DDOST

Summary

DDOST (dolichyl-diphosphooligosaccharide–protein glycosyltransferase non-catalytic subunit, HGNC:2728) is a protein-coding gene on chromosome 1p36.12, encoding Dolichyl-diphosphooligosaccharide–protein glycosyltransferase 48 kDa subunit (P39656). 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 polypep…. It is a common-essential gene (DepMap: required in 96.3% of cancer cell lines).

This gene encodes a component of the oligosaccharyltransferase complex which catalyzes the transfer of high-mannose oligosaccharides to asparagine residues on nascent polypeptides in the lumen of the rough endoplasmic reticulum. The protein complex co-purifies with ribosomes. The product of this gene is also implicated in the processing of advanced glycation endproducts (AGEs), which form from non-enzymatic reactions between sugars and proteins or lipids and are associated with aging and hyperglycemia.

Source: NCBI Gene 1650 — RefSeq curated summary.

At a glance

• Gene–disease (curated): DDOST-congenital disorder of glycosylation (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 321 total — 2 pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 96.3% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005216

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2728
Approved symbol	DDOST
Name	dolichyl-diphosphooligosaccharide–protein glycosyltransferase non-catalytic subunit
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	OST, KIAA0115, OST48, WBP1
Ensembl gene	ENSG00000244038
Ensembl biotype	protein_coding
OMIM	602202
Entrez	1650

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000415136, ENST00000464364, ENST00000475210, ENST00000477229, ENST00000602624

RefSeq mRNA: 1 — MANE Select: NM_005216 NM_005216

CCDS: CCDS212

Canonical transcript exons

ENST00000602624 — 11 exons

Exon	Start	End
ENSE00000000156	20651777	20652528
ENSE00000756208	20652621	20652727
ENSE00000756209	20652851	20652971
ENSE00000756210	20653627	20653774
ENSE00000756211	20654223	20654371
ENSE00000756212	20654614	20654707
ENSE00003189747	20656101	20656187
ENSE00003368657	20661197	20661369
ENSE00003696592	20655676	20655779
ENSE00003701820	20660881	20660991
ENSE00003785899	20655440	20655534

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 123.0146 / max 1144.8656, expressed in 1826 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10765	85.8598	1824
10767	15.7072	1809
10768	10.3676	1775
10766	9.5099	1792
10769	1.5701	1098

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.22	gold quality
stromal cell of endometrium	CL:0002255	98.96	gold quality
body of pancreas	UBERON:0001150	98.93	gold quality
caput epididymis	UBERON:0004358	98.57	gold quality
islet of Langerhans	UBERON:0000006	98.55	gold quality
rectum	UBERON:0001052	98.52	gold quality
smooth muscle tissue	UBERON:0001135	98.44	gold quality
placenta	UBERON:0001987	98.38	gold quality
type B pancreatic cell	CL:0000169	98.36	gold quality
spleen	UBERON:0002106	98.36	gold quality
adenohypophysis	UBERON:0002196	98.29	gold quality
cartilage tissue	UBERON:0002418	98.20	gold quality
pituitary gland	UBERON:0000007	98.19	gold quality
right ovary	UBERON:0002118	98.18	gold quality
left ovary	UBERON:0002119	98.17	gold quality
bone marrow cell	CL:0002092	98.13	gold quality
left adrenal gland	UBERON:0001234	98.12	gold quality
gall bladder	UBERON:0002110	98.12	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.11	gold quality
body of stomach	UBERON:0001161	98.09	gold quality
left adrenal gland cortex	UBERON:0035825	98.05	gold quality
right lobe of thyroid gland	UBERON:0001119	98.04	gold quality
pancreas	UBERON:0001264	98.04	gold quality
monocyte	CL:0000576	97.98	gold quality
right adrenal gland	UBERON:0001233	97.97	gold quality
penis	UBERON:0000989	97.96	gold quality
mononuclear cell	CL:0000842	97.95	gold quality
left lobe of thyroid gland	UBERON:0001120	97.95	gold quality
mucosa of transverse colon	UBERON:0004991	97.95	gold quality
leukocyte	CL:0000738	97.94	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	85.05
E-MTAB-9467	yes	56.75
E-HCAD-4	yes	41.90
E-CURD-122	yes	38.00
E-HCAD-9	yes	14.84
E-MTAB-9067	yes	13.39
E-CURD-46	yes	11.33
E-MTAB-10553	yes	8.43
E-CURD-53	no	349.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting DDOST, 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-150-5P	99.99	66.69	1976
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-6776-3P	98.38	66.34	655
HSA-MIR-6883-3P	97.97	67.35	643
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-924	97.78	66.21	681
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-3616-3P	96.96	65.45	983

