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ALG3
ALG3 alpha-1,3- mannosyltransferase
ALG3 is located on the long (q) arm of chromosome 3, at band 3q27.1. Arm ratio per GRCh38 - banding schematic.
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Overview
ALG3 is located on chromosome 3 and encodes an alpha-1,3-mannosyltransferase enzyme that catalyses a specific step in the assembly of lipid-linked oligosaccharides in the endoplasmic reticulum. These oligosaccharide precursors are subsequently transferred to newly made proteins during N-linked glycosylation, a modification essential for proper protein folding, stability, and function throughout the body.
Pathogenic variants in ALG3 follow an autosomal recessive inheritance pattern, meaning that affected individuals inherit two altered copies of the gene, one from each parent. Loss of ALG3 function impairs the addition of mannose residues to the growing glycan chain, resulting in incomplete or abnormal glycosylation of numerous proteins. The resulting congenital disorder of glycosylation presents with a spectrum of clinical features, most commonly including neurological impairment, developmental delay, and seizures.
What the gene does
The ALG3 protein functions as a mannosyltransferase enzyme within the endoplasmic reticulum membrane, where it transfers a mannose sugar from a donor molecule to the growing dolichol-linked oligosaccharide precursor. This enzymatic step adds the first alpha-1,3-linked mannose to the mannose branch of the core oligosaccharide structure, positioning the precursor for subsequent glycosylation steps.
N-linked glycosylation is a highly conserved biosynthetic pathway that modifies asparagine residues on hundreds of proteins, affecting their folding, trafficking, and interactions with other cellular components. The mannosyltransferase activity of ALG3 is essential for assembling the complete oligosaccharide structure before its en bloc transfer to nascent polypeptides. Without functional ALG3, the glycan precursor remains truncated, leading to hypoglycosylation of target proteins and disrupting cellular processes that depend on correctly modified glycoproteins, particularly in the developing nervous system.
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Chromosome location
ALG3 is located on the long arm of chromosome 3 at band 3q27.1. This chromosomal region contains multiple genes involved in metabolic and developmental processes. The gene spans several kilobases of genomic DNA and comprises multiple exons that encode a 438-amino acid protein product.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The ALG3 protein is predicted to be an integral membrane protein with multiple transmembrane segments that anchor it within the endoplasmic reticulum membrane, positioning the catalytic region appropriately for access to its lipid-linked substrate. The protein's topology facilitates its role in transferring mannose residues during oligosaccharide assembly on the cytoplasmic face of the endoplasmic reticulum.
Key variants
Pathogenic variants in ALG3 are relatively rare and include missense changes, nonsense mutations, and small deletions that disrupt enzyme function. Most disease-causing variants impair the mannosyltransferase activity of the protein, preventing proper assembly of the oligosaccharide precursor. The variant spectrum observed in affected individuals reflects loss-of-function changes that substantially reduce or abolish enzymatic activity, leading to clinical manifestations of congenital disorder of glycosylation.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1061G>A | p.Arg354His | Pathogenic/Likely pathogenic | ★★☆☆ | ALG3-congenital disorder of glycosylation |
c.1188G>A | p.Trp396Ter | Pathogenic | ★★☆☆ | ALG3-congenital disorder of glycosylation |
c.165C>T | p.Gly55= | Pathogenic/Likely pathogenic | ★★☆☆ | ALG3-congenital disorder of glycosylation |
c.2T>C | p.Met1Thr | Pathogenic/Likely pathogenic | ★★☆☆ | ALG3-congenital disorder of glycosylation |
c.512G>A | p.Arg171Gln | Pathogenic/Likely pathogenic | ★★☆☆ | ALG3-congenital disorder of glycosylation |
c.796C>T | p.Arg266Cys | Pathogenic | ★★☆☆ | ALG3-congenital disorder of glycosylation |
c.116del | p.Pro39fs | Pathogenic | ★☆☆☆ | ALG3-congenital disorder of glycosylation |
c.470T>C | p.Met157Thr | Pathogenic | ★☆☆☆ | ALG3-congenital disorder of glycosylation |
c.606-2A>C | - | Pathogenic | ★☆☆☆ | ALG3-congenital disorder of glycosylation |
c.859C>T | p.Arg287Ter | Pathogenic | ★☆☆☆ | ALG3-congenital disorder of glycosylation |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in ALG3 cause a congenital disorder of glycosylation characterised primarily by neurological involvement. Affected individuals typically present with intellectual disability, developmental delay, and seizures, reflecting the critical role of protein glycosylation in brain development and function. Additional features may include hypotonia, microcephaly, and structural brain abnormalities. The phenotypic severity can vary among individuals depending on the specific variants present and the degree of residual enzyme activity.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ALG3 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
ALG3 is included on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical relevance for several presentations. The gene appears on the Congenital disorders of glycosylation panel, the Intellectual disability panel (R29), and the Early onset or syndromic epilepsy panel (R59), among others. It is also listed on panels for Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), Fetal anomalies (R21), and Arthrogryposis (R83), indicating the broad spectrum of features associated with ALG3-related glycosylation defects. All memberships hold green (high-evidence) ratings, supporting the gene's established role in these clinical contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ALG3 gene do?
ALG3 encodes an enzyme that adds a specific mannose sugar to a growing oligosaccharide chain during the early steps of protein glycosylation in cells. This modification is essential for many proteins to fold correctly and function properly, particularly in the developing brain.
How is ALG3-related glycosylation disorder inherited?
ALG3-related conditions follow an autosomal recessive inheritance pattern. An individual must inherit two pathogenic variants, one from each parent, to be affected. Carrier parents typically have one working copy of the gene and do not show symptoms.
What are the main features of ALG3-related conditions?
The primary features include intellectual disability, developmental delay, and seizures. Some individuals may also have low muscle tone, a small head size, or structural brain differences. The severity and specific combination of features can vary among affected individuals.