)

ESM2 similar proteins: A2AJQ3, A6X919, A8Y3M2, D4AD75, E2RG47, F1PJP5, F1QYC4, G5EBX4, O13898, O59802, O76689, O94335, P0CW70, P34413, P46977, P46978, P53730, P53868, P54002, P97564, Q09216, Q09837, Q0VGW4, Q18600, Q2KJI2, Q2PZI1, Q3TDQ1, Q3UVK0, Q5R8N9, Q5RCE2, Q66J01, Q6CN27, Q6F2Z1, Q6NUT2, Q6UPR8, Q6ZN68, Q754G0, Q7Z2K6, Q7Z388, Q8BI36

Diamond homologs: E2RG47, F1PJP5, O29867, O94335, P39007, P46975, P46977, P46978, Q2KJI2, Q3TDQ1, Q54NM9, Q5RCE2, Q6F2Z1, Q7XQ88, Q8TCJ2, Q93ZY3, Q9FX21

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
STT3A	“form complex”	“OST-A complex”	binding
STT3A	“up-regulates quantity by stabilization”	CD274	glycosylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 189 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	8	33.8×	3e-08
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	8	21.9×	3e-07
Maturation of spike protein	9	19.4×	1e-07
Maturation of DENV proteins	10	17.2×	8e-08
SARS-CoV-2 Infection	9	5.9×	2e-03
Asparagine N-linked glycosylation	12	5.9×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	8	36.4×	4e-08
protein N-linked glycosylation	9	16.0×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	4
Uncertain significance	106
Likely benign	79
Benign	62

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
102443	NM_152713.5(STT3A):c.1877T>C (p.Val626Ala)	Likely pathogenic
1334779	NM_152713.5(STT3A):c.479G>A (p.Arg160Gln)	Likely pathogenic
1895409	NM_152713.5(STT3A):c.251T>C (p.Ile84Thr)	Likely pathogenic
2431752	NM_152713.5(STT3A):c.1213C>A (p.Arg405Ser)	Likely pathogenic

SpliceAI

2488 predictions. Top by Δscore:

Variant	Effect	Δscore
11:125592907:A:T	donor_gain	1.0000
11:125592915:CCAGG:C	donor_loss	1.0000
11:125592916:CAG:C	donor_loss	1.0000
11:125592917:AG:A	donor_loss	1.0000
11:125595879:A:AG	acceptor_gain	1.0000
11:125595880:G:GG	acceptor_gain	1.0000
11:125595880:GCT:G	acceptor_gain	1.0000
11:125596001:TATGT:T	donor_loss	1.0000
11:125596002:ATG:A	donor_loss	1.0000
11:125596003:TG:T	donor_loss	1.0000
11:125596004:G:GA	donor_loss	1.0000
11:125596004:G:GG	donor_gain	1.0000
11:125596005:T:G	donor_loss	1.0000
11:125596006:G:GT	donor_loss	1.0000
11:125597054:TGCA:T	acceptor_loss	1.0000
11:125597055:GCA:G	acceptor_loss	1.0000
11:125597056:CAGC:C	acceptor_loss	1.0000
11:125597057:A:AG	acceptor_gain	1.0000
11:125597057:A:C	acceptor_loss	1.0000
11:125597058:G:GC	acceptor_gain	1.0000
11:125597058:G:GT	acceptor_loss	1.0000
11:125597058:GCC:G	acceptor_gain	1.0000
11:125597115:GATCC:G	donor_gain	1.0000
11:125597117:TCC:T	donor_gain	1.0000
11:125597120:G:GG	donor_gain	1.0000
11:125602298:TATA:T	acceptor_loss	1.0000
11:125602300:TAG:T	acceptor_loss	1.0000
11:125602302:G:GA	acceptor_loss	1.0000
11:125602422:CAGGT:C	donor_loss	1.0000
11:125602423:AGGT:A	donor_loss	1.0000