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 96.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 10)

• AGER1 provides protection against AGE-induced reactive oxygen species generation via NADPH oxidase and protein kinase C delta. (PMID:19955485)
• The common SNPs tested in DDOST, PRKCSH and LGALS3 do not seem to be associated with diabetic micro- or macrovascular complications or with type 1 diabetes in Finnish patients. (PMID:20490454)
• Found a 22 bp deletion and a missense mutation in DDOST. (PMID:22305527)
• the cell-cycle-dependent post-translation modification of TREX1 regulates its interaction with OST. (PMID:28297665)
• Study using transgenic human OST48 knock-in mice demonstrated that OST48 (encoded by DDOST gene) is a facilitator of increased advanced glycation end-products (AGE) deposition in the liver and OST48-AGE pathway leads to the onset of liver injury in combination with central adiposity and glucose intolerance, despite ample physical activity. (PMID:28947796)
• DDOST and SIRT1 are differently expressed in peripheral blood mononuclear cells from type 1 diabetes patients with and without microvascular complications. Their expression is also influenced by dietary advanced glycation end-products and by statins and angiotensin receptor blockers. (PMID:29027826)
• his review summarizes our current knowledge regarding the functions of OST in the light of health and tumor progression, and discusses perspectives on the clinical relevance of inhibiting OST as a tumor treatment. (PMID:31810196)
• Advanced Glycation End Products: A Sweet Flavor That Embitters Cardiovascular Disease. (PMID:35269546)
• Functional classification of DDOST variants of uncertain clinical significance in congenital disorders of glycosylation. (PMID:37848450)
• AGER-1 Long Non-Coding RNA Levels Correlate with the Expression of the Advanced Glycosylation End-Product Receptor, a Regulator of the Inflammatory Response in Visceral Adipose Tissue of Women with Obesity and Type 2 Diabetes Mellitus. (PMID:38139276)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddost	ENSDARG00000037318
mus_musculus	Ddost	ENSMUSG00000028757
rattus_norvegicus	Ddost	ENSRNOG00000015079
drosophila_melanogaster	Ost48	FBGN0014868
caenorhabditis_elegans		WBGENE00011638

Protein

Protein identifiers

Dolichyl-diphosphooligosaccharide–protein glycosyltransferase 48 kDa subunit — P39656 (reviewed: P39656)

All UniProt accessions (3): A0A0C4DGS1, P39656, U3KQ84

UniProt curated annotations — full annotation on UniProt →

Function. 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. Required for the assembly of both SST3A- and SS3B-containing OST complexes.

Subunit / interactions. Component of the oligosaccharyltransferase (OST) complex. OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits. STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes. Interacts with SMIM22.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1R (CDG1R) [MIM:614507] 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.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the DDOST 48 kDa subunit family.

Isoforms (3)

UniProt ID	Names	Canonical?
P39656-1	1	yes
P39656-2	2
P39656-3	3

RefSeq proteins (1): NP_005207* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005013	DDOST_48_kDa_subunit	Family
IPR055457	OST48_N	Domain
IPR055459	OST48_MD	Domain

Pfam: PF03345, PF23358

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

UniProt features (58 total): strand 34, helix 9, sequence conflict 3, turn 3, topological domain 2, splice variant 2, sequence variant 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9N9J	ELECTRON MICROSCOPY	3.2
6S7O	ELECTRON MICROSCOPY	3.5
6S7T	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-P39656-F1	89.27	0.85

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-6798695	Neutrophil degranulation
R-HSA-879415	Advanced glycosylation endproduct receptor signaling
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

MSigDB gene sets: 376 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, KEGG_N_GLYCAN_BIOSYNTHESIS, MORF_HDAC1, RACCACAR_AML_Q6, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, PATIL_LIVER_CANCER, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS

GO Biological Process (7): protein N-linked glycosylation (GO:0006487), glycoprotein biosynthetic process (GO:0009101), obsolete protein N-linked glycosylation via asparagine (GO:0018279), regulation of protein stability (GO:0031647), response to cytokine (GO:0034097), T cell activation (GO:0042110), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (2): enzyme activator activity (GO:0008047), protein binding (GO:0005515)

