Pathogenic mutations in Neurofibromatosis type 1 gene (NF1) are numerous, almost 3000, and distributed throughout this gene. They correspond to deletions, nonsense or missense mutations, these latter representing 17% of the total pathogenic variants. Addressing the molecular basis responsible for the pathogenicity of NF1 missense variants is crucial to establish a molecular diagnosis of the disease and develop more appropriate therapies. We focused on twelve NF1 missense and one small in frame deletion variants whose mutations are localized in SecPH, a domain adjacent to the GRD (GAP Related Domain) which harbours the Ras-GTPase activity of neurofibromin (Nf1), the protein encoded by NF1. We evaluated multiple biochemical and molecular features of full length Nf1 mutant proteins comprising steady state level, half-life and Ras-GTPase activity analysis. Furthermore, we also tested the pattern of SecPH SUMOylation (Small Ubiquitin-related Modifier), a structure-based Nf1 Post Translational Modification, we recently discovered (the unique mechanistic details of SecPH SUMOylation are depicted in B.Vallée poster). These features allowed us to delineate four groups of mutants. One of them is particularly interesting with profound defects in all the parameters we tested. The five variants of this group harbour mutations inducing a misfolding of the SecPH domain, which then triggers the ubiquitylation and proteasomal degradation of the corresponding full length Nf1 mutant protein thereby explaining the defects in all the parameters tested. These results deepen our understanding of the molecular mechanisms responsible for these variants pathogenicity. The instability of other NF1 missense pathogenic variants in codons 844 to 848 has already been described (Li et al., 2016; Young et al., 2023) and it is likely that many other missense variants in NF1 acquire their pathogenic character by a similar mechanism of misfolding and subsequent instability. New therapeutic approaches aimed at stabilizing Nf1 by preventing its ubiquitylation might constitute valued therapeutic options for this class of variants.