Objective Vacuoles, E1‐ubiquitin–activating enzyme, X‐linked, autoinflammatory, somatic (VEXAS) syndrome is a progressive systemic autoinflammatory disorder caused by somatic variants in UBA1 in blood. Previous analyses have shown discordant disease penetrance. In this study, we examine the associations between demographic features and UBA1 variant allele frequency (VAF) with disease manifestations. Methods Whole exome sequencing data from 192,584 participants from Geisinger MyCode Community Health Initiative and Mount Sinai Bio Me Biobank were analyzed for disease‐causing variants in UBA1 . Clinical manifestations were analyzed across individuals with the UBA1 variant. Results Nine UBA1 variants (VAF range 2.9%–79%) in 23 participants (69.6% men) were identified. Cases with high VAF (>20%) developed macrocytic anemia more often (87.5%) than patients with low VAF (≤20%) variants (27%; P = 0.009). Specifically, at the time of genetic testing, 87.5% of high VAF cases had macrocytic anemia compared with 13.3% of low VAF cases ( P = 0.001). However, there was no significant difference in the development of anemia or thrombocytopenia ( P = 0.53). In two high VAF cases, macrocytosis developed more than five years before the time of sample collection, followed by anemia approximately at the time of sample collection. In one low VAF case with other inflammatory symptoms, macrocytic anemia did not develop until five years after sample collection. Conclusion VEXAS syndrome disease severity and penetrance increase at higher VAFs. Low VAF cases demonstrate incomplete penetrance, and the disease tends to be milder in those with it. Female individuals are enriched in lower VAFs and have milder symptoms, suggesting a protective role against disease severity. Low VAF cases, especially ≤10%, can be initially asymptomatic and later develop disease. image