I saw a really interesting talk by Katie Pollard at ISMB this year about the limitations of variant prediction.

The gist was, can existing variation provide enough context to infer impact of variation? The answer seemed to be no.

Kind of like how frontier LLMs need to ingest larger and large amounts of text to advance. We are going to need to leverage comparative data from other species, and likely tremendous amounts of laboratory mutagenesis experiments to actually make headway on variant prediction. Nature, as it stands, just doesn't have enough human variation.