ALG3

Summary

ALG3 (ALG3 alpha-1,3- mannosyltransferase, HGNC:23056) is a protein-coding gene on chromosome 3q27.1, encoding Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase (Q92685). Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.

This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10195 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ALG3-congenital disorder of glycosylation (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 268 total — 18 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 78
• Druggable target: yes
• MANE Select transcript: NM_005787

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23056
Approved symbol	ALG3
Name	ALG3 alpha-1,3- mannosyltransferase
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	NOT56L, Not56, CDGS4, D16Ertd36e
Ensembl gene	ENSG00000214160
Ensembl biotype	protein_coding
OMIM	608750
Entrez	10195

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 7 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000397676, ENST00000411922, ENST00000414845, ENST00000423996, ENST00000445626, ENST00000446569, ENST00000455059, ENST00000461415, ENST00000462735, ENST00000463495, ENST00000477959, ENST00000482048, ENST00000485912, ENST00000488976, ENST00000885311, ENST00000885312, ENST00000918329

RefSeq mRNA: 2 — MANE Select: NM_005787 NM_001006941, NM_005787

CCDS: CCDS46967, CCDS46968

Canonical transcript exons

ENST00000397676 — 9 exons

Exon	Start	End
ENSE00001529651	184242301	184242676
ENSE00003511305	184242813	184242957
ENSE00003540107	184245468	184245615
ENSE00003561248	184248745	184248962
ENSE00003599288	184245713	184245812
ENSE00003639117	184244601	184244721
ENSE00003647968	184243554	184243630
ENSE00003654734	184245198	184245358
ENSE00003669013	184243791	184243996

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 95.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.9966 / max 451.4714, expressed in 1819 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45874	45.6236	1818
45876	2.2360	1251
45872	2.0752	1076
45875	1.9138	936
45873	1.6689	1038
45870	0.4791	249

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.09	gold quality
stromal cell of endometrium	CL:0002255	94.19	gold quality
right lobe of liver	UBERON:0001114	93.91	gold quality
right adrenal gland	UBERON:0001233	93.70	gold quality
body of pancreas	UBERON:0001150	93.66	gold quality
left adrenal gland	UBERON:0001234	93.47	gold quality
left adrenal gland cortex	UBERON:0035825	93.26	gold quality
right adrenal gland cortex	UBERON:0035827	93.14	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.24	gold quality
granulocyte	CL:0000094	92.13	gold quality
minor salivary gland	UBERON:0001830	91.94	gold quality
esophagus mucosa	UBERON:0002469	91.75	gold quality
body of stomach	UBERON:0001161	91.67	gold quality
transverse colon	UBERON:0001157	91.57	gold quality
right lobe of thyroid gland	UBERON:0001119	91.41	gold quality
left testis	UBERON:0004533	91.36	gold quality
left coronary artery	UBERON:0001626	91.22	gold quality
adrenal cortex	UBERON:0001235	91.20	gold quality
right testis	UBERON:0004534	91.17	gold quality
gastrocnemius	UBERON:0001388	91.13	gold quality
adrenal gland	UBERON:0002369	91.05	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.74	gold quality
esophagus	UBERON:0001043	90.73	gold quality
apex of heart	UBERON:0002098	90.67	gold quality
pancreas	UBERON:0001264	90.64	gold quality
lower esophagus mucosa	UBERON:0035834	90.61	gold quality
skin of abdomen	UBERON:0001416	90.57	gold quality
saliva-secreting gland	UBERON:0001044	90.36	gold quality
muscle of leg	UBERON:0001383	90.31	gold quality
mouth mucosa	UBERON:0003729	90.26	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NCOR1, NCOR2, NOTO, SP1

miRNA regulators (miRDB)

7 targeting ALG3, 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-3202	99.66	67.70	2737
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-9900	96.06	65.48	557
HSA-MIR-571	95.38	66.54	671

Literature-anchored findings (GeneRIF, showing 17)

