Proposed pathways underlying the phenotype of the SLFN14^K219N variant. SLFN14^K219N mutant leads to degradation of rRNA accompanied with compensatory activation of the mTORC1 pathway via phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) at threonine 389 and enhanced ribosomal biogenesis. Inhibition of the mTORC1 pathway by rapamycin blocks ribosomal protein and increases degradation of rRNA. mTORC1 activation also leads to transcriptomic alteration and mitochondrial stress, resulting in thrombocytopenia and platelet dysfunction.