Schizophrenia is a psychiatric disorder which does not have a definite cure till date. Most notably, the disease is still not completely explored at the genetic level. One of the major genes that play an important role in this illness is RGS4 (Regulator of G protein Signaling 4). Owing to the importance of RGS4 in Schizophrenia, we made an attempt to identify the deleterious missense mutations in this gene by computational analysis. A total of 44 variants were retrieved from dbSNP for the RGS4 gene in Homo sapiens. Out of these 44 SNPs, 36% of amino acid substitutions were identified as deleterious by the SIFT program, 42% of amino acid substitutions were identified as damaging by PolyPhen-2 program, 57% and 47% of single point mutations were identified as less stable disease associated deleterious mutations using I-Mutant 2.0 and SNPs&GO programs respectively. Furthermore, the results obtained from the different algorithms were clustered to increase the accuracy of prediction. It was interesting to note that 5 variants namely Y165H, Y147H, Y262H, E135H and E117H were found to have significant impact on RGS4 protein structure and function. These results were also validated by means of PhD-SNP, PANTHER and FoldX programs. Hence, we infer that these missense mutations could be important candidates for Schizophrenia caused by RGS4 gene. © IDOSI Publications, 2013.