• a mutation in ALG3 affects splicing and may have a role in development of congenital disorder of glycosylation type Id [case report] (PMID:16006436)
• ALG3-CDG is due to an autosomal recessive defect in the ER mannosyl-transferase VI, which is involved in protein N-glycosylation. The enzyme is encoded by the ALG3 gene (PMID:23791010)
• our data suggest the involvement of hNOT-1/ALG3-1 in various molecular contexts determining essential processes associated with distinct cellular machineries and related to various pathologies, such as cancer, viral infections, neuronal and immunological disorders and Congenital Disorders of Glycosylation. (PMID:29547901)
• Silencing ALG3 or HSF2 inhibited the proliferation, migration, and invasion abilities of MCF-7 cells. (PMID:29799832)
• We found that PPFIA1 and ALG3 were distinctively overexpressed at the mRNA level in HNSCC tissues compared with normal tissues, they had a significant co-occurrence relationship. Patients without both PPFIA1 and ALG3 mRNA expression alterations had better overall survival and disease/progression-free survival compared with patients with both PPFIA1 and ALG3 alterations. (PMID:30805892)
• Study adds four new biochemically confirmed variants to the list of ALG3-congenital disorder of glycosylation (CDG) inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. (PMID:31067009)
• ALG3 contributes to the malignancy of non-small cell lung cancer and is negatively regulated by MiR-98-5p. (PMID:31899049)
• ALG3-CDG: lethal phenotype and novel variants in Chinese siblings. (PMID:32655146)
• ALG3 contributes to the malignant properties of OSCC cells by regulating CDK-Cyclin pathway. (PMID:33084111)
• Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: Complex glycosylation defect with embryonic lethal phenotype. (PMID:33187827)
• ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-beta receptor II in breast cancer. (PMID:33931075)
• ALG3 Is a Potential Biomarker for the Prognosis of Bladder Cancer. (PMID:35181625)
• Inhibition of ALG3 stimulates cancer cell immunogenic ferroptosis to potentiate immunotherapy. (PMID:35676564)
• CircPTK2 promotes cell viability, cell cycle process, and glycolysis and inhibits cell apoptosis in acute myeloid leukemia by regulating miR-582-3p/ALG3 axis. (PMID:35980117)
• ALG3 Promotes Peritoneal Metastasis of Ovarian Cancer through Increasing Interaction of alpha1,3-mannosylated uPAR and ADAM8. (PMID:36231102)
• Comprehensive analysis of ALG3 in pan-cancer and validation of ALG3 as an onco-immunological biomarker in breast cancer. (PMID:38329424)
• Deficient glycan extension and endoplasmic reticulum stresses in ALG3-CDG. (PMID:38597022)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alg3	ENSDARG00000053155
mus_musculus	Alg3	ENSMUSG00000033809
rattus_norvegicus	Alg3	ENSRNOG00000001712
drosophila_melanogaster	Alg3	FBGN0011297
caenorhabditis_elegans		WBGENE00010720

Protein

Protein identifiers

Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase — Q92685 (reviewed: Q92685)

Alternative names: Asparagine-linked glycosylation protein 3 homolog, Dol-P-Man-dependent alpha(1-3)-mannosyltransferase, Dolichyl-P-Man:Man(5)GlcNAc(2)-PP-dolichyl mannosyltransferase, Dolichyl-phosphate-mannose–glycolipid alpha-mannosyltransferase, Not56-like protein

All UniProt accessions (6): C9J7S5, F8WE30, F8WF93, Q92685, H7BZZ2, H7C0X4

UniProt curated annotations — full annotation on UniProt →

Function. Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation. The assembly of dolichol-linked oligosaccharides begins on the cytosolic side of the endoplasmic reticulum membrane and finishes in its lumen. The sequential addition of sugars to dolichol pyrophosphate produces dolichol-linked oligosaccharides containing fourteen sugars, including two GlcNAcs, nine mannoses and three glucoses. Once assembled, the oligosaccharide is transferred from the lipid to nascent proteins by oligosaccharyltransferases. In the lumen of the endoplasmic reticulum, adds the first dolichyl beta-D-mannosyl phosphate derived mannose in an alpha-1,3 linkage to Man(5)GlcNAc(2)-PP-dolichol to produce Man(6)GlcNAc(2)-PP-dolichol. Man(6)GlcNAc(2)-PP-dolichol is a substrate for ALG9, the following enzyme in the biosynthetic pathway.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1D (CDG1D) [MIM:601110] 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 glycosyltransferase ALG3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92685-1	1	yes
Q92685-2	2

