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.

That's an interesting statement: "The gist was, can existing variation provide enough context to infer impact of variation? The answer seemed to be no."

Is this saying that if we were to sequence every human being on the planet, we'd still be unable to explain some phenotype differences caused by variation simply becase there aren't enough humans/enough variation? Interesting, as that's the first time I've heard that claim, and it would suggest that we spend our time working on mechanistic models of variant to phenotype.

Yes, and genetic variant generally do not act in isolation. We currently focus on the small additive effects of variants because we can with small sample sizes—and 1 million humans is marginal using a GWAS cohort to dive into epistasis. But these interaction effects among variants are critical. Now almost completely deprecated.