The most frequent glycosylation (CDG) disorder affecting the N-glycosylation pathway is caused by a deficiency of Phosphomannomutase (PMM2) the enzyme that isomerize Mannose-6-Phosphate. For this disorder, which is known as CDG-PMM2 (MIM: 212065) [a], there is no therapy at present, but, at least in principle patients could benefit from a therapy based on pharmacological chaperones (PC)[b]. PC are small molecules that preferentially bind the folded state of a protein and stabilize it. Disease mutations can lower the free energy difference between the folded and the unfolded protein shifting the equilibrium towards the latter one. Unstable proteins, although retaining the functional chemical groups needed for the biological activity, are sensitive to proteolysis and are cleared by the protein quality control systems in the cell. Hence for these mutations the reduction of the protein concentration in the cell is the primary effect and the reduction of total activity is only a secondary effect. Exploiting non-biased ligand migration and protein dynamics, we have produced the first accurate model of a ligand bound complex for PMM2 which can be used for high throughput screening to find PC for CDG-PMM2[c]. We have characterized in vitro the mutants that are most commonly found in European population, we have demonstrated that the genotype R141H/F119L is eligible for the therapy with PC. Moreover we have demonstrated that a small molecule, glucose-1,6 bisphosphate acts as PC for F119L stabilizing the mutant protein towards thermal induced denaturation and proteolysis. The same metabolite enhances the activity and promotes the correct quaternary structure of the mutant enzyme [d].