GO Cellular Component (9): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), oligosaccharyltransferase complex (GO:0008250), membrane (GO:0016020), azurophil granule membrane (GO:0035577), intracellular membrane-bounded organelle (GO:0043231), oligosaccharyltransferase complex A (GO:0160226), oligosaccharyltransferase complex B (GO:0160227)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Innate Immune System	2
Translation	1
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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oligosaccharyltransferase complex	2
glycoprotein biosynthetic process	1
macromolecule biosynthetic process	1
glycoprotein metabolic process	1
carbohydrate derivative biosynthetic process	1
regulation of biological quality	1
response to peptide	1
lymphocyte activation	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
cellular anatomical structure	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1
intracellular anatomical structure	1
membrane-bounded organelle	1
intracellular organelle	1

Protein interactions and networks

STRING

2378 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDOST	RPN2	P04844	999
DDOST	DAD1	P46966	999
DDOST	RPN1	P04843	999
DDOST	STT3A	P46977	996
DDOST	OST4	P0C6T2	991
DDOST	STT3B	Q8TCJ2	987
DDOST	PRKCSH	P14314	932
DDOST	TUSC3	Q13454	880
DDOST	TMEM258	P61165	865
DDOST	SEC61A1	P38378	834
DDOST	MAGT1	Q9H0U3	826
DDOST	KRTCAP2	Q8N6L1	780
DDOST	SCARB1	Q8WTV0	734
DDOST	SSR4	P51571	701
DDOST	MOGS	Q13724	678

IntAct

220 interactions, top by confidence:

A	B	Type	Score
IGBP1	PPP6C	psi-mi:“MI:0914”(association)	0.940
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
MLEC	RPN1	psi-mi:“MI:0915”(physical association)	0.690
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
DDOST	RPN1	psi-mi:“MI:0915”(physical association)	0.560
STT3A	RPN1	psi-mi:“MI:0914”(association)	0.560
RPN2	SMPD2	psi-mi:“MI:0914”(association)	0.530
DAD1	RPN1	psi-mi:“MI:0915”(physical association)	0.530
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
STING1	DDOST	psi-mi:“MI:0915”(physical association)	0.500
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
LTK	PIK3R2	psi-mi:“MI:0914”(association)	0.420
XAB2	DDOST	psi-mi:“MI:0915”(physical association)	0.400
DDOST	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
SRSF11	DDOST	psi-mi:“MI:0915”(physical association)	0.370
NXT1	DDOST	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (565): DDOST (Affinity Capture-MS), DDOST (Affinity Capture-RNA), DDOST (Affinity Capture-RNA), DDOST (Affinity Capture-MS), DDOST (Affinity Capture-MS), DDOST (Affinity Capture-MS), DDOST (Affinity Capture-MS), CANX (Co-fractionation), DDOST (Co-fractionation), DDOST (Co-fractionation), DDOST (Co-fractionation), DDOST (Co-fractionation), DDOST (Co-fractionation), DDOST (Co-fractionation), DDOST (Co-fractionation)

ESM2 similar proteins: A2VE61, A6QPY0, B1H3C9, O54734, O54956, O77783, O95782, O95803, P11029, P11497, P17426, P21343, P39656, P48440, P52848, P70428, Q02353, Q05052, Q0J035, Q13085, Q28559, Q29381, Q2QNG7, Q2TBU2, Q3UHN9, Q4R4U1, Q5R501, Q5R5F8, Q5R7B1, Q5SWU9, Q5U4X8, Q5ZIT8, Q641Y0, Q6GNR9, Q6GQK9, Q6IS24, Q6NYS8, Q6P1X5, Q7TT15, Q8C176

Diamond homologs: A6QPY0, B1H3C9, O54734, O59866, P39656, P45971, P48440, Q05052, Q24319, Q29381, Q54E62, Q5R501, Q641Y0, Q6GNR9, Q6NYS8, Q6ZLK0, Q944K2

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
DDOST	“form complex”	“OST-B complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 211 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	9	33.1×	1e-09
Maturation of spike protein	11	20.7×	1e-09
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	7	16.7×	3e-05
Maturation of DENV proteins	11	16.5×	1e-08
Translation of Structural Proteins	5	14.5×	3e-03
Asparagine N-linked glycosylation	13	5.5×	9e-05

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	9	34.9×	3e-09
protein N-linked glycosylation	10	15.1×	7e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	153
Likely benign	97
Benign	39

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
30245	NM_005216.5(DDOST):c.1214_1235del (p.Ile405fs)	Pathogenic
30246	NM_005216.5(DDOST):c.599G>A (p.Gly200Asp)	Pathogenic

SpliceAI

1310 predictions. Top by Δscore:

