Heterozygous de novo variants in the TBR1 cause a rare form of autism called TBR1 Syndrome, which involces intellectual disability, behavioral disturbances, and speech and motor delays. TBR1 encodes a neuronally expressed transcription factor with a conserved T-box DNA-binding domain (T-box) and a T-Box transcription factor-associated domai (T-box_assoc) of unknown function. We sought to identify how TBR1 variants impacting different domains contribute to shared autism risk as well as clinical heterogeneity in TBR1 Syndrome.