Bioinformatic analysis of rare endothelial protein C receptor missense variants associated with coagulation and thrombophilia risk

The protein C receptor (PROCR) plays a crucial role in regulating coagulation and maintaining vascular integrity. Mutations in PROCR gene have been associated with thrombophilia and coagulation abnormalities. This study aimed to identify, characterize, and functionally analyze pathogenic nonsynonymous single nucleotide polymorphisms (nsSNPs) in PROCR via an integrative computational approach. Text mining revealed that PROCR is frequently associated with thrombophilia, highlighting its role in coagulation regulation. Protein‒protein interaction analysis revealed strong interactions between PROCR and key coagulation proteins, including F2, F5, THBD, and SERPINC1, suggesting its central role in the coagulation cascade. Functional predictions were generated using SIFT, PolyPhen-2, PROVEAN, and FATHMM, with further scoring by REVEL, ClinPred, and CADD. Structural and stability assessments were conducted using HOPE, I-Mutant2.0, MUpro, and AlphaFold substitution modeling. Evolutionary conservation was analyzed via PhyloP, PhastCons, GERP++, and ConSurf to assess residue functional importance. Posttranslational modifications (PTMs) were investigated using MusiteDeep, PhosphoSitePlus, and SwissPalm. Human Phenotype Ontology (HPO) mapping was used to explore clinical correlations. Six variants N64T, F93L, R113C, P145L, R173H, and R236W were consistently predicted to be deleterious. F93L showed the highest AlphaFold pathogenicity score (0.97), indicating significant structural disruption. N64T, P145L, and R173H were highly conserved residues, supporting functional relevance. PTM analysis revealed that N64T overlapped with a validated N-glycosylation site, whereas R113C, R173H, and R236W affected phosphorylation and ubiquitination. Structural modeling revealed disruptions in protein folding, secondary structure, aggregation potential, and chaperone-binding capacity. HPO mapping associated several variants with coagulation disorders, cardiovascular dysfunction, and systemic phenotypes. This analysis highlights PROCR variants with predicted structural and regulatory disruption. Variants F93L, N64T, and R236W may increase thrombophilia risk by impairing EPCR function and interactions with coagulation factors. These findings support using computational pipelines to prioritize functionally relevant nsSNPs and provide basis for future experimental validation and personalized risk assessment in thrombotic disorders.