An AGCAG motif at 3′ splice acceptor sites in a diverse set of genes creates alternate in-frame splice acceptor sites that produce alternate protein isoforms differing by a single amino acid. Among a group of over 12,000 EST-verified splice acceptor sites, only 74 genes were identified that contained the AGCAG motif, comprising about 0.7% of the total. In some cases the location of the single amino acid insertion occurs in a region with the potential to affect protein function. Analysis of cDNA from five different human genes of immunologic interest that contain the AGCAG motif, CD3ζ, CD79B, PLCγ1, CD19, and CD32B (FcγRIIB), confirms that each gene encodes the two predicted splice variants. Variations occur in the splice variant ratio in all five of the genes tested during T and B cell activation, suggesting that the ratio is regulated by the cellular activation state. These results suggest that activation-induced variation in mRNA splicing may represent a mechanism for functional modulation of these proteins. © 2007 Elsevier Inc. All rights reserved.