In-silico identification and functional analysis of high-risk oncogenic nsSNPs in the human SDHB gene and their implications for cancer susceptibility.

A total of 442 non-synonymous SNPs (nsSNPs) in the SDHB gene were screened using four predictive tools: SIFT, AlignGVGD, PANTHER, and MutPred. Four high-risk variants (H132P, R177C, R217C, and R230C) were consistently predicted to be deleterious across all tools. Among them, the R217C variant was prioritized for detailed downstream analysis due to its high oncogenic scores and significant structural disruptions. Conservation profiling indicated these variants occurred at highly conserved and solvent-accessible residues. Molecular dynamics simulation revealed the R217C mutant exhibits increased rigidity, altered radius of gyration, reduced flexibility, and constrained principal motions, suggesting functional damage in mitochondrial Complex II. MuTarget analysis revealed that SDHB has limited transcriptional impact as a genotype but is significantly modulated by upstream mutations in cancers such as colon adenocarcinoma, sarcoma, and ovarian cancer. Survival analysis using TCGA datasets showed a trend toward poorer disease-free survival in sarcoma and lower overall survival in SDHB-mutated stomach adenocarcinoma and PCPG cases. Together, these results highlight the pathogenic potential of specific SDHB nsSNPs, particularly R217C, and support their relevance in cancer development and prognosis.