Pulmonary arterial hypertension (PAH) is a fatal vasculopathy in which germline variation in Bone Morphogenetic Protein Receptor Type II (BMPR2) is considered a major genetic factor for disease susceptibility. This study systematically screened BMPR2 single nucleotide variants using a multi-step in silico pipeline that combined functional annotation, pathogenicity prediction, structural stability assessment, evolutionary conservation, post-translational modification mapping, and protein-protein interaction analysis. From 1569 variants retrieved from gnomAD and annotated with the Variant Effect Predictor, missense substitutions were prioritized and evaluated with multiple classifiers (PredictSNP, PolyPhen-2, SIFT, SNAP), while MuPro and I-Mutant 3.0 estimated effects on protein stability. ConSurf was used to map residue conservation, MusiteDeep to predict post-translational modification sites, and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to interrogate the BMPR2 interaction network. Most selected missense variants yielded negative ΔΔG values, consistent with predicted reductions in protein structure stability; substitutions such as G68D, G210D and D344Y were predicted to alter polarity, hydrogen bonding and steric constraints. Approximately 92% of prioritized variants were located to highly conserved residues within extracellular cysteine-rich and intracellular kinase domains, often near phosphorylation or glycosylation clusters. Taken together, these in silico findings prioritize several BMPR2 missense variants as candidates for future functional investigation and provide a framework for targeted experimental validation and improved genetic interpretation in PAH.
Günay et al. (Mon,) studied this question.