The Lutheran blood group system currently consists of 20 antigens that have been assigned ISBT numbers. Of these, all but LU7 have been associated with one or more nucleotide changes in LU. The purpose of this study was to determine the molecular basis associated with the LU:-7 phenotype. We obtained a stored sample from one proband with this phenotype and sequenced LU. Using genomic DNA, exons 1 through 15, and their flanking intronic regions, of LU were amplified by polymerase-chain reaction, and the products were sequenced. A homozygous novel missense nucleotide change of 1274A>C in exon 10 of LU was observed. This change is predicted to encode Ala at position 425 in place of Glu of the consensus Lu glycoprotein. Based on these results, and an absence of a record of this change in the Single Nucleotide Polymorphism database, Glu425 in the Lu glycoprotein is required for expression of Lu7, and Ala425 is associated with the LU:-7 phenotype. This completes the molecular basis associated with all antigens known to be in the Lutheran blood group system.