We demonstrate that circulating monocytes from UBA1-mutated individuals, when compared with VEXAS-like, MDS and healthy controls, were quantitatively and qualitatively impaired and displayed features of exhaustion associated with aberrant expression of chemokine receptors, and dysregulation of IL-1β and IL-18 processing consistent with activation of the inflammasome pathway. Here, UBA1 is linked to myelodysplastic syndrome.