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G6PC3
glucose-6-phosphatase catalytic subunit 3
G6PC3 is located on the long (q) arm of chromosome 17, at band 17q21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
G6PC3 encodes the third member of the glucose-6-phosphatase catalytic subunit family, a group of enzymes responsible for the final step in glucose production pathways. Whilst other family members primarily function in the liver and kidney to maintain blood glucose levels, G6PC3 plays a specialised role in neutrophils and other immune cells. The protein catalyses the conversion of glucose-6-phosphate to glucose, supporting cellular energy requirements particularly during neutrophil maturation and activation. Pathogenic changes in G6PC3 disrupt this metabolic process, compromising neutrophil development and survival, which can result in severe immunodeficiency and increased susceptibility to bacterial infections.
What the gene does
The G6PC3 enzyme catalyses the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate, functioning within the endoplasmic reticulum membrane of cells. This reaction represents the terminal step in both gluconeogenesis and glycogenolysis, metabolic pathways that generate free glucose for cellular use. Within neutrophils, G6PC3 activity supports the energy demands of these rapidly responding immune cells, which require substantial glucose for oxidative burst reactions and phagocytosis. The enzyme appears particularly crucial during neutrophil maturation in the bone marrow, where developing cells transition through energy-intensive differentiation stages. Research suggests that G6PC3 also contributes to maintaining neutrophil stability under metabolic stress, helping these cells survive the challenging environment of active infection sites. Beyond neutrophils, evidence indicates the protein functions in other haematopoietic lineages, though neutrophils demonstrate the greatest dependence on G6PC3 activity for normal development and function.
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Chromosome location
G6PC3 is located on chromosome 17 at position q21.31, a region on the long arm of chromosome 17. The gene spans approximately 5.5 kilobases of genomic DNA and contains six exons that encode the mature messenger RNA transcript. This chromosomal region has been associated with various metabolic and immunological conditions, reflecting the concentration of genes involved in cellular homeostasis.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The G6PC3 protein comprises 346 amino acids and functions as an integral membrane protein embedded in the endoplasmic reticulum. The polypeptide chain contains multiple transmembrane segments that anchor the enzyme within the lipid bilayer, positioning the catalytic residues appropriately for substrate access. Structural predictions suggest the protein adopts a conformation similar to other glucose-6-phosphatase family members, with a catalytic site accessible from the endoplasmic reticulum lumen where glucose-6-phosphate substrate accumulates.
Key variants
Pathogenic variants in G6PC3 typically result in loss of enzyme function through various molecular mechanisms. Missense changes may disrupt the catalytic activity or destabilise the protein structure, whilst nonsense and frameshift variants often lead to premature termination and absent protein production. The majority of clinically significant variants are inherited in an autosomal recessive pattern, meaning affected individuals carry pathogenic changes on both gene copies.
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.481C>T | p.Arg161Ter | Pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.482G>A | p.Arg161Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.565C>T | p.Arg189Ter | Pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.758G>A | p.Arg253His | Pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.765_766del | p.Ala257fs | Pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.778G>C | p.Gly260Arg | Pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.911dup | p.Gln305fs | Pathogenic | ★★☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.295C>T | p.Gln99Ter | Pathogenic | ★☆☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.326G>T | p.Gly109Val | Pathogenic | ★☆☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
c.373_385del | p.Ile125fs | Pathogenic | ★☆☆☆ | Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency |
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 G6PC3 cause congenital neutropenia (G6PC3), a severe primary immunodeficiency characterised by persistently low neutrophil counts from birth or early infancy. Affected individuals experience recurrent, often life-threatening bacterial infections due to impaired innate immune defence. The condition may also involve additional features beyond neutropenia, including cardiovascular abnormalities, urogenital malformations, and visible venous patterns on the skin. Disease severity varies among affected individuals, though most require ongoing medical management to prevent and treat infections.
Inheritance pattern
Conditions caused by pathogenic G6PC3 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
Within the NHS Genomic Medicine Service, G6PC3 appears on multiple clinical gene panels reflecting its role in immune and metabolic disorders. The gene holds green classification status on panels including Congenital disorders of glycosylation, Cytopenia - NOT Fanconi anaemia, Cytopenias and congenital anaemias, Primary immunodeficiency or monogenic inflammatory bowel disease, and Likely inborn error of metabolism. Green status indicates strong evidence supporting the gene-disease relationship, making G6PC3 analysis appropriate for patients presenting with relevant clinical features such as severe early-onset neutropenia, recurrent infections, or unexplained immunodeficiency.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for G6PC3-related conditions?
Conditions associated with G6PC3 follow an autosomal recessive inheritance pattern. This means an individual must inherit a pathogenic variant from both parents to develop the condition, whilst carriers with one variant copy typically remain unaffected.
How does G6PC3 differ from other glucose-6-phosphatase genes?
Whilst G6PC functions primarily in liver and kidney to regulate blood glucose, and G6PC2 operates in pancreatic beta cells, G6PC3 specialises in supporting neutrophil metabolism. This tissue-specific expression explains why G6PC3 variants predominantly affect immune function rather than systemic glucose control.
Can G6PC3 testing help diagnose unexplained neutropenia?
Genetic testing including G6PC3 analysis can be valuable when evaluating individuals with severe neutropenia of unknown cause, particularly when neutropenia appears from infancy and other explanations have been excluded. Such testing is typically arranged through specialist immunology or haematology services within the NHS.