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Somatic mutations involving the canonical exon 10 hotspots of the thrombopoietin receptor gene (MPL) are established drivers in myeloproliferative neoplasms (MPNs), whereas the significance of rare, atypical variants remain unclear. We investigated the relevance of three uncommon MPL variants affecting residues Y591 and R592. Among a multicenter cohort with myeloid neoplasms undergoing next-generation sequencing (NGS), eight individuals harbouring MPL p.Y591D, p.Y591H, or p.R592Q variants were identified. Clinical data were integrated with a comprehensive literature review, in silico pathogenicity prediction, and structural bioinformatics modelling of the MPL-JAK2 complex. Clinically, these variants were observed across heterogeneous myeloid disorders and consistently co-occurred with canonical driver mutations in MPN cases. Certain patients with Y591 substitutions seem to exhibit aggressive disease phenotypes and/or suboptimal responses to JAK-inhibitors, whereas R592Q cases showed variable outcomes influenced by co-mutational profiles. Computational predictors yielded discordant pathogenicity assessments. Structural modeling indicated that these substitutions induce minor local rearrangement and do not significantly disrupt the overall MPL-JAK2 complex assembly. However, the Y591 substitutions may lead to loss of critical regulatory motifs by removing a key phosphorylation-dependent docking site and disrupting the YXXφ motif, potentially leading to receptor hypersensitivity to thrombopoietin. Regarding pathogenicity classification, the p.R592Q substitution should be considered as a variant of uncertain significance (VUS), whereas the Y591 alterations may be categorized either as VUS or as "likely oncogenic" depending on the chosen framework. Crucially, current evidence indicates that MPL p.Y591D, p.Y591H, and p.R592Q variants do not act as primary oncogenic drivers but may function only as disease modifiers.