<i>In Silico</i> analysis of the structural and functional impact of deleterious nsSNPs in the human <i>RETREG1</i> gene associated with congenital sensory neuropathy type II

Abstract Background Mutations in the RETREG1 gene are known to cause Hereditary Sensory and Autonomic Neuropathy type II (HSAN II), a severe congenital disorder affecting sensory neurons. However, the full spectrum of pathogenic single nucleotide polymorphisms (SNPs) and their specific structural consequences remain incompletely characterized. Objectives This study aimed to elucidate pathogenic nsSNPs and their role in the Congenital Sensory Neuropathy (HSAN II) by employing in-silico analysis. Method The nsSNPs of RETREG1 were retrieved from the dbSNP in NCBI database. Different in silico tools, SIFT, PolyPhen-2, SNP&amp;GO, PHD-SNP, SNAP2, I-mutant, Project Hope, MutPred, ConSurf, phyre2, Chimera, and GeneMANIA, were used for predicting the pathogenicity, protein stability, evolutionary conservation, structural alterations, and protein–protein interaction networks.for RETREG1 gene. Result Five nsSNPs were identified as “damaging” or deleterious by using the above software (Y221C, G216R, G211R, L119V, W107C). Four SNPs (Y221C, G211R, L119V, and W107C) were predicted to decrease protein stability, while the fifth SNP (G216R) was expected to increase it. Structural modeling revealed that all five mutations are located within the critical Reticulon Homology Domain (RHD), where they are predicted to cause steric clashes, disrupt hydrophobic packing, and impair protein-membrane interactions. Conclusion This integrated in silico analysis identifies four novel deleterious nsSNPs in RETREG1 (W107C, L119V, G211R, Y221C) and confirms the established G216R variant. These mutations are predicted to impair RETREG1 structure and function, providing mechanistic insight into HSAN II pathogenesis and prioritizing candidates for future experimental validation.