Faith Ogundimu

Diffuse midline glioma is a paediatric brainstem cancer that is almost uniformly fatal: about ninety percent of children die within two years, and the first systemic drug, approved in 2025, does not cure. Its biology is largely non-coding, which is exactly where variant prediction is least trustworthy. NCypher is a triage layer, not another predictor. In the matched fetal-OPC cell context it couples a regulatory-activity score, the mechanism (the motif and the exact base that breaks), and an honest confidence flag into one agent call, promoting a variant only when independent lines of evidence agree. Across 10,869 somatic non-coding variants from an H3 K27M cohort it returns a two-sided finding, not a manufactured driver: somatic mutation does not drive the super-enhancers this tumour depends on, yet those enhancers sit on markedly more conserved OPC regulatory sequence (matched-permutation p<0.001), with NPAS3 leading the shortlist. The engine is validated where it should work (progenitor caQTLs, AUROC 0.69) and honest where it should not. Six independent stress tests, each re-derived by a separate reviewer agent, harden it. NCypher ships as a rich MCP tool, an Agent Skill with a built-in sceptic, a reproducibility gate, and a downloadable regulatory map.