biostudies-literatureJang SKNHGRINational Institute of Mental HealthNIGMS101068https://www.ebi.ac.uk/biostudies/studies/S-EPMC12903449biostudies-literatureUnknown6(2)Protein language models (PLMs) improve variant effect predictions, but their role in gene discovery for complex traits remains unclear. We introduce an allelic series-based regression test that uses PLM-derived variant effect predictions as proxies for effect sizes, identifying ∼46% more associations than standard burden tests. Extending this to isoform-level analysis, we find 26 gene-trait pairs with stronger associations in non-canonical versus canonical transcripts, highlighting isoform-specific effects. Finally, we identify evolutionary plausible variants (EPVs), missense variants assigned higher likelihoods than the wild-type alleles by PLMs, representing 0.45% of missense variants. EPVs show higher allele frequencies than synonymous variants, consistent with differential selection prCell genomicsLeveraging protein language models to identify complex trait associations with previously inaccessible classes of functional rare variants.PMC12903449R01MH130581Ntranos VZaitlen NBorder RWei ATuan DJang SKFlint JSankararaman SWang ZAn UfalseLeveraging protein language models to identify complex trait associations with previously inaccessible classes of functional rare variants.Protein language models (PLMs) improve variant effect predictions, but their role in gene discovery for complex traits remains unclear. We introduce an allelic series-based regression test that uses PLM-derived variant effect predictions as proxies for effect sizes, identifying ∼46% more associations than standard burden tests. Extending this to isoform-level analysis, we find 26 gene-trait pairs with stronger associations in non-canonical versus canonical transcripts, highlighting isoform-specific effects. Finally, we identify evolutionary plausible variants (EPVs), missense variants assigned higher likelihoods than the wild-type alleles by PLMs, representing 0.45% of missense variants. EPVs show higher allele frequencies than synonymous variants, consistent with differential selection pr2026-01-01T00:00:00Z2026 Feb2026-07-15T18:02:43.737Z2026-07-08T03:08:33.915ZS-EPMC129034494126544710.1016/j.xgen.2025.101068