ALG1

Summary

ALG1 (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase, HGNC:18294) is a protein-coding gene on chromosome 16p13.3, encoding Chitobiosyldiphosphodolichol beta-mannosyltransferase (Q9BT22). Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation. It is a common-essential gene (DepMap: required in 90.5% of cancer cell lines).

The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik.

Source: NCBI Gene 56052 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ALG1-congenital disorder of glycosylation (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 949 total — 65 pathogenic, 42 likely-pathogenic
• Phenotypes (HPO): 53
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 90.5% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_019109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18294
Approved symbol	ALG1
Name	ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	HMT-1, HMAT1, CDG1K, Mat-1
Ensembl gene	ENSG00000033011
Ensembl biotype	protein_coding
OMIM	605907
Entrez	56052

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 20 protein_coding, 7 retained_intron, 6 nonsense_mediated_decay

ENST00000262374, ENST00000544428, ENST00000586840, ENST00000588623, ENST00000591783, ENST00000591822, ENST00000592793, ENST00000632058, ENST00000650085, ENST00000682020, ENST00000682206, ENST00000682314, ENST00000682327, ENST00000682349, ENST00000682703, ENST00000682797, ENST00000682985, ENST00000683433, ENST00000683685, ENST00000683710, ENST00000683739, ENST00000683772, ENST00000684008, ENST00000684190, ENST00000684335, ENST00000902497, ENST00000902498, ENST00000902499, ENST00000940711, ENST00000940712, ENST00000940713, ENST00000961948, ENST00000961949

RefSeq mRNA: 2 — MANE Select: NM_019109 NM_001330504, NM_019109

CCDS: CCDS10528, CCDS81946

Canonical transcript exons

ENST00000262374 — 13 exons

Exon	Start	End
ENSE00002769714	5071843	5072057
ENSE00002845208	5084750	5087379
ENSE00003503280	5077907	5078017
ENSE00003510272	5073153	5073256
ENSE00003567225	5080946	5081056
ENSE00003572259	5083682	5083757
ENSE00003582007	5075388	5075536
ENSE00003582823	5079064	5079102
ENSE00003593961	5079748	5079807
ENSE00003641126	5078757	5078878
ENSE00003650980	5077445	5077534
ENSE00003657955	5082559	5082673
ENSE00003672899	5072951	5073028

Expression profiles

Bgee: expression breadth ubiquitous, 185 present calls, max score 92.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.4048 / max 145.9400, expressed in 1801 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
152516	17.8028	1801
152515	0.6020	321

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	92.05	gold quality
buccal mucosa cell	CL:0002336	89.88	silver quality
body of pancreas	UBERON:0001150	89.38	gold quality
left adrenal gland	UBERON:0001234	89.19	gold quality
right adrenal gland cortex	UBERON:0035827	88.99	gold quality
right adrenal gland	UBERON:0001233	88.94	gold quality
mucosa of transverse colon	UBERON:0004991	88.69	gold quality
left adrenal gland cortex	UBERON:0035825	88.56	gold quality
body of stomach	UBERON:0001161	87.40	gold quality
islet of Langerhans	UBERON:0000006	87.25	gold quality
right testis	UBERON:0004534	87.20	gold quality
left testis	UBERON:0004533	87.13	gold quality
pancreas	UBERON:0001264	87.11	gold quality
granulocyte	CL:0000094	86.52	gold quality
adrenal gland	UBERON:0002369	86.31	gold quality
adrenal cortex	UBERON:0001235	85.87	gold quality
rectum	UBERON:0001052	85.42	gold quality
bone marrow cell	CL:0002092	85.39	gold quality
transverse colon	UBERON:0001157	85.29	gold quality
minor salivary gland	UBERON:0001830	84.51	gold quality
stomach	UBERON:0000945	84.30	gold quality
leukocyte	CL:0000738	84.19	gold quality
right lobe of liver	UBERON:0001114	84.11	gold quality
monocyte	CL:0000576	83.93	gold quality
testis	UBERON:0000473	83.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.91	gold quality
smooth muscle tissue	UBERON:0001135	83.59	gold quality
right lobe of thyroid gland	UBERON:0001119	83.57	gold quality
vermiform appendix	UBERON:0001154	83.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.93
E-MTAB-7606	no	1522.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

