enTrust

What it is. A trust-first interpreter for non-coding, regulatory DNA variants — the frontier where variant-of-uncertain-significance (VUS) calls mostly fail. Coding-variant tools are mature; a variant in regulatory DNA usually gets no principled call at all*, because its effect isn't "changes a protein," it's "changes how much a gene is expressed." I fine-tune a DNA language model on the Deng et al. 2024 cortical MPRA (*Science*, adh0559), score a single-base change's effect via in-silico saturation mutagenesis, annotate the mechanism via transcription-factor motif gain/loss, and — the core contribution — ground every prediction in independent evidence (held-out MPRA, GTEx eQTLs, an independent organoid-context model, TSS proximity) to return a calibrated confidence with an auditable evidence chain**. When the model and evidence agree, confidence is high; when they conflict, the tool surfaces it instead of hiding it behind a number. What I found. 1. Optimizing the allelic-difference directly — a shared-weight "siamese" model trained on measured skew — beats the standard subtract-endpoints proxy by **+47%** on a bidirectional Caduceus backbone (variant-effect Δ-Pearson 0.19 → 0.28**, emVar AUC → 0.67**), the project's biggest gain. 2. A stacking meta-learner that fuses the primary model with an independent organoid model beats a single-feature calibrator (emVar AUC 0.623 vs 0.610**), the independent model being the lever. 3. I reproduce Deng's headline emVar set end-to-end (**163 ≈ 164**), and I report honest negatives — reverse-complement averaging, lower calibration τ, bigger HyenaDNA, and a frozen Enformer feature (tested to full 15k-variant coverage) — each logged with its reason, including one case where I caught our own thin-coverage artifact (a promising feature weight that collapsed to zero under full coverage). Why it matters. The deliverable isn't a bare score — it's a calibrated confidence and an auditable evidence chain for a class of variants curators currently can't call. A confident-but-wrong regulatory call is dangerous; a calibrated "uncertain — here's the conflicting evidence" is usable. The tool works on any variant and outlives the hackathon as a variant-curation aid.