Different types of germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders: Schinzel-Giedion syn- drome (SGS, via missense variants at a critical degron region) and SETBP1 - haploinsuf fi ciency disorder. However, due to the lack of systematic investi- gation of genotype-phenotype associations of different types of SETBP1 var- iants, and limited understanding of its roles in neurodevelopment, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remains elusive. This imposes challenges for diagnosis. Here, we present a comprehensive investigation of the largest cohort to date of indi- viduals carrying SETBP1 missense variants outside the degron region ( n = 18). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our fi ndings suggest that such variants cause a clinically and functionally variable developmental syn- drome, showing only partial overlaps with classical SGS and SETBP1- hap- loinsuf fi ciency disorder. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding, transcription, and neuronal differentiation capacity and morphologies. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care, and aetiology of SETBP1-related disorders.