Preprint maps functional impact of 1,456 ARID1B variants linked to neurodevelopmental disorders and cancer

A preprint posted to bioRxiv on 19 June 2026 by researchers at Cold Spring Harbor Laboratory presents a large-scale functional characterisation of missense variants in ARID1B, the most frequently de novo mutated gene across a spectrum of human neurodevelopmental disorders — including Coffin-Siris syndrome — and several cancers.

Using integrative structural modelling of ARID1B within the cBAF chromatin remodelling complex and in a DNA-bound state, the authors analysed 1,456 missense variants identified from more than one million genomes. They report that 94% of these variants are currently clinically uninterpreted, and that 59% have been observed in individuals with neurodevelopmental disorders or cancers. Applying their models, the team classified 617 variants as clearly damaging to one or more functional properties: interactions within the BAF complex, DNA binding, fold stability, or post-translational modification sites.

The work represents a variant-effect prediction resource that could, in principle, help prioritise variants of uncertain significance (VUS) for further experimental follow-up. The authors do not report clinical reclassification of variants; this is a computational modelling study and the findings have not yet been peer-reviewed.

ARID1B encodes a subunit of the SWI/SNF (BAF) chromatin remodelling complex, which regulates gene expression across many cell types. Loss-of-function variants are the established cause of Coffin-Siris syndrome, a rare Mendelian neurodevelopmental condition.