GeneBe

ALG1

protein-coding

ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase, the group of Glycosyl transferases group 1 domain containing

Gene summary

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. [provided by RefSeq, Dec 2008]

MANE transcript

NM_019109.5

Inheritance

AR

ClinVar variants

P:136U:279B:273

Top phenotype

Congenital disorder of glycosylation, type Ik

gnomAD constraint

pLI —, LoF o/e 1.09

Max pathogenic AF

—

Genomic locus

chr16:5,033,702-5,087,379

External References & Databases

Ensembl (ENSG00000033011)NCBI Gene (56052)OMIM (605907)HGNC:18294GenCCUniProt (Q9BT22)AlphaFoldClinVar (ALG1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~53.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALG1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012052

Submitter: Labcorp Genetics (formerly Invitae)

ALG1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012052

Submitter: PanelApp Australia

ALG1-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012052

Submitter: Ambry Genetics

ALG1-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012052

Submitter: G2P

ALG1-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012052

Submitter: Orphanet

ALG1-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012052

Submitter: ClinGen

*ALG1* was first reported in relation to autosomal recessive ALG1-congenital disorder of glycosylation (also known as congenital disorder of glycosylation type 1k) in 2004 (Grubenmann et al., PMID: 14709599). Common phenotypes in affected individuals include severe developmental delay, intellectual disability, microcephaly, hypotonia, early-onset epilepsy, and facial dysmorphism. Additional variable features include coagulation defects, immunodeficiency, and nephrotic syndrome. The most severely affected patients die during the first years of life. Eleven homozygous and compound heterozygous variants (8 missense, including 3 recurrent; 2 splice, 1 nonsense) that have been reported in 10 probands in eight publications (PMIDs: 14709599, 14973782, 20679665, 22966035, 24157261, 26931382, 27325525, 35221878) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by the biochemical function of *ALG1*, which encodes a protein involved in N-linked glycosylation. Multiple members of the asparagine-linked glycosylation (ALG) family of glycosyltransferases have been implicated in congenital disorders of glycosylation (PMID: 37858231). In summary, there is definitive evidence supporting the relationship between *ALG1* and autosomal recessive ALG1-congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 7, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IkAR

Manifestation: Biochemical; Gastrointestinal; Hematologic; Neurologic; Renal

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 14709599; 14973782; 14973778; 20679665; 22966035Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG1 variants in ClinVar

13 Conditions Cataloged
ALG1-congenital disorder of glycosylationTotal: 842
not providedTotal: 109
Inborn genetic diseasesTotal: 104
not specifiedTotal: 44
Congenital disorder of glycosylationTotal: 32
ALG1-related disorderTotal: 32
Finnish congenital nephrotic syndromeTotal: 2
Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019109.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
3
clinvar
246
clinvar
 251
missense
8
clinvar
34
clinvar
270
clinvar
26
clinvar
1
clinvar
 339
nonsense
20
clinvar
9
clinvar
1
clinvar
 30
start loss
1
clinvar
 1
frameshift
25
clinvar
5
clinvar
1
clinvar
 31
splice donor/acceptor (+/-2bp)
4
clinvar
28
clinvar
4
clinvar
 36
Total57792792721688

Highest pathogenic variant AF is 0.00060393964

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_019109.5RefSeqNP_061982.313MANE Select
ENST00000262374.10EnsemblENSP00000262374.513MANE Select
NM_001330504.2RefSeqNP_001317433.111Standard
NM_001438123.1RefSeqNP_001425052.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • N-Glycan biosynthesis - Homo sapiens (human)
  • Post-translational protein modification
  • Metabolism of proteins
  • dolichyl-diphosphooligosaccharide biosynthesis
  • Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein

Biological Process

  • protein glycosylation
  • dolichol-linked oligosaccharide biosynthetic process
  • mannosylation

Molecular Function

  • mannosyltransferase activity
  • chitobiosyldiphosphodolichol beta-mannosyltransferase activity

Cellular Component

  • endoplasmic reticulum
  • endoplasmic reticulum membrane
  • membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000262374
Coding exons
13
Length
53678
Individuals with no LoFs
125694
Homozygous LoFs
0
Heterozygous LoFs
54
Defined
125748
p
0.000215
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-2.053572641.350.00001592969
Missense (PolyPhen)9386.8361.0711072
Synonymous-3.741621121.450.00000702932
Loss of Function-0.4052724.81.090.00000126277

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.000300.00030rare
East Asian0.000550.00054rare
Finnish00.0absent
European (Non-Finnish)0.000280.00027rare
South Asian0.000130.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Participates in the formation of the lipid-linked precursor oligosaccharide for N-glycosylation. Involved in assembling the dolichol-pyrophosphate-GlcNAc(2)-Man(5) intermediate on the cytoplasmic surface of the ER. {ECO:0000269|PubMed:10704531, ECO:0000269|PubMed:26931382}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:14709599, ECO:0000269|PubMed:14973778, ECO:0000269|PubMed:14973782, ECO:0000269|PubMed:26931382}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.190

Intolerance Scores

LoFtool
0.384
RVIS EVS
0.04
RVIS percentile EVS
57.41

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.604

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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