Variant	Effect	Δscore
1:20652526:TAC:T	acceptor_gain	1.0000
1:20652527:ACCT:A	acceptor_loss	1.0000
1:20652528:CCTG:C	acceptor_loss	1.0000
1:20652529:CT:C	acceptor_loss	1.0000
1:20652530:T:C	acceptor_loss	1.0000
1:20652532:C:CT	acceptor_gain	1.0000
1:20652533:A:T	acceptor_gain	1.0000
1:20652616:CTTA:C	donor_loss	1.0000
1:20652617:TTA:T	donor_loss	1.0000
1:20652618:TACC:T	donor_loss	1.0000
1:20652619:A:AC	donor_gain	1.0000
1:20652619:ACC:A	donor_loss	1.0000
1:20652620:C:CC	donor_gain	1.0000
1:20652620:CCTGA:C	donor_gain	1.0000
1:20652724:CCAC:C	acceptor_gain	1.0000
1:20652725:CAC:C	acceptor_gain	1.0000
1:20652725:CACC:C	acceptor_gain	1.0000
1:20652726:ACC:A	acceptor_loss	1.0000
1:20652727:CCTG:C	acceptor_loss	1.0000
1:20652728:C:CC	acceptor_gain	1.0000
1:20652728:CTGC:C	acceptor_loss	1.0000
1:20652729:T:A	acceptor_loss	1.0000
1:20652846:CTCA:C	donor_loss	1.0000
1:20652847:TCA:T	donor_loss	1.0000
1:20652848:CAC:C	donor_loss	1.0000
1:20652849:A:AC	donor_gain	1.0000
1:20652849:AC:A	donor_gain	1.0000
1:20652850:C:CT	donor_gain	1.0000
1:20652850:CC:C	donor_gain	1.0000
1:20652850:CCTTT:C	donor_gain	1.0000

AlphaMissense

2882 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:20652678:G:C	F388L	1.000
1:20652678:G:T	F388L	1.000
1:20652680:A:G	F388L	1.000
1:20652901:A:G	L355P	1.000
1:20653726:C:A	W298C	1.000
1:20653726:C:G	W298C	1.000
1:20653728:A:G	W298R	1.000
1:20653728:A:T	W298R	1.000
1:20655441:C:A	G201W	1.000
1:20655767:C:G	R139P	1.000
1:20652421:G:C	S443R	0.999
1:20652421:G:T	S443R	0.999
1:20652423:T:G	S443R	0.999
1:20652476:G:T	A425D	0.999
1:20652649:C:T	G398D	0.999
1:20652650:C:G	G398R	0.999
1:20652655:C:G	R396P	0.999
1:20652673:A:G	F390S	0.999
1:20652685:C:T	G386D	0.999
1:20652686:C:A	G386C	0.999
1:20652686:C:G	G386R	0.999
1:20652871:C:A	R365M	0.999
1:20652876:A:C	F363L	0.999
1:20652876:A:T	F363L	0.999
1:20652878:A:G	F363L	0.999
1:20652886:A:T	I360N	0.999
1:20653703:A:G	L306P	0.999
1:20653736:A:G	L295P	0.999
1:20653756:G:C	N288K	0.999
1:20653756:G:T	N288K	0.999

dbSNP variants (sampled 300 via entrez): RS1000295586 (1:20651373 T>C,G), RS1000492454 (1:20662908 A>G), RS1001022882 (1:20655596 T>A,G), RS1001093857 (1:20661571 T>C), RS1001278016 (1:20661468 G>A,T), RS1001515451 (1:20654773 G>A,C), RS1001750883 (1:20661134 A>G), RS1002318996 (1:20661894 C>T), RS1002941163 (1:20657733 C>T), RS1003183448 (1:20656599 A>G), RS1003288262 (1:20656368 T>C), RS1003293418 (1:20658634 C>A), RS1003533489 (1:20652278 C>T), RS1003689798 (1:20662156 C>T), RS1003813219 (1:20651426 G>C)

Disease associations

OMIM: gene MIM:602202 | disease phenotypes: MIM:614507

GenCC curated gene-disease

Disease	Classification	Inheritance
DDOST-congenital disorder of glycosylation	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
DDOST-congenital disorder of glycosylation	Moderate	AR

Mondo (2): DDOST-congenital disorder of glycosylation (MONDO:0013789), intellectual disability (MONDO:0001071)