RefSeq proteins (2): NP_001006942, NP_005778* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007873	Glycosyltransferase_ALG3	Family

Pfam: PF05208

Enzyme classification (BRENDA):

• EC 2.4.1.258 — dolichyl-P-Man:Man5GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase (BRENDA: 9 organisms, 11 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• an alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + a di-trans,poly-cis-dolichyl beta-D-mannosyl phosphate = an alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->3)-alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + a di-trans,poly-cis-dolichyl phosphate + H(+) (RHEA:29527)

UniProt features (17 total): transmembrane region 11, sequence variant 3, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92685-F1	89.05	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 13

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-446193	Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein
R-HSA-4720475	Defective ALG3 causes CDG-1d
R-HSA-1643685	Disease
R-HSA-3781860	Diseases associated with N-glycosylation of proteins
R-HSA-3781865	Diseases of glycosylation
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 323 (showing top): AAGTCCA_MIR422B_MIR422A, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, KEGG_N_GLYCAN_BIOSYNTHESIS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, KLEIN_PRIMARY_EFFUSION_LYMPHOMA_UP, MORF_RFC4, MORF_PRKDC, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, MORF_AATF, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, RIZKI_TUMOR_INVASIVENESS_3D_UP, GOCC_LUMENAL_SIDE_OF_MEMBRANE

GO Biological Process (3): protein N-linked glycosylation (GO:0006487), dolichol-linked oligosaccharide biosynthetic process (GO:0006488), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (6): alpha-1,3-mannosyltransferase activity (GO:0000033), dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity (GO:0052925), mannosyltransferase activity (GO:0000030), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), lumenal side of endoplasmic reticulum membrane (GO:0098553), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Asparagine N-linked glycosylation	1
Diseases associated with N-glycosylation of proteins	1
Diseases of glycosylation	1
Diseases of metabolism	1
Post-translational protein modification	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycoprotein biosynthetic process	1
protein N-linked glycosylation	1
carbohydrate derivative biosynthetic process	1
mannosyltransferase activity	1
alpha-1,3-mannosyltransferase activity	1
GlcNAc(2)-PP-Dol mannosyltransferase activity	1
hexosyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	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
endoplasmic reticulum membrane	1
lumenal side of membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALG3	ALG2	Q9H553	890
ALG3	ALG12	Q9BV10	881
ALG3	ALG6	Q9Y672	873
ALG3	ALG8	Q9BVK2	839
ALG3	ALG1	Q9BT22	833
ALG3	ALG11	Q2TAA5	765
ALG3	ALG5	Q9Y673	744
ALG3	ALG14	Q96F25	744
ALG3	DPAGT1	Q9H3H5	743
ALG3	ALG13	Q9NP73	730
ALG3	DPM1	O60762	716
ALG3	PMM2	O15305	706
ALG3	PDCD11	Q14690	661
ALG3	MAN1B1	Q9UKM7	649
ALG3	MOGS	Q13724	644

IntAct

93 interactions, top by confidence:

