# When Genomic Masking Priors Fail to Transfer: Strong Variant Prediction, Weak Functional Generation

arXiv: https://arxiv.org/abs/2609.04861 · HTML: https://mlsanity.com/paper/2609.04861/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 11 of its 19 references that are in the map.
- First posted on arXiv 4 Sep 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 11 of 11)

- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [MaskGIT: Masked Generative Image Transformer](https://mlsanity.com/paper/2202.04200/) (2022)
- [Large Language Diffusion Models](https://mlsanity.com/paper/2502.09992/) (2025)
- [Simple and Effective Masked Diffusion Language Models](https://mlsanity.com/paper/2406.07524/) (2024)
- [HyenaDNA: Long-Range Genomic Sequence Modeling at Single Nucleotide Resolution](https://mlsanity.com/paper/2306.15794/) (2023)
- [Dirichlet Flow Matching with Applications to DNA Sequence Design](https://mlsanity.com/paper/2402.05841/) (2024)
- [Caduceus: Bi-Directional Equivariant Long-Range DNA Sequence Modeling](https://mlsanity.com/paper/2403.03234/) (2024)
- [Fine-Tuning Discrete Diffusion Models via Reward Optimization with Applications to DNA and Protein Design](https://mlsanity.com/paper/2410.13643/) (2024)
- [Reward-Guided Iterative Refinement in Diffusion Models at Test-Time with Applications to Protein and DNA Design](https://mlsanity.com/paper/2502.14944/) (2025)
- [D3LM: A Discrete DNA Diffusion Language Model for Bidirectional DNA Understanding and Generation](https://mlsanity.com/paper/2603.01780/) (2026)
- [Ctrl-DNA: Controllable Cell-Type-Specific Regulatory DNA Design via Constrained RL](https://mlsanity.com/paper/2505.20578/) (2025)

## Abstract (arXiv)

Bidirectional discrete diffusion model appears naturally suited to genomic modeling because it can reconstruct missing sequence from both flanks. We developed GenDA (Genomic Density-optimized Absorbing Diffusion) under the additional hypothesis that entropy-guided span placement would concentrate reconstruction pressure on compositionally complex regions, improving both downstream variant-effect prediction and functional sequence generation. Our results only partially support this premise. After supervised fine-tuning, the 202M-parameter GenDA model reaches a pooled ClinVar SNV AUROC of 0.774, exceeding a similarly scaled autoregressive model by 0.103. However, a matched random-span variant reaches 0.777, providing no evidence that entropy guidance causes the ClinVar improvement. More unexpectedly, GenDA fails a zero-shot functional inpainting stress test: across promoters, enhancers, exon boundaries, and intron boundaries, it does not consistently outperform a control that shuffles the native gap while exactly preserving 3-mer composition. Failure is already present for 50--500-bp gaps, although enhancer degradation worsens at longer gaps. Diagnostics identify several boundary conditions: entropy measures local sequence complexity rather than functional importance; 1-mer tokenization limits physical context; training spans are capped at 300 bp; and high absolute AlphaGenome fidelity can coexist with negative control-normalized restoration. These results show that strong fine-tuned variant prediction, a plausible corruption prior, and functional generation are distinct claims that require separate validation.