How to identify follicular lymphoma (FL) patients with low disease burden but high risk for early progression is unclear. Building on a prior study demonstrating the early transformation of FLs with high variant allele frequency (VAF)BCL2mutations at activation-induced cytidine deaminase (AICDA) sites, we examined 11 AICDA mutational targets, includingBCL2,BCL6,PAX5, PIM1,RHOH,SOCS, andMYC, in 199 newly diagnosed grade 1 and 2 FLs.BCL2mutations with VAF ≥20% occurred in 52% of cases. Among 97 FL patients who did not initially receive rituximab-containing therapy, nonsynonymousBCL2mutations at VAF ≥20% were associated with increased transformation risk (HR 3.01, 95% CI 1.04–8.78,p= 0.043) and a trend toward shorter event-free survival (EFS, median 20 months with mutations versus 54 months without,p= 0.052). Other sequenced genes were less frequently mutated and did not increase the prognostic value of the panel. Across the entire population, nonsynonymousBCL2mutations at VAF ≥20% were associated with decreased EFS (HR 1.55, 95% CI 1.02–2.35,p= 0.043 after correction for FLIPI and treatment) and decreased overall survival after median 14-year follow-up (HR 1.82, 95% CI 1.05–3.17,p= 0.034). Thus, high VAF nonsynonymousBCL2mutations remain prognostic even in the chemoimmunotherapy era.