AlphaMissense

4622 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:125597109:G:A	E47K	1.000
11:125597110:A:T	E47V	1.000
11:125597119:C:A	P50Q	1.000
11:125602312:T:A	N53K	1.000
11:125602312:T:G	N53K	1.000
11:125602317:G:C	R55P	1.000
11:125602382:T:A	W77R	1.000
11:125602382:T:C	W77R	1.000
11:125602384:G:C	W77C	1.000
11:125602384:G:T	W77C	1.000
11:125602394:G:A	G81R	1.000
11:125602394:G:C	G81R	1.000
11:125602395:G:A	G81E	1.000
11:125602395:G:T	G81V	1.000
11:125602398:G:C	R82P	1.000
11:125602407:G:A	G85E	1.000
11:125602879:T:G	C116W	1.000
11:125604169:G:T	G144W	1.000
11:125604221:C:T	S161F	1.000
11:125604229:G:C	G164R	1.000
11:125604230:G:A	G164D	1.000
11:125604238:G:C	D167H	1.000
11:125604239:A:C	D167A	1.000
11:125604239:A:T	D167V	1.000
11:125604243:T:A	N168K	1.000
11:125604243:T:G	N168K	1.000
11:125604245:A:T	E169V	1.000
11:125604246:A:C	E169D	1.000
11:125604246:A:T	E169D	1.000
11:125604247:G:T	G170W	1.000

dbSNP variants (sampled 300 via entrez): RS1000057998 (11:125593640 A>G), RS1000174481 (11:125608667 A>G), RS1000256379 (11:125623078 A>C,T), RS1000309263 (11:125615996 G>A), RS1000325697 (11:125620096 C>T), RS1000343802 (11:125601611 G>A), RS1000368020 (11:125599933 T>C), RS1000394600 (11:125601398 A>C,G), RS1000547329 (11:125620565 G>A), RS1000580864 (11:125595600 G>A,T), RS1000762710 (11:125590441 G>A,T), RS1000788717 (11:125605247 A>G), RS1000860554 (11:125609118 T>C), RS1000972719 (11:125595988 A>G), RS1000974971 (11:125598327 C>T)

Disease associations

OMIM: gene MIM:601134 | disease phenotypes: MIM:615596, MIM:619714

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital disorder of glycosylation, type Iw, autosomal dominant	Definitive	Autosomal dominant
STT3A-congenital disorder of glycosylation	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
STT3A-congenital disorder of glycosylation	Moderate	AR
congenital disorder of glycosylation, type Iw, autosomal dominant	Definitive	AD

Mondo (3): STT3A-congenital disorder of glycosylation (MONDO:0014270), congenital disorder of glycosylation, type Iw, autosomal dominant (MONDO:0859223), microcephaly (MONDO:0001149)

Orphanet (1): STT3A-CDG (Orphanet:370921)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000431	Wide nasal bridge
HP:0000486	Strabismus
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0002389	Cavum septum pellucidum
HP:0002758	Osteoarthritis
HP:0003186	Inverted nipples
HP:0003394	Muscle spasm
HP:0003593	Infantile onset
HP:0003596	Middle age onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001242_18	Schizophrenia	1.000000e-06
GCST001877_34	Autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia (combined)	9.000000e-07
GCST002861_2	Breast cancer (survival)	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0000714	survival time

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066234 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.10	Kd	7.943	nM	CHEMBL5583975
8.01	Kd	9.862	nM	CHEMBL5653589
8.01	ED50	9.862	nM	CHEMBL5653589
5.95	Kd	1124	nM	CHEMBL3752910
5.95	ED50	1124	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 5 total; 3 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
N-methyl-3-(6-methyl-1H-indol-2-yl)-N-[2-[(3S)-3-methylmorpholin-4-yl]-2-oxoethyl]-4-pyrrolidin-1-ylbenzenesulfonamide	2114916: Binding affinity to STT3A in human HepG2 cells assessed as apparent dissociation constant incubated for 1 hr by competition binding assay	kd	0.0079	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149518: Binding affinity to human STT3A incubated for 45 mins by Kinobead based pull down assay	kd	0.0099	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149518: Binding affinity to human STT3A incubated for 45 mins by Kinobead based pull down assay	kd	1.1239	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	increases abundance, increases expression, decreases reaction	2
Tunicamycin	increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
ginger extract	decreases reaction, increases abundance, increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
sodium arsenite	increases expression	1
1-hydroxypyrene	affects cotreatment, decreases methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Atrazine	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Cuprizone	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylstilbestrol	increases expression	1
Diuron	decreases expression	1
Haloperidol	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5579432	Binding	Binding affinity to STT3A in human HepG2 cells assessed as apparent dissociation constant incubated for 1 hr by competition binding assay	Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3IJ	Abcam HEK293T STT3A KO	Transformed cell line	Female
CVCL_D9TF	Ubigene HEK293 STT3A KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.