Sickling in &;HbS&; disease is primarily caused by

sickle-cell disease, which is caused by mutation of a single base out of the 3 x 109 in the genome, a T-to-A DNA substitution, which in turn results in an A-to-U change in the mRNA corresponding to the sixth codon of the b-globin gene. The altered codon specifies a different amino acid (valine rather than glutamic acid), and this causes a structural abnormality of the b-globin molecule leading to haemoglobin aggregation and red blood cell "sickling.".When HbS is deoxygenated, it undergoes a pronounced decrease in solubility