Our study describes eight individuals with SATB2-associated syndrome (SAS), an autosomal dominant disorder caused by variants in the SATB2 gene and characterized by developmental delay, behavioral challenges, craniofacial/dental problems, growth delay, and skeletal anomalies, all with variable severity. The individuals included carry genetic variants that affect the exact same location in the SATB2 protein but result in different amino acid changes. Through various experiments, we document for the first time that different genetic SATB2 variants in the same location can affect its protein function differently, consistent with differences we observed in phenotype severity in the affected individuals. (By Professor Yuri Zárate, https://jmg.bmj.com/content/early/2024/09/26/jmg-2024-110015 )