University College Hospital, Ibadan

Many variants found in monogenic diabetes genes remain variants of uncertain significance because evidence is insufficient or conflicting. A pipeline trained on 7,706 confidently classified single nucleotide variants across 22 such genes reached ROC-AUC 0.9989 and AUPRC 0.9970 on 771 held-out variants, with recall 1.00 on the pathogenic class. Feature ablation showed that part of this accuracy reflects overlap with the ACMG criteria used to assign ClinVar labels, yet on non-missense variants, where computational evidence could not have been directly invoked, the model still beat a majority-class baseline, 99.0% versus 87.0%; it then ranked 6,306 uncertain variants with per-variant explanations.

Many variants found in monogenic diabetes genes remain variants of uncertain significance because evidence is insufficient or conflicting. A pipeline trained on 7,706 confidently classified single nucleotide variants across 22 such genes reached ROC-AUC 0.9989 and AUPRC 0.9970 on 771 held-out variants, with recall 1.00 on the pathogenic class. Feature ablation showed that part of this accuracy reflects overlap with the ACMG criteria used to assign ClinVar labels, yet on non-missense variants, where computational evidence could not have been directly invoked, the model still beat a majority-class baseline, 99.0% versus 87.0%; it then ranked 6,306 uncertain variants with per-variant explanations.