ALG2

Summary

ALG2 (ALG2 alpha-1,3/1,6-mannosyltransferase, HGNC:23159) is a protein-coding gene on chromosome 9q22.33, encoding Alpha-1,3/1,6-mannosyltransferase ALG2 (Q9H553). 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 98.4% of cancer cell lines).

This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 85365 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ALG2-congenital disorder of glycosylation (Strong, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 373 total — 6 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 100
• Cancer dependency (DepMap): dependent in 98.4% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_033087

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23159
Approved symbol	ALG2
Name	ALG2 alpha-1,3/1,6-mannosyltransferase
Location	9q22.33
Locus type	gene with protein product
Status	Approved
Aliases	CDGIi, FLJ14511, hALPG2, NET38, CDG1I
Ensembl gene	ENSG00000119523
Ensembl biotype	protein_coding
OMIM	607905
Entrez	85365

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 nonsense_mediated_decay

ENST00000238477, ENST00000319033, ENST00000476832, ENST00000906837

RefSeq mRNA: 1 — MANE Select: NM_033087 NM_033087

CCDS: CCDS6739

Canonical transcript exons

ENST00000476832 — 2 exons

Exon	Start	End
ENSE00001894476	99221547	99221942
ENSE00001911308	99216425	99218836

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.3634 / max 180.3867, expressed in 1815 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101702	25.3634	1815

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	98.12	gold quality
corpus epididymis	UBERON:0004359	97.41	gold quality
caput epididymis	UBERON:0004358	97.21	gold quality
secondary oocyte	CL:0000655	96.78	gold quality
germinal epithelium of ovary	UBERON:0001304	96.10	gold quality
tibia	UBERON:0000979	95.98	gold quality
cartilage tissue	UBERON:0002418	95.71	gold quality
islet of Langerhans	UBERON:0000006	95.67	gold quality
body of pancreas	UBERON:0001150	95.62	gold quality
visceral pleura	UBERON:0002401	95.58	gold quality
parietal pleura	UBERON:0002400	95.36	gold quality
pancreas	UBERON:0001264	95.20	gold quality
ileal mucosa	UBERON:0000331	95.13	gold quality
parotid gland	UBERON:0001831	95.06	gold quality
palpebral conjunctiva	UBERON:0001812	94.95	gold quality
cauda epididymis	UBERON:0004360	94.76	gold quality
seminal vesicle	UBERON:0000998	94.00	gold quality
decidua	UBERON:0002450	93.95	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.62	gold quality
esophagus squamous epithelium	UBERON:0006920	93.22	gold quality
placenta	UBERON:0001987	93.19	gold quality
epithelium of nasopharynx	UBERON:0001951	93.11	gold quality
colonic mucosa	UBERON:0000317	93.07	gold quality
bronchial epithelial cell	CL:0002328	92.75	gold quality
pancreatic ductal cell	CL:0002079	92.74	gold quality
gingival epithelium	UBERON:0001949	92.69	gold quality
endometrium	UBERON:0001295	92.57	gold quality
right adrenal gland	UBERON:0001233	92.55	gold quality
left adrenal gland	UBERON:0001234	92.54	gold quality
adrenal tissue	UBERON:0018303	92.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

84 targeting ALG2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4719	99.73	72.10	3329

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 98.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 2)

• We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome (PMID:23404334)
• Topological and enzymatic analysis of human Alg2 mannosyltransferase reveals its role in lipid-linked oligosaccharide biosynthetic pathway. (PMID:35136180)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	alg2	ENSDARG00000070399
mus_musculus	Alg2	ENSMUSG00000039740
rattus_norvegicus	Alg2	ENSRNOG00000006369
drosophila_melanogaster	Alg2	FBGN0035401
caenorhabditis_elegans		WBGENE00017282

Paralogs (3): GLT1D1 (ENSG00000151948), PIGA (ENSG00000165195), ALG11 (ENSG00000253710)

