rs1050828
mixedMag 8.5This is a variant in the G6PD gene that changes a valine to an methionine.
Key Literature Trait Associations
Rasburicase/Primaquine Hemolytic Risk
G6PD A- (V68M) defines the most common G6PD deficiency variant in African populations (10-25% allele frequency), causing moderate enzyme deficiency (~10-20% residual activity). Carriers face potentially severe hemolytic anemia when exposed to oxidant drugs including rasburicase, primaquine, dapsone, and certain sulfonamides. The FDA mandates G6PD testing before rasburicase administration (black box warning). WHO also recommends G6PD testing before primaquine for malaria treatment.
G6PD deficiency
The rs1050828 T allele (c.202G>A, Val98Met) is the defining molecular lesion of G6PD A-, the most common G6PD-deficiency variant worldwide and the predominant cause of G6PD deficiency in people of African descent. Hemizygous males and homozygous females are enzyme-deficient and at high risk for acute hemolytic episodes upon exposure to oxidant triggers. Heterozygous females show variable enzyme activity due to X-chromosome inactivation mosaicism. Multiple ClinVar submissions classify this variant as pathogenic/likely pathogenic for nonspherocytic hemolytic anemia due to G6PD deficiency, with allele frequencies up to ~16% in some sub-Saharan African populations.
Malaria susceptibility
The G6PD A- allele (rs1050828-T) has been maintained at high frequency in malaria-endemic regions through balancing selection, providing heterozygous females protection against Plasmodium falciparum malaria mortality — a textbook example of X-linked balanced polymorphism. A Ghanaian cohort study (n=6,108) found that homozygous A-A- females had only 0.07% malaria prevalence versus 36% overall, with OR=0.08 for P. falciparum infection. ClinVar includes a pathogenic annotation for malaria susceptibility, reflecting the complex bidirectional relationship: while the allele protects against severe malaria, it may also complicate treatment with oxidant antimalarials.
Diabetic retinopathy
The rs1050828-T allele causes falsely low HbA1c readings in G6PD-deficient individuals due to accelerated erythrocyte turnover, leading to underestimation of glycemic exposure and potentially delayed or insufficient diabetes treatment. A 2024 Nature Medicine study found that G6PD deficiency accounts for an estimated 12% of diabetic retinopathy and 9% of neuropathy cases in individuals of African ancestry with diabetes, with the effect fully mediated by actual glucose levels rather than HbA1c. The authors recommend glucose-based monitoring strategies over HbA1c alone for carriers of the G6PD A- allele.
Erythrocyte count
GWAS data from the EBI GWAS Catalog identify rs1050828-T as significantly associated with reduced erythrocyte (red blood cell) count (beta = −0.20 ×10¹²/L, p=4×10⁻¹³) and increased mean corpuscular volume (MCV; beta = +2.46 fL, p=1×10⁻¹⁴). These effects are consistent with the mild chronic compensated hemolysis and altered erythrocyte morphology observed in G6PD A- carriers, particularly under conditions of physiological stress. The associations are driven predominantly by the high frequency of the T allele in African-ancestry populations included in these studies.
▶GWAS Catalog Trait Associations (12)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (12)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
HbA1c measurement
Red cell distribution width
erythrocyte count
erythrocyte volume
pyruvate measurement
mean corpuscular hemoglobin
hemoglobin measurement
hematocrit
type 2 diabetes mellitus
low density lipoprotein cholesterol measurement
▶ClinVar annotation
G6PD ASAHI; Anemia, nonspherocytic hemolytic, due to G6PD deficiency; not provided; G6PD deficiency; not specified; Anemia, nonspherocytic hemolytic, due to G6PD deficiency;G6PD deficiency; Inborn genetic diseases; Malaria, susceptibility to
View on ClinVar →▶Research that mentions this SNP (3)
▶Genetic polymorphisms in oxidative stress‐related genes are associated with outcomes following treatment for aggressive B‐cell non‐Hodgkin lymphomaAssociationN=909Heather L. Gustafson et al.(2014)· American Journal of Hematology
Genetic polymorphisms in oxidative stress-related genes were associated with treatment outcomes in aggressive B-cell non-Hodgkin lymphoma. In discovery (n=337) and validation (n=572) cohorts, rare homozygotes for MPO rs2243828 (HR=1.87, P=0.013) and AKR1C3 rs10508293 (HR=2.09, P=0.0032) were associated with increased risk of progression, while NCF4 rs1883112 rare homozygotes showed protective effects against progression (HR=0.66, P=0.06 discovery; HR=0.66, P=0.05 validation). Meta-analysis confirmed NCF4 association with improved survival outcomes (HR=0.66, P<0.01).
▶Association of glycosylated hemoglobin with the gene encoding CDKAL1 in the Korean Association Resource (KARE) studyMeta-analysisN=159,940Jihye Ryu et al.(2012)· Human Mutation
Transethnic genome-wide meta-analysis in 159,940 individuals identified 60 common genetic variants associated with HbA1c levels. Variants were classified as glycemic (19), erythrocytic (22), or unclassified (19) based on their biological mechanisms. Glycemic variants were associated with higher type 2 diabetes risk (OR=1.05 per allele, p=3×10⁻²⁹), while erythrocytic variants were not. The X-linked G6PD G202A variant showed a large effect in African Americans (0.81% HbA1c reduction per allele) but minimal effects in other ancestries, potentially causing 2% of African American T2D cases to remain undiagnosed when using HbA1c screening.
▶Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African AmericansAssociationN=30,551Ken Sin Lo et al.(2011)· Human Genetics
Genetic association study in 23,439 Caucasians and 7,112 African Americans identified novel loci modulating hematological traits. G6PD rs1050828 (Val68Met) shows strong association with red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume in African Americans (P < 2.0 × 10^−13), while TPM4 rs8109288 associates with platelet count in both Caucasians and African Americans (P = 3.0 × 10^−7). HBA2-HBA1 rs1211375 associates with red blood cell traits specifically in African Americans (P < 7 × 10^−8). Study replicated 36 previously reported associations and highlights ethnic differences in genetic architecture of blood traits.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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