GeneBe

ALG5

protein-coding

ALG5 dolichyl-phosphate beta-glucosyltransferase, the group of Glycosyltransferase family 2

Gene summary

This gene encodes a member of the glycosyltransferase 2 family. The encoded protein participates in glucosylation of the oligomannose core in N-linked glycosylation of proteins. The addition of glucose residues to the oligomannose core is necessary to ensure substrate recognition, and therefore, effectual transfer of the oligomannose core to the nascent glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

MANE transcript

NM_013338.5

Inheritance

AD

ClinVar variants

P:10U:57B:14

Top phenotype

Polycystic kidney disease 7

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr13:36,949,738-37,000,763

External References & Databases

Ensembl (ENSG00000120697)NCBI Gene (29880)OMIM (604565)HGNC:20266GenCCUniProt (Q9Y673)AlphaFoldClinVar (ALG5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~51.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

polycystic kidney disease 7LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0031062

Submitter: Ambry Genetics

polycystic kidney disease 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031062

Submitter: Labcorp Genetics (formerly Invitae)

polycystic kidney disease 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031062

Submitter: Ambry Genetics

polycystic kidney disease 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0031062

Submitter: PanelApp Australia

autosomal dominant polycystic kidney diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: ClinGen

*ALG5* is located at chromosome 13q13.3 and encodes dolichyl phosphate glucosyltransferase, an transmembrane-bound enzyme of the endoplasmic reticulum that is involved in protein N-linked glycosylation via catalyzing the transfer of glucose from UDP glucose to dolichyl phosphate (PMID: 8076653). *ALG5* was first reported in relation to autosomal dominant polycystic kidney disease(ADPKD) in 2022 (Lemoine H et al., 2022 PMID: 35896117). Common phenotypes for individuals *ALG5* variants and ADPKD include late-onset development of CKD, atrophic kidneys, and multiple millimeter-sized kidney cysts (PMID: 35896117). Five unique variants (1 frameshift, 1 deletion, 1 nonsense, 2 missense) reported in five probands in one publication (PMID: 35896117) were included in this curation. The mechanism of pathogenicity is known to be loss-of-function. A total of 7.1 genetic evidence points was reached, considering case-level and segregation data. This gene-disease relationship is also supported by biochemical functional assay demonstrating that disruption of *ALG5*-mediated N-linked protein glycosylation leads to impaired maturation of polycystin 1 (PC1); impaired maturation of PC1 is implicated in the pathogenesis of cyst formation and polycystic kidney disease (PMID: 30523303). A total number of 0.5 experimental evidence points was reached. In summary, there is moderate evidence supporting the relationship between *ALG5* and ADPKD. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 03/22/2023 (SOP version 9).

Clinical Genomic Database (CGD)

Polycystic kidney disease 7AD

Manifestation: Gastrointestinal; Renal

Intervention: Renal

Rationale: Treatment for hypertension and end-stage renal disease is frequently required, and nephrotoxic agents should be avoided

Refs: 35896117Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG5 variants in ClinVar

4 Conditions Cataloged
not specifiedTotal: 40
ALG5-related disorderTotal: 24
Polycystic kidney disease 7Total: 16
not providedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013338.5. 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
4
clinvar
2
clinvar
 8
missense
3
clinvar
47
clinvar
8
clinvar
 58
nonsense
3
clinvar
2
clinvar
2
clinvar
 7
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
1
clinvar
6
clinvar
 7
Total735712281

Highest pathogenic variant AF is 0.0000037312875

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_013338.5RefSeqNP_037470.110MANE Select
ENST00000239891.4EnsemblENSP00000239891.310MANE Select
NM_001142364.1RefSeqNP_001135836.19Standard
ENST00000443765.6EnsemblENSP00000390533.19Standard

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
  • Synthesis of dolichyl-phosphate-glucose

Biological Process

  • protein glycosylation
  • protein N-linked glycosylation
  • determination of left/right symmetry
  • protein N-linked glycosylation via asparagine

Molecular Function

  • oligosaccharyl transferase activity
  • dolichyl-phosphate beta-glucosyltransferase activity

Cellular Component

  • endoplasmic reticulum membrane
  • membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000239891
Coding exons
10
Length
50487
Individuals with no LoFs
125737
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125748
p
0.0000437
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.011431810.7900.00001002087
Missense (PolyPhen)3159.8270.51816634
Synonymous-0.2796562.21.040.00000321628
Loss of Function3.50523.20.2150.00000145238

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000870.000087rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000480.000044rare
South Asian0.0000740.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec
0.150

Intolerance Scores

LoFtool
0.551
RVIS EVS
0.08
RVIS percentile EVS
60.09

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.949

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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