Sta is an antigen of the human MNSs blood group system carried by a variant glycophorin residing in the erythrocyte membrane. We examined the structure, organization, and inheritance of Sta gene identified in genomic DNA from an Oriental family. Southern blotting detected a useful genetic marker tightly linked to the Sta gene. Differential hybridization and secondary restriction analyses showed that Sta gene is a fusion hybrid of delta and alpha glycophorin genes. Genomic mapping by extensive use of synthetic oligonucleotides, with overlapping sequence specificity, allowed us to define the delta-alpha junction site and disclose the organization of the variant gene. The junction point of Sta hybrid gene is encompassed by an unexpressed exonlike sequence of the delta gene at the 5′ site, and an expressed sequence of the alpha gene spanning codons 59 through 71, at the 3′ site. Dosage quantification demonstrated the occurrence of Sta gene as a single copy in the genome. Blood group inheritance, evaluated by DNA typing, established the tight linkage of Sta to the alpha M and delta S genes. The data support a single unequal crossing-over event between misaligned delta and alpha genes on the homologous chromosomes as the mechanism for the origin of Sta gene. The Sta gene is similar in overall structure to another delta-alpha hybrid gene, Dantu, but differs from it in junction structure, copy number, gene linkage, and antigen specificity.