Computational analysis of functional, structural and pathogenic impacts of missense SNPs in the human SOCS3 gene

The Suppressor of Cytokine Signaling 3 (SOCS3) protein is a crucial negative regulator of cytokine-mediated signaling pathways, and genetic variations in SOCS3 have been implicated in the development of multiple multi-factorial diseases (MFDs). In this study, a comprehensive insilico analysis was performed to evaluate the functional and structural consequences of eight missense single nucleotide polymorphisms (SNPs) (rs37610117, rs111889212, rs1061489, rs376015024, rs17849241, rs201763454, rs200504273, rs150709546) retrieved from the NCBI dbSNP database. Functional predictions using SIFT, PolyPhen-2, PhD-SNP, PANTHER, and SNP&GO identified several potentially deleterious variants, with rs201763454 (L156F) notably predicted to impair protein function. Conservation analysis with ConSurf revealed that key residues such as H126Y and A223S are highly conserved, indicating their functional importance. Homology-based structural modeling via Phyre2 indicated SNP-induced alterations in secondary structure, while stability and flexibility assessments suggested destabilizing effects for multiple variants. Structural mapping confirmed that high-risk SNPs are localized within critical functional domains of SOCS3. CScape cancer susceptibility prediction revealed that E98V and A223S as oncogenic SNPs. Further analysis using cBioPortal and CanSAR Black confirmed the involvement of E98V and other variants (S26N, F136L, A223S) in various cancers, highlighting their potential clinical significance. Protein-protein interaction analyses (STRING, GeneMANIA) further highlighted the biological relevance. Collectively, this study identifies critical SOCS3 SNPs that may modulate protein function and contribute to MFD pathogenesis. These findings suggest that SOCS3 missense SNPs, particularly E98V, H126Y, and A223S, may serve as candidate biomarkers for cancer susceptibility and warrant further experimental validation.