Hypereosinophilia (HE) has been defined as persistent eosinophilia >1.5 × 109/L; 
it is broadly divided into primary HE (clonal or neoplastic; HEN), 
secondary/reactive HE (HER), or HE of undetermined significance (HEUS) when no 
cause is identified. The use of myeloid next-generation sequencing (NGS) panels 
has led to the detection of several mutations in patients previously diagnosed 
with HEUS, reassigning some patients to the category of HEN, specifically the 
World Health Organization category of chronic eosinophilic leukemia, not 
otherwise specified (CEL, NOS). Here, we describe a novel somatic JAK1 
pseudokinase domain mutation (R629_S632delinsSA) in a patient with HE that had 
initially been characterized as a variant of uncertain significance. We 
performed functional studies that demonstrated that this mutation results in 
growth factor independence of Ba/F3 cells in vitro and activation of the 
JAK-STAT pathway. These effects were abrogated by the JAK1/JAK2 inhibitor 
ruxolitinib. R629_S632delinsSA is the first known somatic mutation in JAK1 
linked to a clonal eosinophilic neoplasm, and highlights the importance of the 
JAK-STAT pathway in eosinophil survival.