ALG8

protein-coding

ALG8 alpha-1,3-glucosyltransferase, the group of Alpha-1,3-glucosyltransferases

Gene summary

This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_024079.5

Inheritance

AR, AD

ClinVar variants

P:74U:201B:60

Top phenotype

Congenital disorder of glycosylation, type Ih

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr11:78,095,244-78,139,660

External References & Databases

Ensembl (ENSG00000159063)

Transcript & Mutation Effects

hg38 • Region Span ~44.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ALG8-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011969

Submitter: Labcorp Genetics (formerly Invitae)

ALG8-congenital disorder of glycosylationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011969

Submitter: G2P

autosomal dominant polycystic kidney diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004691

Submitter: ClinGen

The *ALG8* gene is located on chromosome 11 at q14.1 and encodes the protein alpha-1,3 glucosyltransferase. It is involved in N-linked glycosylation of proteins, catalyzing the addition of a second glucose to lipid-linked oligosaccharides, a key step in post-translational protein modification. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their inheritance pattern and phenotypic spectrum. Therefore, the following disease entities have been split into two disease entities: polycystic liver disease 3 with or without kidney cysts (OMIM:617874) and congenital disorder of glycosylation, type Ih (CDG-1h; OMIM:608104). Autosomal recessive CDG-1h has been curated separately. The preferred disease name suggested for this disorder is autosomal dominant polycystic kidney and/or liver disease - *ALG8* (ADPKLD - *ALG8*). *ALG8* was first reported in relation to ADPLD in 2017 (Besse et al., PMID: 28375157) and in relation to an ADPKD-like phenotype in 2023 (Apple et al. PMID: 36574950). Evidence by Apple et al. 2023 (PMID 36574950) showed that individuals carrying heterozygous *ALG8* protein truncating variants (PTV) were at a significantly increased risk of mild cystic kidney disease phenotypes. Jawaid et al 2025 (PMID: 39899384) detected *ALG8* variants in 51 families with cystic kidneys and/or livers and illustrated the segregation of 5 different PTV variants with cystic phenotypes in 7 families. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) showed an enrichment of *ALG8* variants in cystic kidney populations, identified by ICD codes. *ALG8* variants have incomplete penetrance and a spectrum of clinical presentations from normal kidney structure and function to multiple kidney cysts with CKD. The typical presentation is of limited kidney cysts with preserved kidney function. However, it can also be of severe PLD with limited kidney involvement (ADPLD). 9 variants (4 nonsense, 2 frameshift, 2 canonical splice, and 1 missense) that have been reported in four publications are included in this re-curation (PMIDs: 39899384, 28375157; 32457805; 36574950). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data, case-control data, and segregation data. This gene-disease relationship is also supported by in vitro functional assays showing reduced maturation of polycystin 1 in *ALG8* -/- mouse kidney epithelial cells (PMID: 28375157). A total of 1.0/6.0 pts. for experimental evidence was reached. This gene-disease pair was originally evaluated by the Kidney Cystic and Ciliopathy Disorders GCEP on 07/08/2020 (SOP version 7). It was re-evaluated on 03/10/2025 (SOP version 11). As a result of this reevaluation, the classification increased from Limited to Definitive. In summary, there is definitive evidence supporting the relationship between *ALG8* and ADPKD and ADPLD. This has been repeatedly demonstrated in the diagnostic setting and has been upheld over time. However, many individuals harboring *ALG8* PTV do not have any reported cystic phenotypes, suggesting that *ALG8* truncating variants may be of low penetrance.

polycystic liver disease 3 with or without kidney cystsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054743

Submitter: Labcorp Genetics (formerly Invitae)

ALG8-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011969

Submitter: PanelApp Australia

polycystic liver disease 3 with or without kidney cystsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054743

Submitter: Genomics England PanelApp

ALG8-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011969

Submitter: Ambry Genetics

polycystic liver disease 3 with or without kidney cystsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0054743

Submitter: PanelApp Australia

ALG8-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011969

Submitter: Orphanet

polycystic liver disease 3 with or without kidney cystsLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0054743

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type IhAR

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: 12480927; 15235028; 19648040; 19688606; 22306853; 28375157

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALG8 variants in ClinVar

10 Conditions Cataloged

ALG8 congenital disorder of glycosylationTotal: 299

Polycystic liver disease 3 with or without kidney cystsTotal: 127

not providedTotal: 107

Inborn genetic diseasesTotal: 60

ALG8-related disorderTotal: 54

not specifiedTotal: 21

Autosomal dominant polycystic liver diseaseTotal: 9

Familial cystic renal diseaseTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024079.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	47 clinvar	2 clinvar	55
missense	3 clinvar	7 clinvar	186 clinvar	11 clinvar		207
nonsense	4 clinvar	14 clinvar	5 clinvar			23
start loss			1 clinvar			1
frameshift	8 clinvar	18 clinvar	3 clinvar			29
splice donor/acceptor (+/-2bp)	1 clinvar	19 clinvar				20
Total	16	58	201	58	2	335

Highest pathogenic variant AF is 0.00020600155

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 152 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024079.5	RefSeq	NP_076984.2	13	MANE Select
ENST00000299626.10	Ensembl	ENSP00000299626.5	13	MANE Select
NM_001007027.3	RefSeq	NP_001007028.1	13	Standard
NM_001425219.1	RefSeq	NP_001412148.1	13	Standard

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 N-linked glycosylation
dolichol-linked oligosaccharide biosynthetic process
oligosaccharide-lipid intermediate biosynthetic process
mannosylation

Molecular Function

alpha-1,3-mannosyltransferase activity
dolichyl-phosphate-glucose-glycolipid alpha-glucosyltransferase activity
protein binding
dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase activity
dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299626
Coding exons: 13
Length: 38725
Individuals with no LoFs: 125547
Homozygous LoFs: 0
Heterozygous LoFs: 200
Defined: 125747
p: 0.000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.604	240	268	0.896	0.0000129	3381
Missense (PolyPhen)		88	91.844	0.95814		1180
Synonymous	-0.968	114	102	1.12	0.00000489	1039
Loss of Function	2.31	18	32.1	0.560	0.00000197	348

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0014	0.0014	notable
Latino/Admixed American	0.00043	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.0029	0.0029	notable
European (Non-Finnish)	0.00078	0.00077	rare
South Asian	0.00023	0.00023	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adds the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Glc(1)Man(9)GlcNAc(2)-PP-Dol before it is transferred to the nascent peptide (By similarity). Required for PKD1/Polycystin-1 maturation and localization to the plasma membrane of the primary cilia (By similarity). {ECO:0000250|UniProtKB:P40351, ECO:0000250|UniProtKB:Q6P8H8}.;
Disease: DISEASE: Congenital disorder of glycosylation 1H (CDG1H) [MIM:608104]: 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:15235028}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polycystic liver disease 3 with or without kidney cysts (PCLD3) [MIM:617874]: A form of polycystic liver disease, an autosomal dominant hepatobiliary disease characterized by overgrowth of biliary epithelium and supportive connective tissue, resulting in multiple liver cysts. PCLD3 patients may also develop kidney cysts that usually do not result in clinically significant renal disease. {ECO:0000269|PubMed:28375157}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.173

Intolerance Scores

LoFtool: 0.159
RVIS EVS: 0.49
RVIS percentile EVS: 79.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.720

Gene Damage Prediction

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