Single-Minded 2 (SIM2) is a member of the basic-helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) family of transcription factors. These proteins are known to play important roles in biological processes such as development, oxygen homeostasis and stress responses, however the physiological role of SIM2 is largely unknown. SIM2 functions as a heterodimer with ARNT2 to regulate gene expression, and can act as both a transcriptional repressor and activator in a highly context dependant manner. Sim2 mRNA is expressed within the brain both during development and postnatally, however the function neuronal function of SIM2 is not well characterised. Sim2 knockout (KO) mice die perinatally, displaying varying phenotypes including dysmorphologies such as cleft palates and sporadic scoliosis. These mice also display a reduced number of somatostatin and thyrotropin releasing hormone expressing neurons within the hypothalamus. A screen was performed on an exome sequencing database to identify SIM2 variants in patients with intellectual disabilities, delayed development of speech, dysmorphic features and scoliosis. We performed reporter gene assays on a number of the variants and identified non-synonymous mutations that cause a change in transcriptional activity. These variants were then further characterised in order to determine the molecular mechanism behind this change in activity. This study highlighted several SIM2 variants found in patients with disabilities and validated a candidate set as potential disease causing or contributing variants.