A	B	Type	Score
CREB3	ALG3	psi-mi:“MI:0915”(physical association)	0.730
ALG3	CREB3	psi-mi:“MI:0915”(physical association)	0.730
ALG3	CREB3	psi-mi:“MI:0915”(physical association)	0.670
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
ALG3	SYPL1	psi-mi:“MI:0915”(physical association)	0.580
SERP1	ALG3	psi-mi:“MI:0915”(physical association)	0.560
TMEM52B	ALG3	psi-mi:“MI:0915”(physical association)	0.560
CD79A	ALG3	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	ALG3	psi-mi:“MI:0915”(physical association)	0.560
SSMEM1	ALG3	psi-mi:“MI:0915”(physical association)	0.560
ALG3	SERP1	psi-mi:“MI:0915”(physical association)	0.560
ZNF7	IPO8	psi-mi:“MI:0914”(association)	0.530
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CD93	RARS1	psi-mi:“MI:0914”(association)	0.530
SLC7A1	STXBP3	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
ALG3	LRP1	psi-mi:“MI:0915”(physical association)	0.510
ALG3	OSBP	psi-mi:“MI:0915”(physical association)	0.510
ALG3	OSBPL9	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (73): ALG3 (Affinity Capture-MS), ALG3 (Affinity Capture-MS), ALG3 (Affinity Capture-MS), GFAP (Affinity Capture-MS), ALDH3B1 (Affinity Capture-MS), TSGA10IP (Affinity Capture-MS), KLHL14 (Affinity Capture-MS), ALG3 (Affinity Capture-MS), ALG3 (Proximity Label-MS), ALG3 (Proximity Label-MS), CREB3 (Two-hybrid), CREB3 (Two-hybrid), TSGA10IP (Affinity Capture-MS), KLHL14 (Affinity Capture-MS), GFAP (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2M425, A1L1J9, B0BNG2, O60725, O75908, O77759, O88269, O88908, O95255, Q0P4J9, Q290J8, Q3T1L5, Q3TAE8, Q3UV71, Q499P8, Q49LS7, Q4R4E1, Q4VV71, Q5F380, Q5KR61, Q5R8F6, Q5RAH7, Q5RKL5, Q6AZ83, Q6NVG1, Q7SXZ1, Q7T310, Q7TPN3, Q7TQM4, Q86VD9, Q8AVI9, Q8BTP0, Q8C0T0, Q8C3X8, Q8CI59, Q8IUR5, Q8K2A8, Q8L638, Q8R1J1, Q8R4P9

Diamond homologs: A1CBE6, A1DDZ3, A2RA94, A3LTB7, A5DJQ5, O82244, P0CN92, P0CN93, P38179, P82149, Q0TVF9, Q24332, Q27333, Q2U6A4, Q4WVG2, Q55F69, Q6BYY8, Q6CMF1, Q6DNA2, Q6FXS2, Q751K5, Q8K2A8, Q92685, Q9C1K8, Q9Y7I4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	16
Uncertain significance	116
Likely benign	71
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1172674	NM_005787.6(ALG3):c.72G>A (p.Trp24Ter)	Pathogenic
1184848	NM_005787.6(ALG3):c.796C>T (p.Arg266Cys)	Pathogenic
1184850	NM_005787.6(ALG3):c.1154G>C (p.Arg385Thr)	Pathogenic
2000151	NM_005787.6(ALG3):c.1188dup (p.Asn397fs)	Pathogenic
2127	NM_005787.6(ALG3):c.353G>A (p.Gly118Asp)	Pathogenic
2131	NM_005787.6(ALG3):c.470T>A (p.Met157Lys)	Pathogenic
2741374	NM_005787.6(ALG3):c.29_45dup (p.Gln16fs)	Pathogenic
2780035	NM_005787.6(ALG3):c.1188G>A (p.Trp396Ter)	Pathogenic
3251416	NM_005787.6(ALG3):c.67C>T (p.Gln23Ter)	Pathogenic
3588985	NM_005787.6(ALG3):c.116del (p.Pro39fs)	Pathogenic
3609293	NM_005787.6(ALG3):c.890_891del (p.His297fs)	Pathogenic
4706770	NM_005787.6(ALG3):c.859C>T (p.Arg287Ter)	Pathogenic
4795102	NM_005787.6(ALG3):c.606-2A>C	Pathogenic
521583	NM_005787.6(ALG3):c.991C>T (p.Gln331Ter)	Pathogenic
57995	GRCh38/hg38 3q27.1(chr3:184200139-184656801)x3	Pathogenic
617476	NM_005787.6(ALG3):c.1263G>A (p.Trp421Ter)	Pathogenic
617513	NM_005787.6(ALG3):c.1037A>G (p.Asn346Ser)	Pathogenic
617517	NM_005787.6(ALG3):c.163_196+3del	Pathogenic
1184851	NM_005787.6(ALG3):c.521A>G (p.Asn174Ser)	Likely pathogenic
1184852	NM_005787.6(ALG3):c.410_411insTGTCTTCTTGCT (p.Leu137_Leu138insValPheLeuLeu)	Likely pathogenic
1695520	NM_005787.6(ALG3):c.668_669del (p.Leu223fs)	Likely pathogenic
2734602	NM_005787.6(ALG3):c.1060C>T (p.Arg354Cys)	Likely pathogenic
3076030	NM_005787.6(ALG3):c.921C>A (p.Cys307Ter)	Likely pathogenic
3374936	NM_005787.6(ALG3):c.444+1G>A	Likely pathogenic
3896067	NM_005787.6(ALG3):c.206T>C (p.Ile69Thr)	Likely pathogenic
4082581	NM_005787.6(ALG3):c.566T>C (p.Leu189Pro)	Likely pathogenic
4531886	NM_005787.6(ALG3):c.488G>A (p.Arg163His)	Likely pathogenic
4849462	NM_005787.6(ALG3):c.511C>T (p.Arg171Trp)	Likely pathogenic
502711	NM_005787.6(ALG3):c.444+1G>T	Likely pathogenic
617514	NM_005787.6(ALG3):c.296+4A>G	Likely pathogenic

