Sickle Cell Anemia: Missense mutation (GAG→GUG, Glu→Val, codon 6 of beta-globin). HbS polymerizes under hypoxia → sickle RBCs → vaso-occlusion. Autosomal recessive. Heterozygotes have sickle cell trait (partial protection against malaria).

Phenylketonuria (PKU): Loss-of-function mutation in phenylalanine hydroxylase gene → accumulation of phenylalanine → brain damage. Autosomal recessive. Demonstrates how a single enzyme deficiency (due to gene mutation) disrupts an entire metabolic pathway.

Thalassemia: Mutations reducing or eliminating globin chain synthesis. Alpha-thalassemia: mutations in alpha-globin genes; Beta-thalassemia: mutations in beta-globin genes (often splice-site mutations affecting intron removal). Both demonstrate the importance of post-transcriptional processing.

Fragile X Syndrome: CGG trinucleotide repeat expansion in the FMR1 gene on the X chromosome. When repeats exceed ~200, the gene is silenced by methylation (epigenetic silencing). Most common cause of inherited intellectual disability.

Cystic Fibrosis: Most common: deletion of phenylalanine at position 508 ($\Delta F$508) in the CFTR chloride channel protein. Frameshift or missense mutations. Demonstrates how a 3-nucleotide deletion (in-frame) removes one amino acid, causing protein misfolding.

Nonsense Mutations and Disease: Premature stop codons create truncated, non-functional proteins. Example: Duchenne Muscular Dystrophy often involves frameshift mutations in the dystrophin gene, creating premature stop codons → non-functional dystrophin protein.

Silent Mutations: Changes in the third codon position (wobble position) often substitute one synonymous codon for another → same amino acid → no protein change. Example: CGA → CGU both encode Arg. Demonstrates code degeneracy buffering against mutation effects.