The delta-type phospholipase C (PLC) is thought to be evolutionally the most basal form in the mammalian PLC family. One of the delta-type isoforms, PLC-delta 1, binds to both phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) with a high affinity via its pleckstrin homology (PH) domain. We report here a missense mutation in the region encoding the C-terminal PH domain of the human PLC-delta 1. This is also the first report of a mutation in the human PLC genes. A single base substitution (G to A) causes the amino acid replacement, Arg105 to His. Site-directed mutagenesis of the glutathione-S-transferase (GST)/PLC-delta 1 fusion protein changing Arg105 to His resulted in a fourfold decrease in the affinity of specific Ins(1,4,5)P3 binding and a reduction in PtdIns(4,5)P2 hydrolysing activity to about 40% of that of the wild-type enzyme. This remarkable loss of function can be interpreted in terms of a conformational change in the PH domain.