97 targeting ALG1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4728-5P	99.85	69.39	4718

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 90.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 6)

• DNA sequencing of ALG1 revealed nine different mutations, seven of which have not been previously reported. Clinical presentations of deficiency are severe, with dysmorphias, CNS involvement and ocular disturbances (PMID:20679665)
• Family study defining the phenotype of deficiency of beta-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Four novel ALG1 mutations were identified. (PMID:22966035)
• Was detected in the patient’s ALG1-coding sequence. (PMID:24157261)
• Study presents molecular, clinical and biochemical findings in the largest collection of ALG1-CDG cases ever reported at a single time with 39 cases, bringing the total number to 57. This ranks it the third most common CDG type behind PMM2-CDG and ALG6-CDG. In addition, highly lethal genotype were identified and confirm the presence of a unique xeno-tetrasaccharide in ALG1-CDG patients. (PMID:26931382)
• evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) (PMID:29309433)
• Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts. (PMID:38470198)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alg1	ENSDARG00000054963
mus_musculus	Alg1	ENSMUSG00000039427
rattus_norvegicus	Alg1	ENSRNOG00000002883
drosophila_melanogaster	Alg1	FBGN0038552
caenorhabditis_elegans		WBGENE00020820

Paralogs (1): ALG1L2 (ENSG00000251287)

Protein

Protein identifiers

Chitobiosyldiphosphodolichol beta-mannosyltransferase — Q9BT22 (reviewed: Q9BT22)

Alternative names: Asparagine-linked glycosylation protein 1 homolog, Beta-1,4-mannosyltransferase, GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase, GDP-mannose-dolichol diphosphochitobiose mannosyltransferase, Mannosyltransferase-1

All UniProt accessions (14): A0A804HHW1, A0A804HIG6, A0A804HJE3, A0A804HJL6, A0A804HJQ1, A0A804HKJ4, A0A804HKK4, A0A804HKU4, A0A804HKX7, Q9BT22, A0A804HLB7, K7EID2, K7EPU3, K7EQK1

UniProt curated annotations — full annotation on UniProt →

Function. 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. Catalyzes, on the cytoplasmic face of the endoplasmic reticulum, the addition of the first mannose residues to the dolichol-linked oligosaccharide chain, to produce Man1GlcNAc(2)-PP-dolichol core oligosaccharide. Man1GlcNAc(2)-PP-dolichol is a substrate for ALG2, the following enzyme in the biosynthetic pathway.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1K (CDG1K) [MIM:608540] 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 group 1 family. Glycosyltransferase 33 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BT22-1	1	yes
Q9BT22-2	2

RefSeq proteins (2): NP_001317433, NP_061982* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001296	Glyco_trans_1	Domain
IPR026051	ALG1-like	Family

Pfam: PF00534

Enzyme classification (BRENDA):

• EC 2.4.1.142 — chitobiosyldiphosphodolichol beta-mannosyltransferase (BRENDA: 5 organisms, 8 substrates, 5 inhibitors, 2 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GDP-MANNOSE	0.0005–0.0017	2

Catalyzed reactions (Rhea), 1 shown:

• an N,N’-diacetylchitobiosyl-diphospho-di-trans,poly-cis-dolichol + GDP-alpha-D-mannose = a beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP + H(+) (RHEA:13865)

UniProt features (38 total): sequence variant 29, topological domain 3, chain 1, transmembrane region 1, intramembrane region 1, region of interest 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BT22-F1	93.24	0.83

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): 242

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-4549380	Defective ALG1 causes CDG-1k
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: 225 (showing top): GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, KEGG_N_GLYCAN_BIOSYNTHESIS, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, USF_01, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, GRADE_COLON_AND_RECTAL_CANCER_UP, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, GOCC_CYTOPLASMIC_SIDE_OF_MEMBRANE, GOCC_SIDE_OF_MEMBRANE, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK, GOCC_ORGANELLE_SUBCOMPARTMENT, GOMF_HEXOSYLTRANSFERASE_ACTIVITY, GOMF_MANNOSYLTRANSFERASE_ACTIVITY

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 (4): mannosyltransferase activity (GO:0000030), chitobiosyldiphosphodolichol beta-mannosyltransferase activity (GO:0004578), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554)

