Glycogen storage disease due to glucose-6-phosphatase deficiency: genes and variants

Genes linked to Glycogen storage disease due to glucose-6-phosphatase deficiency

• G6PC1: Glucose-6-phosphatase catalytic subunit 1

  It catalyzes the final step of hepatic and renal glucose production by hydrolyzing glucose-6-phosphate to free glucose. Biallelic loss-of-function variants cause glycogen storage disease type Ia, with fasting hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, and hepatomegaly.

  64 disease-causing and 94 uncertain variants in G6PC1 are linked to Glycogen storage disease due to glucose-6-phosphatase deficiency.

• ASS1: Argininosuccinate synthase

  It catalyzes formation of argininosuccinate from citrulline and aspartate in the urea cycle, enabling nitrogen disposal and arginine synthesis. Biallelic loss-of-function variants cause citrullinemia type I, which can lead to severe hyperammonemia.

  1 disease-causing and 0 uncertain variants in ASS1 are linked to Glycogen storage disease due to glucose-6-phosphatase deficiency.

• SLC37A4: Glucose-6-phosphate exchanger SLC37A4

  It transports glucose-6-phosphate into the endoplasmic reticulum so glucose-6-phosphatase can release free glucose during fasting. Biallelic loss-of-function variants cause glycogen storage disease type Ib, with fasting hypoglycemia, hepatomegaly, neutropenia, and inflammatory bowel disease.

  0 disease-causing and 0 uncertain variants in SLC37A4 are linked to Glycogen storage disease due to glucose-6-phosphatase deficiency.

Where Glycogen storage disease due to glucose-6-phosphatase deficiency variants cluster

• G6PC1 Transmembrane (positions 118–138): 10 of 64 disease-causing changes, 2.7× more than its size predicts.
• G6PC1 Transmembrane (positions 255–275): 9 of 64 disease-causing changes, 2.4× more than its size predicts.
• G6PC1 Lumenal (positions 169–179): 6 of 64 disease-causing changes, 3.0× more than its size predicts.
• G6PC1 Transmembrane (positions 61–81): 8 of 64 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Glycogen storage disease due to glucose-6-phosphatase deficiency

Showing 60 of 65.

Uncertain variants in Glycogen storage disease due to glucose-6-phosphatase deficiency that look disease-causing

Which prediction tools work for Glycogen storage disease due to glucose-6-phosphatase deficiency

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• phyloP: 68 out of 100

Same protein, different disease

• Citrullinemia is also caused by ASS1 variants; they fall mostly in different places as the Glycogen storage disease due to glucose-6-phosphatase deficiency variants (69 disease-causing).

Diseases related to Glycogen storage disease due to glucose-6-phosphatase deficiency

• Glycogen storage disease, also linked to G6PC1 and SLC37A4
• Cardiac arrhythmia, also linked to ASS1
• Citrullinemia, also linked to ASS1
• Glucose-6-phosphate transport defect, also linked to SLC37A4
• Congenital disorder of glycosylation, type IIw, also linked to SLC37A4
• Phosphate transport defect, also linked to SLC37A4

Frequently asked questions

Which genes are linked to Glycogen storage disease due to glucose-6-phosphatase deficiency?

In CATVariant, Glycogen storage disease due to glucose-6-phosphatase deficiency is linked to 3 analyzed proteins: G6PC1 (Glucose-6-phosphatase catalytic subunit 1), ASS1 (Argininosuccinate synthase) and SLC37A4 (Glucose-6-phosphate exchanger SLC37A4).

How many genetic variants are linked to Glycogen storage disease due to glucose-6-phosphatase deficiency?

255 variants: 65 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 94 are of uncertain significance or have conflicting reports.

Which uncertain variants in Glycogen storage disease due to glucose-6-phosphatase deficiency look disease-causing?

4 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example G6PC1 G188D, G6PC1 H119R, G6PC1 C109Y and G6PC1 P257H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Glycogen storage disease due to glucose-6-phosphatase deficiency?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 60 disease-causing and 9 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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