Benchmarking DNA Foundation Models for zero-shot variant effect prediction: the role of context, training, and architecture

In this study, we systematically evaluate the performance of several DNA foundation models (NT, DNABERT, and HyenaDNA) in predicting the functional impact of genetic variants using Zero-shot scoring, a method that does not require task-specific fine-tuning. We assess the models’ sensitivity to sequence alterations introduced by Single Nucleotide Variants (SNVs), comparing their ability to capture both local and extended contextual effects. Using pathogenic, benign, and uncertain SNVs from ClinVar, we show that large multi-species NT models outperform other architectures in detecting functional consequences, not only at the mutation site but also in adjacent regions. These models exhibit superior discriminative power across variant categories, especially when aggregating Zero-shot scores over multiple surrounding tokens. Conversely, models trained solely on human sequences, such as DNABERT and HyenaDNA, show limited contextual awareness and reduced ability to differentiate variant effects. Our findings highlight the critical importance of model size, training objective, and training data diversity in shaping model performance. Furthermore, we discuss current limitations in modeling long-range dependencies in genomic sequences and suggest that innovations in transformer architectures, such as sparse attention or memory-augmented models, may provide viable paths toward scalable, genome-wide variant effect prediction.