Protein

Protein identifiers

Alpha-1,3/1,6-mannosyltransferase ALG2 — Q9H553 (reviewed: Q9H553)

Alternative names: Asparagine-linked glycosylation protein 2 homolog, GDP-Man:Man(1)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase, GDP-Man:Man(1)GlcNAc(2)-PP-dolichol mannosyltransferase, GDP-Man:Man(2)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase

All UniProt accessions (2): A0A0A0MTE0, Q9H553

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 second and third mannose residues to the dolichol-linked oligosaccharide chain, to produce Man3GlcNAc(2)-PP-dolichol core oligosaccharide. Man3GlcNAc(2)-PP-dolichol is a substrate for ALG11, the following enzyme in the biosynthetic pathway. While both alpha 1,3 and alpha 1,6 linkages are possible, the sequential addition of alpha 1,3 followed by alpha 1,6 is probably the preferred route.

Subcellular location. Endoplasmic reticulum membrane.

Disease relevance. Congenital disorder of glycosylation 1I (CDG1I) [MIM:607906] 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. Myasthenic syndrome, congenital, 14 (CMS14) [MIM:616228] A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness. CMS14 is an autosomal recessive form characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. 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 4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H553-1	1	yes
Q9H553-2	2

RefSeq proteins (1): NP_149078* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001296	Glyco_trans_1	Domain
IPR027054	ALG2	Family
IPR028098	Glyco_trans_4-like_N	Domain

Pfam: PF00534, PF13439

Enzyme classification (BRENDA):

• EC 2.4.1.132 — GDP-Man:Man1GlcNAc2-PP-dolichol alpha-1,3-mannosyltransferase (BRENDA: 8 organisms, 29 substrates, 25 inhibitors, 7 Km, 2 kcat entries)
• EC 2.4.1.257 — GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase (BRENDA: 2 organisms, 9 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GDPMANNOSE	0.0006–0.0014	2
TETRASACCHARIDE-DIPHOSPHORYL-LIPID	0.0002–0.001	2
ALPHA-D-MAN-(1->3)-BETA-D-MAN-(1->4)-BETA-D-GLCN	0.0151	1
ALPHA-D-MAN-(1->6)-BETA-D-MAN-(1->4)-BETA-D-GLCN	0.1367	1
GDP-ALPHA-D-MANNOSE	0.56	1

Catalyzed reactions (Rhea), 4 shown:

• a beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP-alpha-D-mannose = an alpha-D-Man-(1->3)-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP + H(+) (RHEA:29515)
• an alpha-D-Man-(1->3)-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP-alpha-D-mannose = an 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 + GDP + H(+) (RHEA:29519)
• a beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP-alpha-D-mannose = an alpha-D-Man-(1->6)-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP + H(+) (RHEA:79023)
• an alpha-D-Man-(1->6)-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc-diphospho-di-trans,poly-cis-dolichol + GDP-alpha-D-mannose = an 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 + GDP + H(+) (RHEA:79027)

UniProt features (10 total): sequence variant 3, topological domain 2, splice variant 2, chain 1, intramembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H553-F1	91.03	0.75

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-4549349	Defective ALG2 causes CDG-1i
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: 340 (showing top): GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, KEGG_N_GLYCAN_BIOSYNTHESIS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, GTGCCTT_MIR506, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MAGRANGEAS_MULTIPLE_MYELOMA_IGG_VS_IGA_UP, chr9q22, TGCCTTA_MIR124A, GOBP_GLYCOPROTEIN_METABOLIC_PROCESS, CAFFAREL_RESPONSE_TO_THC_24HR_5_DN, GOCC_CYTOPLASMIC_SIDE_OF_MEMBRANE, GOCC_SIDE_OF_MEMBRANE, GOCC_NUCLEAR_OUTER_MEMBRANE_ENDOPLASMIC_RETICULUM_MEMBRANE_NETWORK

