rs334 — HBB Glu6Val (Sickle cell)
Pathogenic · ~8% African Americans (carriers)
rs334 is the sickle cell mutation in beta-globin. Homozygous carriers have sickle cell disease; heterozygous carriers have malaria resistance. It is the most well-characterized pathogenic human variant, studied for over 70 years.
Molecular Mechanism
The Glu6Val substitution creates a hydrophobic patch on deoxy-hemoglobin S that triggers polymerization into rigid fibers, deforming red blood cells into sickle shapes. This causes vaso-occlusion, hemolysis, chronic pain, and organ damage.
Peptide Therapeutic Relevance
Anti-sickling peptides that block HbS polymerization are under active development. PepFold generates candidates targeting the hydrophobic contact site (Val6-acceptor pocket) to prevent fiber formation.
Gene: HBB (Hemoglobin Subunit Beta)
Encodes beta-globin, which pairs with alpha-globin to form adult hemoglobin (HbA). Over 300 pathogenic variants known, including sickle cell (HbS) and beta-thalassemia mutations.
Chromosome 11p15.4
Condition: Sickle Cell Disease
A monogenic disorder caused by the HBB rs334 (Glu6Val) mutation in beta-globin. Hemoglobin S polymerizes under deoxygenation, causing vaso-occlusive crises, chronic hemolysis, and organ damage. Gene therapy and anti-sickling approaches are transforming treatment.
Prevalence: ~300,000 births/year worldwide, predominantly in Sub-Saharan Africa, Mediterranean, Middle East, India
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