ATP2B4 encodes a plasma membrane calcium-ATPase (PMCA4b) that catalyzes ATP-dependent calcium export from cells 1. This calcium pump is the primary regulator of erythrocyte calcium homeostasis 2, maintaining intracellular calcium balance through active transport 3. ATP2B4 has emerged as a significant malaria-resistance gene. Genetic variants in ATP2B4, particularly SNPs in a regulatory haplotype region, reduce PMCA4b expression and calcium extrusion capacity in red blood cells 3. These variants are associated with protection against severe malaria in African populations 4, with homozygous carriers showing suppressed Plasmodium falciparum parasite growth in vitro 2. The protective mechanism appears independent of effects on parasite adhesion or var-gene expression, instead operating through altered erythrocyte calcium handling 2. ATP2B4 polymorphisms also associate with mild malaria risk 5. Notably, ATP2B4 variants in adrenal tissue have been investigated in primary aldosteronism but did not demonstrate pathogenic effects on aldosterone production 6. The gene represents a critical example of how red blood cell membrane protein variants shape malaria susceptibility through calcium regulation mechanisms 7.