Orphanet (2): DDOST-CDG (Orphanet:300536), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000565	Esotropia
HP:0000832	Primary hypothyroidism
HP:0000938	Osteopenia
HP:0000958	Dry skin
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001337	Tremor
HP:0001397	Hepatic steatosis
HP:0001410	Decreased liver function
HP:0001508	Failure to thrive
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002167	Abnormal speech pattern
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003256	Abnormality of the coagulation cascade
HP:0003429	CNS hypomyelination
HP:0003593	Infantile onset
HP:0003642	Type I transferrin isoform profile
HP:0004322	Short stature
HP:0005616	Accelerated skeletal maturation
HP:0007301	Oromotor apraxia
HP:0009125	Lipodystrophy
HP:0012450	Chronic constipation
HP:0012593	Nephrotic range proteinuria
HP:0012758	Neurodevelopmental delay
HP:0031936	Delayed ability to walk

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010916_1	Proportion of activated microglia (inferior temporal cortex)	6.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4239 (SINGLE PROTEIN)

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

ChEMBL bioactivities

14 potent at pChembl≥5 of 14 total, top 14 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	Ki	10	nM	CHEMBL609697
7.75	Ki	18	nM	CHEMBL1160689
7.70	Ki	20	nM	CHEMBL609698
7.43	Ki	37	nM	CHEMBL609696
7.40	Ki	40	nM	CHEMBL609447
7.36	Ki	44	nM	CHEMBL1160693
7.30	Ki	50	nM	CHEMBL1160688
7.21	Ki	61	nM	CHEMBL609446
7.09	Ki	82	nM	CHEMBL1160687
7.01	Ki	98	nM	CHEMBL609699
6.81	Ki	154	nM	CHEMBL2370267
6.77	Kd	168.7	nM	CHEMBL3752910
6.77	ED50	168.7	nM	CHEMBL3752910
6.52	Ki	305	nM	CHEMBL2370266

PubChem BioAssay actives

13 with measured affinity, of 15 total; 13 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
trans-(3R,6S)-N-[(2S,3R)-3-hydroxy-1-[[(2S)-1-[[(2S,3R)-3-hydroxy-1-[2-(4-nitrophenyl)ethylamino]-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-[2-(naphthalen-2-ylamino)ethyl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0100	uM
trans-(3R,6S)-N-[(2S,3R)-3-hydroxy-1-[[(2S)-1-[[(2S,3R)-3-hydroxy-1-oxo-1-(2-phenylethylamino)butan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-[2-(naphthalen-2-ylamino)ethyl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0180	uM
trans-(3R,6S)-6-(2-aminoethyl)-N-[(2S,3R)-3-hydroxy-1-[[(2S)-1-[[(2S,3R)-3-hydroxy-1-[2-(4-nitrophenyl)ethylamino]-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0200	uM
trans-(3R,6S)-6-(2-aminoethyl)-N-[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-3-(4-nitrophenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0370	uM
trans-(3R,6S)-N-[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-3-(4-nitrophenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-6-[2-(naphthalen-2-ylamino)ethyl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0400	uM
trans-(3R,6S)-6-(2-aminoethyl)-N-[(2S,3R)-3-hydroxy-1-[[(2S)-1-[[(2S,3R)-3-hydroxy-1-oxo-1-(2-phenylethylamino)butan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0440	uM
trans-(3R,6S)-6-(2-aminoethyl)-N-[(2S,3R)-3-hydroxy-1-[[(2S)-1-[[(2S,3R)-3-hydroxy-1-oxo-1-(4-phenylbutylamino)butan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0500	uM
trans-(3R,6S)-N-[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-3-(4-nitrophenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-6-[2-(decylamino)ethyl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0610	uM
trans-(3R,6S)-6-(2-aminoethyl)-N-[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0820	uM
trans-(3R,6S)-N-[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-3-(4-nitrophenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]-6-[2-(naphthalen-1-ylamino)ethyl]-5,8-dioxo-1-thia-4,7-diazacyclotridecane-3-carboxamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.0980	uM
(2S)-N-[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]-2-(benzylamino)-5-[(4-nitrophenyl)methylamino]pentanamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.1540	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148210: Binding affinity to human DDOST incubated for 45 mins by Kinobead based pull down assay	kd	0.1687	uM
(2S)-N-[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]-2-(benzylamino)-5-[(4-methoxyphenyl)methylamino]pentanamide	226056: Inhibition of asparagine-linked glycosylation by oligosaccharyl transferase	ki	0.3050	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, increases methylation	2
Tunicamycin	increases expression	2
Cyclosporine	increases expression	2
bisphenol F	affects cotreatment, decreases methylation	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	increases abundance, increases palmitoylation, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Decitabine	affects methylation	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases palmitoylation, decreases reaction, increases abundance	1
Catechin	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Ouabain	decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Selenium	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
CHEMBL5651252	Binding	Binding affinity to human DDOST incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders