TRMT1 is a tRNA methyltransferase that catalyzes N2,N2-dimethylguanosine (m2,2G) modification at position 26 of most nuclear- and mitochondrial-encoded tRNAs, using S-adenosyl-L-methionine as a methyl donor. This modification is required for proper tRNA stability and function in translation, and supports cellular redox homeostasis and proliferation. The enzyme contains a zinc finger domain critical for tRNA binding and catalytic activity 1. Bi-allelic TRMT1 variants cause a neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral abnormalities, epilepsy, and facial dysmorphism 2. Pathogenic variants include missense and loss-of-function mutations that disrupt tRNA modification; cells from affected individuals show deficiency in TRMT1-catalyzed modifications and altered expression of genes associated with cell cycle disruption and neurodegeneration 2. Disease-associated TRMT1 variants lead to reduced levels of tyrosine and serine tRNAs 1. Beyond inherited disease, SARS-CoV-2 main protease cleaves TRMT1, removing the zinc finger domain and eliminating methyltransferase activity, which may impair translation and oxidative stress responses during infection 3. Currently, no specific TRMT1-targeted therapeutics have been approved; management focuses on addressing neurological sequelae in affected individuals.