ALG2

ALG2 alpha-1,3/1,6-mannosyltransferase, the group of Glycosyl transferases group 1 domain containing

Basic information

Region (hg38): 9:99216425-99221942

Links

ENSG00000119523 ∙ NCBI:85365 ∙ OMIM:607905 ∙ HGNC:23159 ∙ Uniprot:Q9H553 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• congenital myasthenic syndrome 14 (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 14 (Moderate), mode of inheritance: AR
• ALG2-congenital disorder of glycosylation (Limited), mode of inheritance: AR
• ALG2-congenital disorder of glycosylation (Strong), mode of inheritance: AR
• ALG2-congenital disorder of glycosylation (Supportive), mode of inheritance: AR
• congenital myasthenic syndromes with glycosylation defect (Supportive), mode of inheritance: AR
• ALG2-congenital disorder of glycosylation (Limited), mode of inheritance: Unknown
• congenital myasthenic syndrome 14 (Strong), mode of inheritance: AR
• ALG2-congenital disorder of glycosylation (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Congenital disorder of glycosylation, type Ii; Myasthenic syndrome, congenital 14	AR	Hematologic; Musculoskeletal; Neurologic	In Congenital disorder of glycosylation, type Ii, awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery; In Myasthenic syndrome, congenital, individuals have been described as manifesting with progressive weakness, and have been reported who have benefited from medical treatment (with anticholinesterase medication)	Craniofacial; Biochemical; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic	12684507; 23404334; 24461433; 30397276
Hepatic-metabolized agents should be avoided

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALG2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALG2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	102	3	107
missense			149	3	3	155
nonsense			5			5
start loss			2			2
frameshift		3	9			12
inframe indel			6			6
splice donor/acceptor (+/-2bp)						0
splice region			1	3		4
non coding			3	13	2	18
Total	0	3	176	118	8

Variants in ALG2

This is a list of pathogenic ClinVar variants found in the ALG2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
9-99216461-CAAT-C		Congenital disorder of glycosylation	Uncertain significance (Jun 14, 2016)
9-99216670-AATAT-A		Congenital disorder of glycosylation	Uncertain significance (Jun 14, 2016)
9-99217420-T-TA		Congenital disorder of glycosylation	Uncertain significance (Jun 14, 2016)
9-99217937-T-C		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Likely benign (Feb 10, 2020)
9-99217939-C-G		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Uncertain significance (Nov 15, 2022)
9-99217946-T-G		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14	Uncertain significance (May 06, 2020)
9-99217950-G-T		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14	Uncertain significance (Jan 16, 2022)
9-99217955-A-G		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Likely benign (Jan 06, 2020)
9-99217955-A-T		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Uncertain significance (May 27, 2022)
9-99217957-A-G		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14	Uncertain significance (Oct 03, 2023)
9-99217959-C-T		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation • Inborn genetic diseases	Conflicting classifications of pathogenicity (Nov 14, 2023)
9-99217966-G-A		Inborn genetic diseases	Uncertain significance (Jun 03, 2024)
9-99217967-C-G		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14 • Inborn genetic diseases	Uncertain significance (Sep 13, 2022)
9-99217985-A-G		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation • ALG2-related disorder	Likely benign (May 01, 2023)
9-99217992-A-G		Congenital myasthenic syndrome 14	Likely pathogenic (Mar 01, 2023)
9-99217994-T-C		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14	Likely benign (Mar 22, 2022)
9-99218000-C-T		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Likely benign (Dec 01, 2023)
9-99218005-C-G		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Uncertain significance (Mar 13, 2022)
9-99218008-T-C		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Uncertain significance (Feb 08, 2022)
9-99218011-C-T		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14	Uncertain significance (Jun 20, 2022)
9-99218022-AGGCCCAT-A		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Uncertain significance (Mar 18, 2022)
9-99218029-T-C		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation • Inborn genetic diseases	Uncertain significance (Oct 28, 2022)
9-99218030-G-C		ALG2-related disorder	Likely benign (Sep 05, 2019)
9-99218032-T-C		ALG2-congenital disorder of glycosylation;Congenital myasthenic syndrome 14	Uncertain significance (Dec 18, 2023)
9-99218035-C-T		Congenital myasthenic syndrome 14;ALG2-congenital disorder of glycosylation	Uncertain significance (Jun 04, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALG2	protein_coding	protein_coding	ENST00000476832	2	5531

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000805	0.779	125692	0	56	125748	0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0790	230	227	1.01	0.0000115	2664
Missense in Polyphen		85	85.738	0.99139		1057
Synonymous	-2.15	128	101	1.27	0.00000519	872
Loss of Function	1.13	8	12.3	0.651	6.23e-7	148

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000886	0.000630
Ashkenazi Jewish	0.00	0.00
East Asian	0.000286	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.000236	0.000229
Middle Eastern	0.000286	0.000272
South Asian	0.000230	0.000229
Other	0.000508	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mannosylates Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)- dolichol diphosphate. {ECO:0000269|PubMed:12684507}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:12684507}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:23404334}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: N-Glycan biosynthesis - Homo sapiens (human);Post-translational protein modification;Metabolism of proteins;Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein;Asparagine N-linked glycosylation (Consensus)

Recessive Scores

• pRec: 0.202

Intolerance Scores

• loftool: 0.389
• rvis_EVS: 0.24
• rvis_percentile_EVS: 69.37

Haploinsufficiency Scores

• pHI: 0.0723
• hipred: Y
• hipred_score: 0.522
• ghis: 0.500

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.933

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Alg2
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: dolichol-linked oligosaccharide biosynthetic process;oligosaccharide-lipid intermediate biosynthetic process;protein glycosylation in endoplasmic reticulum;response to calcium ion;mannosylation
• Cellular component: nucleus;cytoplasm;endoplasmic reticulum membrane;cytosol;actin cytoskeleton;membrane;integral component of membrane;perinuclear region of cytoplasm
• Molecular function: alpha-1,3-mannosyltransferase activity;GDP-Man:Man1GlcNAc2-PP-Dol alpha-1,3-mannosyltransferase activity;protein binding;protein heterodimerization activity;protein N-terminus binding;calcium-dependent protein binding;GDP-Man:Man2GlcNAc2-PP-dolichol alpha-1,6-mannosyltransferase activity