Isocitrate dehydrogenase (IDH) isoform 1 (IDH1) and isoform 2 (IDH2) genes code for proteins that play important roles in the decarboxylation of isocitrate to α-ketoglutarate. Somatic mutations in the IDH1 and IDH2 genes are prognostically significant in patients with glioma and acute myeloid leukemia. However, very little is known about the germline polymorphisms in these two genes. In this study, we aim to comprehensively characterize the single nucleotide polymorphisms (SNPs) located in the IDH1 and IDH2 genes using in silico tools. For this purpose, the data for the SNPs were retrieved from the dbSNP database. The coding non-synonymous SNPs were analyzed for their structural and functional significance using a set of bioinformatics tools including SIFT, PolyPhen-2, PROVEAN, PhD-SNP, PMut, I-Mutant 3.0, MUpro and mutation3D. Structural comparison between normal and mutated residues for the disease-associated functional SNPs was performed using TM-align and SWIS MODEL. The non-coding SNPs located at the 3′-UTR were analyzed using PolymiRTS for assessing the impact of these SNPs in the regulation of binding sites for miRNAs. Moreover, the non-coding SNPs were further analyzed using HaploReg and RegulomeDB databases for assessing SNPs in the context of their chromatin state, regulation of protein binding and associated regulatory potential. A total of 26 SNPs from the IDH1 and 17 SNPs from the IDH2 gene were predicted to be functionally deleterious, damaging and disease associated. Cluster analysis showed that the IDH1 and IDH2 genes have SNPs (R108L, D273G, D279G at the IDH1 and V305M, R377H at the IDH2) clustered in the active site of these enzymes, further potentiating their significance. In these two clusters, the hotspot positions for cancer-specific somatic mutations are also located (R132H for IDH1 and R172H for IDH2). Moreover, SNPs affecting metal binding were also observed at positions 220, 273, and 306 of IDH1 and positions 261 and 356 of IDH2. Analysis of the non-coding SNPs predicted a number of SNPs to be located in the miRNA binding sites and at regulatory loci. In summary, this is the first comprehensive in silico study for the characterization of the germline polymorphisms in these genes and these data should further be validated in clinical studies.