VEXAS patients with the p.Met41Val variant had more systemic undifferentiated inflammatory syndromes and less ear chondritis. A multivariable analysis for survival showed improved outcomes with ear chondritis and worse outcomes with transfusion dependence or the p.Met41Val variant. The p.Met41Leu and p.Met41Thr variants permit higher residual translation of normal cytoplasmic UBA1 (UBA1b), whereas p.Met41Val had lower residual UBA1b, and other permutations at p.Met41 had minimal residual UBA1b, linking VEXAS pathogenesis and severity to a loss of UBA1b function.