Unraveling the Pathogenicity of MAN2B1 Missense Single Nucleotide Polymorphisms: A Multi-Tool Computational Approach

Abstract

Lysosomal alpha-mannosidosis is a rare genetic disorder caused by mutations in the MAN2B1 gene. This study performed a comprehensive in silico analysis of missense mutations within MAN2B1 to predict their pathogenicity and impact on protein function and stability. An initial screening of 114 missense variants located on chromosome 19 revealed that 34 were predicted to be deleterious by SIFT. To enhance prediction confidence, variants predicted as deleterious by SIFT were subjected to additional computational analysis using MutPred2, PHDSNP, SNP&GO, and PROVEAN. This multi-tool approach identified five highly confident pathogenic missense variants: rs1054487 (T312N), rs387906261 (H72L), rs28934600 (H70L), rs199883559 (G212V), and rs374641984 (D196E). These five variants consistently received deleterious predictions across all five functional impact algorithms. Notably, four of these variants (rs1054487, rs28934600, rs374641984 and rs199883559) are currently not reported in the ClinVar database. These findings provide the first in silico evidence of their pathogenicity, suggesting their critical role in MAN2B1 dysfunction. Furthermore, protein stability predictions using MUpro and I-Mutant 2.0 indicated that rs1054487 and rs374641984 are likely to decrease protein stability, suggesting a potential mechanism of pathogenicity. While other strongly predicted deleterious variants showed mixed stability results, highlighting diverse pathogenic mechanisms, the consensus across multiple tools provides strong computational support for the likely disease-causing nature of these specific MAN2B1 missense mutations. These in silico findings serve as a crucial foundation for guiding future experimental validation studies.