In-silico Identification and Structural Characterization of a Missense Variant (p.Gly380Arg) in the FGFR3 Gene Associated with Achondroplasia

Abstract

Background: Achondroplasia is the most common form of short-limbed dwarfism caused mainly by mutations in the FGFR3 gene. Methods: An integrative bioinformatics approach was applied to analyze the FGFR3 c.1138G>A (p.Gly380Arg) variant using gene-disease association analysis, population frequency assessment, pathogenicity prediction, protein interaction mapping, structural modeling, and molecular docking. Results: The variant showed an extremely low global frequency in gnomAD and was predicted to be pathogenic by MutationTaster, PolyPhen-2, and CADD. Protein interaction analysis revealed strong associations of FGFR3 with skeletal development and fibroblast growth factor signaling pathways. Molecular docking demonstrated reduced binding affinity in the mutant protein compared to the wild type, indicating altered structural interactions caused by the p.Gly380Arg substitution. Conclusion: The study highlights the pathogenic significance of the FGFR3 p.Gly380Arg variant and provides computational insights into its role in the molecular pathogenesis of achondroplasia.