Malaria: genes and variants

Genes linked to Malaria

• G6PD: Glucose-6-phosphate 1-dehydrogenase

  It generates NADPH through the pentose-phosphate pathway, providing red blood cells with the reducing power needed to withstand oxidative stress. Deficiency can trigger neonatal jaundice or acute hemolytic anemia after infections, fava beans, or oxidant drugs.

  26 disease-causing and 6 uncertain variants in G6PD are linked to Malaria.

• HBB: Hemoglobin subunit beta

  Beta-globin, one of the two major protein chains in adult hemoglobin. Hemoglobin uses these chains to transport oxygen from the lungs to tissues, and HBB variants are associated with sickle-cell disease and beta-thalassemia.

  2 disease-causing and 4 uncertain variants in HBB are linked to Malaria.

• TLR7: Toll-like receptor 7

  It detects single-stranded viral RNA in endosomes and drives type I interferon and inflammatory responses, particularly in plasmacytoid dendritic cells and B cells. Loss-of-function variants can predispose to severe viral infection, whereas gain-of-function variants cause immune dysregulation and autoimmunity.

  0 disease-causing and 0 uncertain variants in TLR7 are linked to Malaria.

• TLR9: Toll-like receptor 9

  It detects unmethylated CpG-rich DNA in endosomes and activates innate immune and type I interferon responses. Dysregulated signaling can contribute to autoimmunity, while agonists and antagonists of the pathway are being developed for cancer and inflammatory disease.

  0 disease-causing and 0 uncertain variants in TLR9 are linked to Malaria.

Weakly linked (only a few uncertain records): SLC4A1.

Known disease-causing variants in Malaria

Uncertain variants in Malaria that look disease-causing

Which prediction tools work for Malaria

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

• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 94 out of 100
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 86 out of 100
• AlphaMissense: 85 out of 100
• SIFT: 78 out of 100

Same protein, different disease

• Anemia, nonspherocytic hemolytic, due to G6PD deficiency is also caused by G6PD variants; they fall mostly in different places as the Malaria variants (182 disease-causing).
• G6PD deficiency is also caused by G6PD variants; they fall partly in the same places as the Malaria variants (11 disease-causing).
• Erythrocytosis, familial, 6 is also caused by HBB variants; they fall mostly in different places as the Malaria variants (31 disease-causing).
• Beta thalassemia is also caused by HBB variants; they fall mostly in different places as the Malaria variants (21 disease-causing).
• Beta-thalassemia HBB/LCRB is also caused by HBB variants; they fall mostly in different places as the Malaria variants (18 disease-causing).
• Heinz body anemia is also caused by HBB variants; they fall mostly in different places as the Malaria variants (12 disease-causing).
• Hemoglobinopathy is also caused by HBB variants; they fall mostly in different places as the Malaria variants (12 disease-causing).

Diseases related to Malaria

• Systemic lupus erythematosus, also linked to TLR7 and TLR9
• Anemia, nonspherocytic hemolytic, due to G6PD deficiency, also linked to G6PD
• Erythrocytosis, familial, 6, also linked to HBB
• Beta thalassemia, also linked to HBB
• Heinz body anemia, also linked to HBB
• Atypical hemolytic-uremic syndrome, also linked to HBB
• Beta-thalassemia HBB/LCRB, also linked to HBB
• Hemoglobinopathy, also linked to HBB
• G6PD deficiency, also linked to G6PD
• Dominant beta-thalassemia, also linked to HBB
• Alpha Thalassemia, also linked to HBB
• METHEMOGLOBINEMIA, BETA TYPE, also linked to HBB

Frequently asked questions

Which genes are linked to Malaria?

In CATVariant, Malaria is linked to 4 analyzed proteins: G6PD (Glucose-6-phosphate 1-dehydrogenase), HBB (Hemoglobin subunit beta), TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9).

How many genetic variants are linked to Malaria?

40 variants: 28 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 12 are of uncertain significance or have conflicting reports.

Which uncertain variants in Malaria look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example G6PD R136H. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Malaria?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 22 disease-causing and 43 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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