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Cancer is one of the world's major causes of mortality, and it plays a most important role in the world's declining life expectancy. F-box and WD-40 domain protein 7 (FBXW7), a typical participant of the F-box family of proteins, has been considered as an antitumor protein and one of the maximum deregulated ubiquitin-proteasome system proteins in uterine carcinosarcoma, endometrial clear cell carcinoma and cervical carcinoma with the greatest prevalence of alterations. FBXW7 variants with known clinical signi cance, as well as nsSNP's in the F-Box and WD40 domains, were evaluated using functionality prediction web resources. Upon analysing the seventy-three deleterious nsSNP's impact on protein stability and function, we identi ed that forty-one nsSNP's of WD40 domain and three of F-Box domain imply decreased stability of the FBXW7 structure. Next to TP53 and PTEN, FBXW7 was reported with the highest percentage of arginine substitution among mutations related to cancer. The current research concentrated on two arginine residue locations (Arg465, Arg505) within the WD40-repeat domain, which is vital for substrate binding. Computational analysis revealed that signi cant deviation in stability and structural con guration of mutants R505L, R465H, R465P, R505G, R505C, R465C R505S and R505L structures. Proteinprotein interaction network of FBXW7 populated with promising hub proteins NOTCH1, c-Myc, CCNE1, STYX, KLG5, SREB1, NFKB2, SKP1, CUL1, thus alteration in the FBXW7 leads to aberration in their signalling pathways as well as their substrate binding ability makes this protein as attractive target for personalized therapeutic intervention.

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