Sickle cell disease is caused by a missense mutation — a single nucleotide substitution (A→T) at codon 6 of the β-globin gene, changing the codon from GAG (glutamic acid) to GTG (valine). This single amino acid change causes HbS (sickle haemoglobin) to polymerise under low oxygen conditions, deforming red blood cells into a sickle shape. A missense mutation changes one amino acid; a silent mutation does not; frameshift alters the reading frame.