GO Biological Process (4): protein N-linked glycosylation (GO:0006487), dolichol-linked oligosaccharide biosynthetic process (GO:0006488), glycoprotein biosynthetic process (GO:0009101), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (6): alpha-1,3-mannosyltransferase activity (GO:0000033), GDP-Man:Man(1)GlcNAc(2)-PP-Dol alpha-1,3-mannosyltransferase activity (GO:0004378), GDP-Man:Man(2)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase activity (GO:0102704), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (5): endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), endoplasmic reticulum (GO:0005783)

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
carbohydrate derivative biosynthetic process	2
GlcNAc(2)-PP-Dol mannosyltransferase activity	2
cellular anatomical structure	2
glycoprotein biosynthetic process	1
protein N-linked glycosylation	1
macromolecule biosynthetic process	1
glycoprotein metabolic process	1
mannosyltransferase activity	1
alpha-1,3-mannosyltransferase activity	1
alpha-1,6-mannosyltransferase activity	1
binding	1
catalytic activity	1
transferase activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1
endoplasmic reticulum membrane	1
cytoplasmic side of membrane	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1862 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALG2	ATP6V0A2	Q9Y487	925
ALG2	PMM2	O15305	912
ALG2	ALG3	Q92685	890
ALG2	ALG6	Q9Y672	834
ALG2	ATP4A	P20648	730
ALG2	ATP12A	P54707	719
ALG2	EFEMP2	O95967	719
ALG2	ALG1	Q9BT22	693
ALG2	ALG12	Q9BV10	689
ALG2	ALG8	Q9BVK2	666
ALG2	COG8	Q96MW5	654
ALG2	FBLN5	Q9UBX5	652
ALG2	MAN1B1	Q9UKM7	642
ALG2	CP	P00450	615
ALG2	COG1	Q8WTW3	609

IntAct

38 interactions, top by confidence:

A	B	Type	Score
KLHL12	CUL3	psi-mi:“MI:0914”(association)	0.920
KLHL12	KLHL2	psi-mi:“MI:0914”(association)	0.850
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
HTT	ALG2	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	ALG2	psi-mi:“MI:0915”(physical association)	0.560
TGOLN2	DENND11	psi-mi:“MI:0914”(association)	0.530
HMOX2	PRAF2	psi-mi:“MI:0914”(association)	0.530
BSG	BTAF1	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
ALG2	LDHA	psi-mi:“MI:0914”(association)	0.350
TACSTD2	RIMOC1	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
LAMTOR1	DEGS1	psi-mi:“MI:0914”(association)	0.350
ALG2	POTEF	psi-mi:“MI:0914”(association)	0.350
VSIG4	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
ACKR3	PDE2A	psi-mi:“MI:0914”(association)	0.350
ACTL6B	SLC25A16	psi-mi:“MI:0914”(association)	0.350
C1QA	VWA8	psi-mi:“MI:0914”(association)	0.350
CELA3A	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
CHIA	SLC25A16	psi-mi:“MI:0914”(association)	0.350
FPR1	NBAS	psi-mi:“MI:0914”(association)	0.350

BioGRID (67): ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Reconstituted Complex), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Affinity Capture-MS), ALG2 (Far Western), ALG2 (Far Western), ALG2 (Reconstituted Complex), ALG2 (Reconstituted Complex)

ESM2 similar proteins: A0A0P0UZP7, A0A0P0V5U9, A0A0P0WIY3, A2TIL1, A2WYS7, A2WYS8, A3BLS0, B6TNK6, B8ANW0, C0PBF8, O23024, O49312, O64489, P00390, P0C0M2, P51108, Q0D4Z6, Q0DGU2, Q0IP69, Q0JG98, Q0JG99, Q10RE2, Q10S72, Q1JPL4, Q53QK0, Q5W6F9, Q60EJ6, Q60EY8, Q69PS6, Q69RG7, Q6Z9F4, Q6ZD89, Q6ZLA3, Q7XQ85, Q7ZW24, Q8BWN8, Q8RZA1, Q8VZ59, Q94BP3, Q9FM04

