AGO1 (Argonaute RISC component 1) is a core component of the RNA-induced silencing complex (RISC) that mediates gene silencing through microRNAs (miRNAs) and small interfering RNAs (siRNAs) 1. AGO1 binds small non-coding RNAs and represses translation of complementary mRNAs, though it lacks endonuclease activity 1. Beyond cytoplasmic RNAi functions, AGO1 regulates chr1 architecture by associating with active enhancers and topologically associated domain boundaries, fine-tuning gene expression through changes in 3D chr1 organization 2. AGO1 also functions in transcriptional silencing through small RNA-mediated mechanisms 3. De novo heterozygous coding variants in AGO1 cause a novel monogenic neurodevelopmental disorder (NDD) characterized by intellectual disability, speech and motor delay, autistic behavior, and sometimes seizures 1. These variants likely impair function by altering flexibility of AGO1 linker domains critical for mRNA processing 1. Genetic modeling in C. elegans demonstrates that NDD mutations are antimorphic, causing stronger phenotypes than null mutations by sequestering functional miRISC components into non-functional complexes and disrupting miRNA processing and target repression 4. Additionally, suppression of endothelial AGO1 promotes adipose tissue browning and improves metabolic dysfunction through inhibition of the antiangiogenic cytokine thrombospondin-1 5.