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
hexosyltransferase activity	1
beta-1,4-mannosyltransferase activity	1
GlcNAc(2)-PP-Dol mannosyltransferase activity	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
cellular anatomical structure	1
endoplasmic reticulum membrane	1
cytoplasmic side of membrane	1

Protein interactions and networks

STRING

2052 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALG1	ALG6	Q9Y672	964
ALG1	SEC14L5	O43304	959
ALG1	ALG11	Q2TAA5	933
ALG1	ALG3	Q92685	833
ALG1	DPAGT1	Q9H3H5	799
ALG1	ALG8	Q9BVK2	794
ALG1	ALG12	Q9BV10	785
ALG1	PDCD6	O75340	777
ALG1	PMM2	O15305	772
ALG1	ALG13	Q9NP73	772
ALG1	FAM90A1	Q86YD7	767
ALG1	ALG5	Q9Y673	762
ALG1	PLTP	P55058	762
ALG1	ALG14	Q96F25	751
ALG1	DPM1	O60762	708

IntAct

42 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
TGOLN2	PGRMC1	psi-mi:“MI:0914”(association)	0.420
	ESYT2	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
	HAX1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
MAD2L2		psi-mi:“MI:0914”(association)	0.350
	ZFC3H1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
PA	DDX39A	psi-mi:“MI:0914”(association)	0.350
POMK	ESYT2	psi-mi:“MI:0914”(association)	0.350
NTRK1	ILVBL	psi-mi:“MI:0914”(association)	0.350
NTRK3	ILVBL	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
POLD3	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
SLC15A2	LGALS8	psi-mi:“MI:0914”(association)	0.350
SLC22A5	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SLC23A1	NEMP1	psi-mi:“MI:0914”(association)	0.350
SLC2A5	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC35D2	TM9SF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (93): ALG1 (Affinity Capture-RNA), ALG1 (Affinity Capture-RNA), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Reconstituted Complex), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS), ALG1 (Affinity Capture-MS)

ESM2 similar proteins: A2AI05, D3ZDK7, E1BNQ4, O55240, O70249, P21139, P24298, P25409, P50336, P51175, P56602, P97849, Q03426, Q1JPJ0, Q27979, Q2KJF7, Q3T0A0, Q3ZKN0, Q498R1, Q4JIJ2, Q5E9M9, Q5E9T8, Q5R7A2, Q5RK23, Q60714, Q60HD5, Q6AYG0, Q6NRG5, Q6P1M0, Q6P3E7, Q6PCB7, Q6PFP6, Q7TSA0, Q8BNV1, Q8BZG5, Q8C1A3, Q8CHP8, Q8IXI1, Q8JZN7, Q8QZR5

Diamond homologs: C9J202, D4AZD1, O13933, P16661, P90522, Q59Q79, Q5R7A2, Q6BS98, Q6C3K2, Q6CVU2, Q6FLZ2, Q75BA5, Q8L7M0, Q921Q3, Q9BT22

