The most detrimental missense mutations of TAR DNA Binding Protein 43 causing Fronto Temporal Lobar Degeneration were identified computationally and the substrate binding efficiencies of these mutations were analyzed. Out of 24 variants, I-Mutant 2.0, SIFT and PolyPhen programs identified 1 variant (D169G) that was less stable, deleterious and damaging respectively. Modeling of this one variant was performed to understand the change in their conformations with respect to the native TAR DNA Binding Protein 43 by computing their RMSD and Total energy. The native and the variant were docked with RNA to explain the binding efficiencies of those detrimental missense mutations. The loss of binding affinity with their interacting protein namely RNA was investigated by computing the flexibility of binding amino acids of TAR DNA Binding Protein 43 with their interacting proteins and computing the binding free energy (?G) between native and mutant complexes. The novelty of our work is to identify and validate the detrimental missense mutations based on structural stability which could be reliable and competent with other computational programs.