HBB encodes the beta subunit of adult hemoglobin, forming a critical component of the hemoglobin complex responsible for oxygen transport from lungs to tissues. The beta-globin protein combines with alpha-globin subunits, heme, and iron to form functional hemoglobin tetramers that bind and release oxygen in response to tissue demands. Beyond oxygen transport, hemoglobin exhibits peroxidase activity and participates in nitric oxide transport and hydrogen peroxide catabolism. Mutations in HBB cause beta-hemoglobinopathies, including sickle cell disease from the Glu6Val substitution 1 and beta-thalassemia from mutations causing insufficient protein production 2. Sickle cell disease results from a single nucleotide change (c.20T>A) that originated once in Africa and spread due to malaria resistance 3. The mutation rate for this specific HbS substitution is significantly higher than the genome-wide average for this mutation type, with nine instances observed in African populations 4. Clinically, several gene therapies target HBB including betibeglogene autotemcel and lovotibeglogene autotemcel for transfusion-dependent beta-thalassemia, and voxelotor for sickle cell disease. CRISPR/Cas9-based approaches have demonstrated successful correction of pathogenic HBB mutations in patient-derived hematopoietic stem cells 5, and base editing strategies can convert the sickle allele to benign variants 1. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant because heterozygous carriers are viable; this is distinct from clinical pathogenicity in disease contexts.