In silico report on five high-risk protein C pathogenic variants: G403R, P405S, S421N, C238S, and I243T

In this study, we propose reclassification of 5 out of 16 PROC VUS (variants of uncertain significance): C238S, I243T, G403R, P405S, and S421N, as pathogenic variants, associated with thrombophilia due to PROC deficiency. The obtained results are based on in silico analysis, which enables a detailed assessment of variants’ impact, despite limited clinical evidence. In particular, the G403R substitution, next to the S402-active site, is expected to reduce the flexibility of the local coil domain, affecting the catalytic activity of serine protease. The P405S substitution may imply B-factor gain (P = 0.24; p-value=0.040). On the other hand, the S421N variant causes phosphorylation site disruption at S421, which serves as a target for CK2 phosphorylation. C238S substitution alters metal binding, while the I243T variant may alter transmembrane properties (P = 0.27, P-value=0.00071). All five PROC variants hold promise as diagnostic markers for protein C deficiency and may also serve as potential drug targets for therapeutic intervention.