A KIR2DS4 deletion variant allele, previously identified through killer immunoglobulinlike receptor (KIR) polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) typing, was functionally investigated using an in vitro cell line model system and in vivo protein expression studies. The KIR2DS4 deletion variant has previously been found in 80% of individuals from Northern Ireland, indicating that it is present at a high incidence in this population. It differs from the normal KIR2DS4 sequence by a 22 bp deletion in exon 5, which causes a frame shift, yielding a truncated KIR2DS4 protein with loss of the transmembrane and cytoplasmic domains of the full-length KIR2DS4 protein. This study has determined that the deleted variant of KIR2DS4 is not anchored to the cell membrane but encodes a soluble form of the protein that is potentially secreted. The frequencies of the deleted and nondeleted versions were also determined in several world-wide populations. A trend was observed towards decreased frequencies of KIR2DS4 deleted variant occurrence in populations having KIR2DS4 as the only activating KIR gene.