Fair splits flip the leaderboard: CHANRG reveals limited generalization in RNA secondary-structure prediction
Abstract
CHANRG benchmark evaluates RNA structure prediction models with improved rigor, revealing that foundation models lose robustness outside distribution despite higher held-out accuracy.
Accurate prediction of RNA secondary structure underpins transcriptome annotation, mechanistic analysis of non-coding RNAs, and RNA therapeutic design. Recent gains from deep learning and RNA foundation models are difficult to interpret because current benchmarks may overestimate generalization across RNA families. We present the Comprehensive Hierarchical Annotation of Non-coding RNA Groups (CHANRG), a benchmark of 170{,}083 structurally non-redundant RNAs curated from more than 10 million sequences in Rfam~15.0 using structure-aware deduplication, genome-aware split design and multiscale structural evaluation. Across 29 predictors, foundation-model methods achieved the highest held-out accuracy but lost most of that advantage out of distribution, whereas structured decoders and direct neural predictors remained markedly more robust. This gap persisted after controlling for sequence length and reflected both loss of structural coverage and incorrect higher-order wiring. Together, CHANRG and a padding-free, symmetry-aware evaluation stack provide a stricter and batch-invariant framework for developing RNA structure predictors with demonstrable out-of-distribution robustness.
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TL;DR: Do RNA Foundation Models really understand structures, or just memorize? We introduce CHANRG, a strictly deduplicated benchmark of 170k RNAs. We reveal a massive leaderboard flip where FMs crash on OOD data (failing at global topology). Furthermore, we expose a critical bug where dense padding causes ~2% random prediction errors, and solve it with a 3.3x faster, padding-free NestedTensor stack that cuts memory by 6.7x.
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