rs2268574 — GCK c.679+38T>G

GCK rs2268574 — An Intronic GCK Variant of Uncertain Significance

Glucokinase¹¹ Glucokinase
GCK (hexokinase-4): the enzyme that phosphorylates glucose to glucose-6-phosphate in pancreatic beta cells and hepatocytes, functioning as the pancreas's molecular glucose sensor. Its kinetic properties require high glucose to activate, making it the gatekeeper of glucose-stimulated insulin secretion. (GCK) is one of the most consequential metabolic genes in the human genome. Rare loss-of-function mutations cause MODY2 — lifelong mild fasting hyperglycemia. Activating mutations cause congenital hyperinsulinism. Common intronic variants such as rs4607517 are among the most robustly replicated loci for fasting glucose in large-scale GWAS. rs2268574 is a different intronic variant in the same gene, located 38 nucleotides downstream of exon 7 in intron 7, with a more limited and less consistent evidence record.

The Mechanism

rs2268574 (GRCh38 chr7:44149722; coding-strand notation: c.679+38T>G) sits well within intron 7 of GCK, 38 base pairs downstream of the exon 7 splice donor site. At this distance from the canonical splice site, classical splice-disrupting effects are unlikely. The variant does not alter any glucokinase protein sequence. Its potential functional mechanism — if any — would be regulatory, perhaps through intronic enhancer activity or effects on mRNA secondary structure, but no functional characterization has been published for this specific variant.

The A allele (the GRCh38 reference) is the population-minor allele globally (~43%), while the G allele predominates (~57% worldwide). The A allele is somewhat more common in Europeans (~51%) and South Asians (~56%) than in East Asians (~37%) or Africans (~27%), suggesting some population stratification that could confound association studies not appropriately controlling for ancestry.

The Evidence

The evidence base for rs2268574 is small and inconsistent. A 2014 communication²² 2014 communication
Frigeri HR et al. The polymorphism rs2268574 in Glucokinase gene is associated with gestational Diabetes mellitus. Clin Biochem 2014. PMID:24495862 from a Brazilian group reported an association between the A allele and gestational diabetes mellitus (GDM). However, this study is a brief communication with no published abstract, and independent details such as sample size, odds ratios, and population ancestry are not publicly accessible.

The same research group subsequently tested rs2268574 in obese women with type 2 diabetes and found no significant association³³ no significant association
Frigeri HR et al. Polymorphisms rs144723656, rs2268574, and rs2268575 of the glucokinase gene are not associated with obese women with type 2 diabetes mellitus. Clin Biochem 2016. PMID:26436570. A larger Chinese case-control study with 835 GDM patients and 870 controls also found no significant association⁴⁴ no significant association
She L et al. Association of glucokinase gene and glucokinase regulatory protein gene polymorphisms with gestational diabetes mellitus: a case-control study. Gene 2022. PMID:35276241 between rs2268574 and GDM (P > 0.05). That same study did find the neighboring promoter variant rs1799884 (GCK -30G>A, a distinct locus ~40 kb upstream) to be significantly associated, highlighting that the GCK gene contributes to GDM susceptibility through other variants — but not necessarily through rs2268574.

ClinVar classifies the G allele of rs2268574 as Benign (RCV000832813), reflecting the lack of established pathogenicity. Overall, the evidence for rs2268574 as a functional disease variant is emerging at best — one small positive signal, two negative studies, and no mechanistic characterization.

Practical Actions

The weak and inconsistent evidence for rs2268574 means that no strongly evidence-based genotype-specific intervention can be prescribed. For individuals carrying the A allele (particularly AA homozygotes) with concern about gestational diabetes or glucose metabolism, standard GCK-pathway monitoring applies: fasting glucose and HbA1c provide the most actionable information about glucokinase function regardless of which specific GCK variant is present.

Interactions

rs2268574 is located in the same GCK gene as several other catalogued variants with stronger and better-characterized evidence: rs4607517 (a robustly replicated GWAS locus for fasting glucose in up to 122,744 individuals), and rs1799884 (the GCK -30G>A promoter variant with established GDM association in multiple European cohorts). These represent stronger evidential anchors for GCK-related metabolic risk than rs2268574 itself. rs10278336 is another intronic GCK variant studied in the same Chinese GDM cohort (She 2022) that also showed no independent association with GDM.