Homozygosity for the hemoglobin S (Hb S) mutation, as well as a number of heterozygous states involving one gene encoding Hb S, lead to shortened red blood cell survival and hemolysis in sickle cell disease. Variants of the VCAM1 gene could be informative genetic modifiers of phenotypic differences in SS disease. In this work, we have analyzed the genetic variation that can alter the expression and the function in VCAM-1 gene using computational methods. Out of the total 1450 SNPs in Homo sapiens 254 were missense, 255 were non-synonymous SNPs, 207 were synonymous SNPs, 53 were in the 3’un-translated region and 23 were in the 5’un-translated region of the nsSNPs67 SNPs (26.7%) were found to be damaging by both SIFT and Poly Phen server among the 255 ns SNPs investigated. In I-Mutant 3.0,... 100% of ns SNPs changed protein stability with related free energy. There were 51 functional SNPs in 3UTR region, 39% (20/51) of them disrupted a conserved miRNA site and 23 derived allele created a new miRNA site. A structural and functional analysis of ns SNPs was also studied by Project HOPE software. UTR resource tool predicted that one SNP (rs529512508) found in a binding site that may affect the regulation of protein translation. Based on this work, we proposed that these most deleterious ns SNPs with an SNP ids (rs529512508, rs41287272, rs200949878, rs368917883, rs138479988, rs143330690) may be important candidates for the cause of different types of human diseases by VCAM1 gene.