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ALG1	“up-regulates quantity”	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(PP-Dol)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 48 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
SLC-mediated transmembrane transport	5	11.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	65
Likely pathogenic	42
Uncertain significance	291
Likely benign	418
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1179118	GRCh37/hg19 16p13.3(chr16:5129043-5129828)	Pathogenic
1179164	GRCh37/hg19 16p13.3(chr16:5121789-5133778)	Pathogenic
1323043	NM_019109.5(ALG1):c.1073-2A>G	Pathogenic
1323051	NM_019109.5(ALG1):c.791_804del (p.Asp264fs)	Pathogenic
1393773	NC_000016.9:g.(?5121851)(5134882_?)del	Pathogenic
1400583	NM_019109.5(ALG1):c.398_399insCA (p.Gly134fs)	Pathogenic
1416621	NM_019109.5(ALG1):c.309C>G (p.Tyr103Ter)	Pathogenic
1421067	NM_019109.5(ALG1):c.711_726del (p.Gly238fs)	Pathogenic
1457013	NM_019109.5(ALG1):c.621G>A (p.Trp207Ter)	Pathogenic
1458147	NM_019109.5(ALG1):c.1182C>G (p.Phe394Leu)	Pathogenic
1522448	NC_000016.9:g.(?5125369)(5134882_?)del	Pathogenic
193419	NM_019109.5(ALG1):c.15C>A (p.Cys5Ter)	Pathogenic
1994449	NM_019109.5(ALG1):c.235C>T (p.Gln79Ter)	Pathogenic
2095499	NM_019109.5(ALG1):c.710del (p.Leu237fs)	Pathogenic
2103963	NM_019109.5(ALG1):c.1255C>T (p.Gln419Ter)	Pathogenic
2115837	NM_019109.5(ALG1):c.486dup (p.Ile163fs)	Pathogenic
2183419	NM_019109.5(ALG1):c.740_740+5delinsTGTAGA	Pathogenic
2426514	NC_000016.9:g.(?5121851)(5125557_?)del	Pathogenic
2442437	NM_019109.5(ALG1):c.1095_1098del (p.Leu366fs)	Pathogenic
2697122	NM_019109.5(ALG1):c.645C>G (p.Tyr215Ter)	Pathogenic
2698916	NM_019109.5(ALG1):c.875del (p.Phe292fs)	Pathogenic
2698923	NM_019109.5(ALG1):c.301_302dup (p.Gln102fs)	Pathogenic
2706806	NM_019109.5(ALG1):c.1263+2T>C	Pathogenic
2748116	NM_019109.5(ALG1):c.87_91del (p.Arg30fs)	Pathogenic
2759859	NM_019109.5(ALG1):c.743C>G (p.Ser248Ter)	Pathogenic
2772868	NM_019109.5(ALG1):c.185C>A (p.Ser62Ter)	Pathogenic
2773133	NM_019109.5(ALG1):c.920_921del (p.Leu307fs)	Pathogenic
2781356	NM_019109.5(ALG1):c.969del (p.Pro324fs)	Pathogenic
2816535	NM_019109.5(ALG1):c.11C>A (p.Ser4Ter)	Pathogenic
2819765	NM_019109.5(ALG1):c.898G>T (p.Glu300Ter)	Pathogenic

SpliceAI

3431 predictions. Top by Δscore:

Variant	Effect	Δscore
16:5055266:T:TA	donor_gain	1.0000
16:5056051:A:AC	donor_gain	1.0000
16:5056052:C:CT	donor_gain	1.0000
16:5056184:CCCCT:C	acceptor_gain	1.0000
16:5056185:CCCT:C	acceptor_gain	1.0000
16:5056185:CCCTC:C	acceptor_gain	1.0000
16:5056186:CCTC:C	acceptor_gain	1.0000
16:5056187:CT:C	acceptor_gain	1.0000
16:5062421:TCA:T	donor_loss	1.0000
16:5062423:A:T	donor_loss	1.0000
16:5062424:C:T	donor_loss	1.0000
16:5062424:CCT:C	donor_gain	1.0000
16:5062449:G:C	donor_gain	1.0000
16:5062570:CTGCT:C	acceptor_gain	1.0000
16:5062571:TGCT:T	acceptor_gain	1.0000
16:5062573:CT:C	acceptor_gain	1.0000
16:5062575:C:CC	acceptor_gain	1.0000
16:5072055:GCA:G	donor_gain	1.0000
16:5072058:G:GG	donor_gain	1.0000
16:5072949:A:AG	acceptor_gain	1.0000
16:5072950:G:GG	acceptor_gain	1.0000
16:5073151:A:AG	acceptor_gain	1.0000
16:5073151:AGTT:A	acceptor_gain	1.0000
16:5073151:AGTTG:A	acceptor_gain	1.0000
16:5073152:G:GG	acceptor_gain	1.0000
16:5073152:GTTG:G	acceptor_gain	1.0000
16:5073152:GTTGG:G	acceptor_gain	1.0000
16:5077441:TCAGG:T	acceptor_loss	1.0000
16:5077443:A:AG	acceptor_gain	1.0000
16:5077443:AG:A	acceptor_gain	1.0000