SpliceAI

1361 predictions. Top by Δscore:

Variant	Effect	Δscore
3:184243786:CTCAC:C	donor_loss	1.0000
3:184243787:TCAC:T	donor_loss	1.0000
3:184243789:A:C	donor_loss	1.0000
3:184243790:C:CG	donor_loss	1.0000
3:184243993:CCAC:C	acceptor_gain	1.0000
3:184243994:CACC:C	acceptor_gain	1.0000
3:184243995:ACC:A	acceptor_loss	1.0000
3:184243996:CCT:C	acceptor_loss	1.0000
3:184243997:CTG:C	acceptor_loss	1.0000
3:184244732:C:CT	acceptor_gain	1.0000
3:184244733:A:T	acceptor_gain	1.0000
3:184245248:A:AC	donor_gain	1.0000
3:184245249:C:CC	donor_gain	1.0000
3:184245359:C:CC	acceptor_gain	1.0000
3:184245359:CTAAA:C	acceptor_loss	1.0000
3:184245360:T:A	acceptor_loss	1.0000
3:184245464:TCACC:T	donor_loss	1.0000
3:184245465:CA:C	donor_loss	1.0000
3:184245466:A:AC	donor_gain	1.0000
3:184245466:AC:A	donor_gain	1.0000
3:184245466:ACCT:A	donor_loss	1.0000
3:184245467:C:CT	donor_gain	1.0000
3:184245467:CC:C	donor_gain	1.0000
3:184245467:CCT:C	donor_gain	1.0000
3:184245467:CCTTG:C	donor_gain	1.0000
3:184245611:GGTAC:G	acceptor_gain	1.0000
3:184245612:GTAC:G	acceptor_gain	1.0000
3:184245613:TAC:T	acceptor_gain	1.0000
3:184245614:AC:A	acceptor_gain	1.0000
3:184245615:CC:C	acceptor_gain	1.0000

AlphaMissense

2825 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:184242887:G:C	F360L	0.999
3:184242887:G:T	F360L	0.999
3:184242889:A:G	F360L	0.999
3:184242645:A:G	W396R	0.997
3:184242645:A:T	W396R	0.997
3:184245248:A:C	S185R	0.997
3:184245248:A:T	S185R	0.997
3:184245250:T:G	S185R	0.997
3:184245284:G:C	F173L	0.997
3:184245284:G:T	F173L	0.997
3:184245286:A:G	F173L	0.997
3:184245600:G:C	F104L	0.997
3:184245600:G:T	F104L	0.997
3:184245602:A:G	F104L	0.997
3:184242880:A:G	W363R	0.996
3:184242880:A:T	W363R	0.996
3:184242929:G:C	N346K	0.996
3:184242929:G:T	N346K	0.996
3:184243898:G:C	N275K	0.996
3:184243898:G:T	N275K	0.996
3:184243919:A:C	F268L	0.996
3:184243919:A:T	F268L	0.996
3:184243921:A:G	F268L	0.996
3:184245316:G:T	R163S	0.996
3:184245798:A:G	W71R	0.996
3:184245798:A:T	W71R	0.996
3:184242889:A:T	F360I	0.994
3:184243976:G:C	F249L	0.994
3:184243976:G:T	F249L	0.994
3:184243978:A:G	F249L	0.994