Diamond homologs: O94738, P43636, P9WMZ2, P9WMZ3, Q4H4F8, Q59LF2, Q6BVA4, Q6C3V7, Q6CWQ0, Q6FJJ9, Q755C1, Q7KWM5, Q8X0H8, Q96WW6, Q9DBE8, Q9FCG5, Q9H553, P39862, Q59002, A0A059ZV61, D4H6M0, O58762, O65026, P10691, P13708, P31926, P49034, P49035, P49037, P49039, Q01390, Q43009, Q4JAK2, Q7LYW5, Q82G92, Q9HH00, A0QWG6, A1R8N8, A4X1R6, A6YRN9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ALG2	“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”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	6
Uncertain significance	205
Likely benign	132
Benign	9

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1676197	NM_033087.4(ALG2):c.752G>T (p.Arg251Leu)	Pathogenic
183018	NM_033087.4(ALG2):c.214_224delinsAGTCCCCG (p.Gly72_Leu75delinsSerProArg)	Pathogenic
183019	NM_033087.4(ALG2):c.203T>G (p.Val68Gly)	Pathogenic
2700	NM_033087.4(ALG2):c.393G>T (p.Lys131Asn)	Pathogenic
442750	GRCh37/hg19 9q22.33(chr9:100625192-102129138)x1	Pathogenic
992273	NM_033087.4(ALG2):c.215_225del (p.Gly72fs)	Pathogenic
1184506	NM_033087.4(ALG2):c.176G>A (p.Cys59Tyr)	Likely pathogenic
2498382	NM_033087.4(ALG2):c.1193T>C (p.Phe398Ser)	Likely pathogenic
3064139	NM_033087.4(ALG2):c.216delinsTCCCC (p.Asp73fs)	Likely pathogenic
3779328	NM_033087.4(ALG2):c.814G>T (p.Glu272Ter)	Likely pathogenic
442793	GRCh37/hg19 9q22.32-31.1(chr9:97553176-102919383)x3	Likely pathogenic
915335	NM_033087.4(ALG2):c.218_225del (p.Asp73fs)	Likely pathogenic

SpliceAI

362 predictions. Top by Δscore:

Variant	Effect	Δscore
9:99221411:ACAAC:A	donor_gain	0.9900
9:99221412:CAACC:C	donor_gain	0.9900
9:99221543:TCACC:T	donor_loss	0.9900
9:99221544:CA:C	donor_loss	0.9900
9:99218834:CAC:C	acceptor_gain	0.9800
9:99221558:C:CT	donor_gain	0.9800
9:99221559:T:TT	donor_gain	0.9800
9:99218836:CCTAG:C	acceptor_loss	0.9700
9:99218837:CTAG:C	acceptor_loss	0.9700
9:99218842:C:CT	acceptor_gain	0.9700
9:99218843:A:T	acceptor_gain	0.9600
9:99221423:T:TA	donor_gain	0.9600
9:99221557:A:AC	donor_gain	0.9600
9:99218837:C:CC	acceptor_gain	0.9500
9:99218842:C:T	acceptor_gain	0.9400
9:99221412:CAA:C	donor_gain	0.9400
9:99221415:C:A	donor_gain	0.9400
9:99218832:GACAC:G	acceptor_gain	0.9300
9:99221556:CA:C	donor_gain	0.9300
9:99221561:C:CT	donor_gain	0.9300
9:99221058:G:C	donor_gain	0.9200
9:99221413:A:AT	donor_gain	0.9100
9:99218835:AC:A	acceptor_gain	0.9000
9:99218836:CC:C	acceptor_gain	0.9000
9:99221410:CACA:C	donor_gain	0.9000
9:99221411:ACAA:A	donor_gain	0.9000
9:99221412:CAAC:C	donor_gain	0.9000
9:99221545:A:AC	donor_gain	0.8700
9:99221546:C:CC	donor_gain	0.8700
9:99218848:A:T	acceptor_gain	0.8600

