We describe a 0.5-kb region located 1.65 to 1.15 kb upstream of the G gamma fetal globin gene with three polymorphisms of erythroid and ubiquitous nuclear protein binding motifs (GATA, CRE, and a new protein binding site). These three polymorphisms result in high-affinity and low-affinity motifs for nuclear proteins, and are combined in four arrangements called pre-G gamma frameworks (pG gamma Fs). Each pG gamma F is linked with one of the major haplotypes of the beta-globin gene cluster observed in sickle cell disease (SCD) associated with different mean levels of hemoglobin F (Hb F) expression (P < .001). This strong linkage and the differing affinities suggest that this region may be involved in the modulation of Hb F expression in SCD.