Protein destabilization underlies pathogenic missense mutations in ARID1B

ARID1B is a SWI/SNF subunit frequently mutated in human Coffin–Siris syndrome (CSS) and it is necessary for proliferation of ARID1Amutant cancers. While most CSS ARID1Baberrations introduce frameshifts or stop codons, the functional consequence of missense mutations found in ARID1Bis unclear. We here perform saturated mutagenesis screens on ARID1B and demonstrate that protein destabilization is the main mechanism associated with pathogenic missense mutations in patients with Coffin–Siris Syndrome.