SCAF4 is an anti-terminator protein essential for regulating mRNA termination during RNA polymerase II (POLR2A) transcription 1. It functions by binding the phosphorylated C-terminal domain (CTD) of POLR2A and subsequently binding nascent RNA upstream of early polyadenylation sites to suppress premature mRNA cleavage and polyadenylation 1. Working redundantly with SCAF8, SCAF4 prevents accumulation of non-functional truncated proteins by suppressing alternative early poly(A) site usage 1. Independently of SCAF8, SCAF4 also suppresses transcriptional readthrough and ensures correct termination at canonical distal sites 1. Pathogenic variants in SCAF4 cause a variable autosomal dominant neurodevelopmental disorder characterized by developmental delay, seizures, intellectual disability, and skeletal abnormalities 23. Disease-causing variants include truncating, splice-site, and missense mutations predominantly affecting the N-terminal two-thirds of the protein 3. SCAF4 deficiency results in broad mRNA processing dysregulation affecting over 9,000 genes and differential splicing of 2,900 genes 2. Additionally, SCAF4 is implicated in cancer biology, with elevated SCAF4-POLR2A interaction contributing to triple-negative breast cancer progression 4.