AlphaMissense

2694 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:99218773:G:C	H138D	0.997
9:99218472:T:A	K238I	0.996
9:99218657:G:C	N176K	0.996
9:99218657:G:T	N176K	0.996
9:99218207:G:C	H326Q	0.995
9:99218207:G:T	H326Q	0.995
9:99218211:T:A	E325V	0.995
9:99221834:G:C	H21D	0.995
9:99217991:A:C	F398L	0.994
9:99217991:A:T	F398L	0.994
9:99217993:A:G	F398L	0.994
9:99218768:G:C	F139L	0.994
9:99218768:G:T	F139L	0.994
9:99218770:A:G	F139L	0.994
9:99218771:G:C	H138Q	0.994
9:99218771:G:T	H138Q	0.994
9:99218780:A:C	F135L	0.994
9:99218780:A:T	F135L	0.994
9:99218782:A:G	F135L	0.994
9:99221806:T:A	E30V	0.994
9:99218211:T:G	E325A	0.993
9:99218648:G:C	F179L	0.993
9:99218648:G:T	F179L	0.993
9:99218650:A:G	F179L	0.993
9:99218654:G:C	S177R	0.993
9:99218654:G:T	S177R	0.993
9:99218655:C:A	S177I	0.993
9:99218656:T:G	S177R	0.993
9:99218774:A:C	C137W	0.993
9:99221789:C:G	A36P	0.993

dbSNP variants (sampled 300 via entrez): RS1000636995 (9:99222741 A>C,G), RS1001200979 (9:99217470 A>C), RS1001382426 (9:99220741 A>G), RS1001805980 (9:99217448 G>A), RS1002468274 (9:99219165 T>C), RS1002845896 (9:99219455 C>T), RS1003061250 (9:99221774 G>A,T), RS1004585539 (9:99217495 G>C), RS1004705425 (9:99220457 G>A), RS1004738063 (9:99220110 C>A), RS1005121928 (9:99217722 C>A), RS1005280460 (9:99220931 A>G,T), RS1005457265 (9:99222199 C>A,G,T), RS1005579643 (9:99216918 A>G), RS1005610603 (9:99216678 T>C)

Disease associations

OMIM: gene MIM:607905 | disease phenotypes: MIM:607906, MIM:616228

GenCC curated gene-disease

Disease	Classification	Inheritance
ALG2-congenital disorder of glycosylation	Strong	Autosomal recessive
congenital myasthenic syndrome 14	Strong	Autosomal recessive
congenital myasthenic syndromes with glycosylation defect	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
ALG2-congenital disorder of glycosylation	Strong	AR

Mondo (3): ALG2-congenital disorder of glycosylation (MONDO:0011933), congenital myasthenic syndrome 14 (MONDO:0014543), (MONDO:0018144)

Orphanet (3): Congenital myasthenic syndrome with glycosylation defect (Orphanet:353327), Congenital myasthenic syndrome (Orphanet:590), ALG2-CDG (Orphanet:79326)

HPO phenotypes

100 total (30 of 100 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000707	Abnormality of the nervous system
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0000821	Hypothyroidism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002092_1	Callous-unemotional behaviour	3.000000e-06
GCST004899_5	Gestational age at birth (maternal effect)	5.000000e-07
GCST009798_9	Asthma	2.000000e-10
GCST90014325_15	Asthma	6.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005322	callous-unemotional behaviour
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	4
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	increases expression	1
urushiol	decreases expression	1
bisphenol A	decreases expression, increases expression	1
salinomycin	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
NSC 689534	affects binding, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Amiodarone	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases expression	1
Calcium	affects binding	1
Cisplatin	increases expression	1
Copper	affects binding, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Nickel	increases expression	1
Plant Extracts	increases expression, affects cotreatment	1
Progesterone	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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