dbSNP variants (sampled 300 via entrez): RS1000046885 (3:184245268 T>C), RS1000113898 (3:184248463 A>G), RS1000528091 (3:184248123 G>A), RS1000807655 (3:184250007 G>C,T), RS1000869495 (3:184242077 C>A,T), RS1001109841 (3:184250251 G>A), RS1001433075 (3:184246005 T>C), RS1002435023 (3:184250385 G>GA), RS1002463467 (3:184249498 G>A,C,T), RS1002576656 (3:184246657 C>A,T), RS1003452855 (3:184251330 C>T), RS1003870596 (3:184250997 A>G), RS1004074579 (3:184250630 T>C), RS1004093575 (3:184250778 G>A,C,T), RS1004267404 (3:184244709 A>G)

Disease associations

OMIM: gene MIM:608750 | disease phenotypes: MIM:601110, MIM:210200

GenCC curated gene-disease

Disease	Classification	Inheritance
ALG3-congenital disorder of glycosylation	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ALG3-congenital disorder of glycosylation	Definitive	AR

Mondo (4): ALG3-congenital disorder of glycosylation (MONDO:0010998), 3-methylcrotonyl-CoA carboxylase 1 deficiency (MONDO:0008861), congenital disorder of glycosylation (MONDO:0015286), intellectual disability (MONDO:0001071)

Orphanet (4): ALG3-CDG (Orphanet:79321), 3-methylcrotonyl-CoA carboxylase deficiency (Orphanet:6), Congenital disorder of glycosylation (Orphanet:137), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

78 total (30 of 78 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000119	Abnormality of the genitourinary system
HP:0000158	Macroglossia
HP:0000172	Abnormal uvula morphology
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000365	Hearing impairment
HP:0000366	Abnormality of the nose
HP:0000377	Abnormal pinna morphology
HP:0000400	Macrotia
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000654	Decreased light- and dark-adapted electroretinogram amplitude
HP:0000818	Abnormality of the endocrine system
HP:0000938	Osteopenia
HP:0001010	Hypopigmentation of the skin
HP:0001141	Severely reduced visual acuity
HP:0001181	Adducted thumb
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001469_1	Major depressive disorder	5.000000e-06

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C535308	3-methylcrotonyl CoA carboxylase 1 deficiency (supp.)
C535742	Congenital disorder of glycosylation type 1D (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066258 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.54	Kd	29.11	nM	CHEMBL5653589
7.54	ED50	29.11	nM	CHEMBL5653589

PubChem BioAssay actives

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

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147846: Binding affinity to human ALG3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0291	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Arsenic	affects cotreatment, increases abundance, increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
methylselenic acid	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
corosolic acid	increases expression	1
abrine	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	decreases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Estradiol	increases expression	1
Fluorouracil	affects reaction, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Mercury	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Ribonucleotides	affects binding	1
Selenium	increases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650888	Binding	Binding affinity to human ALG3 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

Cellosaurus cell lines

4 cell lines: 2 finite cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_DB06	GM20947	Finite cell line	Female
CVCL_DB09	GM20950	Finite cell line	Male
CVCL_SC26	HAP1 ALG3 (-) 1	Cancer cell line	Male
CVCL_SC27	HAP1 ALG3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

208 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
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
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)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT02089789	Not specified	RECRUITING	Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT02955264	Not specified	COMPLETED	Using D-Galactose as a Food Supplement in Congenital Disorders of Glycosylation
NCT03250728	Not specified	COMPLETED	Role of the Endothelium in Stroke-like Episode Among CDG Patients
NCT03560570	Not specified	COMPLETED	Study of Hemostasis in Patients With Congenital Disorder of Glycosylation
NCT04198987	Not specified	COMPLETED	Dietary Monosaccharide Supplementation in Patients With Congenital Disorders of Glycosylation
NCT04199000	Not specified	RECRUITING	Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
NCT04201067	Not specified	COMPLETED	Large-Scale Metabolomic Profiling for the Diagnosis of Inborn Errors of Metabolism
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