AlphaMissense

3009 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:5078872:T:A	W286R	0.998
16:5078872:T:C	W286R	0.998
16:5075463:T:A	W156R	0.997
16:5075463:T:C	W156R	0.997
16:5078860:A:C	S282R	0.997
16:5078862:C:A	S282R	0.997
16:5078862:C:G	S282R	0.997
16:5082585:C:G	H367D	0.997
16:5075466:C:G	H157D	0.996
16:5078863:A:C	S283R	0.996
16:5078865:C:A	S283R	0.996
16:5078865:C:G	S283R	0.996
16:5082597:A:C	S371R	0.996
16:5082599:T:A	S371R	0.996
16:5082599:T:G	S371R	0.996
16:5071985:A:C	S46R	0.995
16:5071987:C:A	S46R	0.995
16:5071987:C:G	S46R	0.995
16:5075471:C:A	N158K	0.995
16:5075471:C:G	N158K	0.995
16:5077492:C:T	T196I	0.995
16:5078869:A:C	S285R	0.995
16:5078871:C:A	S285R	0.995
16:5078871:C:G	S285R	0.995
16:5082579:T:C	C365R	0.995
16:5082608:C:A	D374E	0.995
16:5082608:C:G	D374E	0.995
16:5082581:T:G	C365W	0.994
16:5082607:A:T	D374V	0.994
16:5083722:T:C	F410L	0.994

dbSNP variants (sampled 300 via entrez): RS1000036457 (16:5071659 G>C), RS1000062991 (16:5070802 G>A,T), RS1000086760 (16:5071780 C>A,G,T), RS1000133382 (16:5075350 T>C), RS1000237447 (16:5085833 T>G), RS1000262891 (16:5076066 C>A,T), RS1000486504 (16:5080049 T>A), RS1000651085 (16:5075249 G>C), RS1000946354 (16:5074410 A>T), RS1000952792 (16:5087531 G>C), RS1001005100 (16:5087653 C>G,T), RS1001291553 (16:5071527 C>G), RS1001394230 (16:5083257 G>A), RS1001426856 (16:5071329 T>A), RS1001598239 (16:5079625 G>A,T)

Disease associations

OMIM: gene MIM:605907 | disease phenotypes: MIM:608540, MIM:256300, MIM:147920, MIM:212065, MIM:607143

GenCC curated gene-disease

Disease	Classification	Inheritance
ALG1-congenital disorder of glycosylation	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ALG1-congenital disorder of glycosylation	Definitive	AR

Mondo (7): ALG1-congenital disorder of glycosylation (MONDO:0012052), congenital nephrotic syndrome, Finnish type (MONDO:0009732), congenital disorder of glycosylation (MONDO:0015286), Kabuki syndrome 1 (MONDO:0007843), congenital disorder of glycosylation type I (MONDO:0005500), ALG12-congenital disorder of glycosylation (MONDO:0011783), intellectual disability (MONDO:0001071)

Orphanet (6): ALG1-CDG (Orphanet:79327), Congenital nephrotic syndrome, Finnish type (Orphanet:839), Congenital disorder of glycosylation (Orphanet:137), Kabuki syndrome (Orphanet:2322), ALG12-CDG (Orphanet:79324), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000100	Nephrotic syndrome
HP:0000135	Hypogonadism
HP:0000233	Thin vermilion border
HP:0000239	Large fontanelles
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000478	Abnormality of the eye
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000924	Abnormality of the skeletal system
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001410	Decreased liver function
HP:0001511	Intrauterine growth retardation
HP:0001522	Death in infancy
HP:0001560	Abnormality of the amniotic fluid
HP:0001627	Abnormal heart morphology

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001414_15	Phospholipid levels (plasma)	1.000000e-08
GCST009391_2050	Metabolite levels	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010508	malate measurement

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
C535745	Congenital disorder of glycosylation type 1G (supp.)
C535749	Congenital disorder of glycosylation type 1K (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067414 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.81	Kd	15.57	nM	CHEMBL5653589
7.79	ED50	16.33	nM	CHEMBL5653589
5.96	Kd	1083	nM	CHEMBL3752910
5.95	ED50	1136	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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	2147844: Binding affinity to human ALG1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0156	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147844: Binding affinity to human ALG1 incubated for 45 mins by Kinobead based pull down assay	kd	1.0832	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
Arsenic	affects methylation	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	increases expression, decreases expression, decreases methylation	1
Cyclosporine	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
CHEMBL5650886	Binding	Binding affinity to human ALG1 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)

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)
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
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
NCT03855631	Not specified	COMPLETED	Exploiting Epigenome Editing in Kabuki Syndrome: a New Route Towards Gene Therapy for Rare Genetic Disorders
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