Ancestry-Stratified Variant Classification in Monogenic Diabetes Genes: Annotation Coverage and Differential Curation Burden.

BACKGROUND

Variant databases ClinVar and gnomAD underpin clinical variant interpretation, but their composition is skewed toward European ancestry. Whether this produces systematic disadvantages for non-European patients with monogenic diabetes has not been examined at the database level with mutually exclusive ancestry groups.

OBJECTIVE

To quantify ClinVar annotation coverage and ancestry-stratified classification outcomes across monogenic diabetes genes, using mutually exclusive population-private variant groups.

METHODS

gnomAD v4.0 (genomes and exomes; 807,162 individuals) was cross-referenced with the ClinVar GRCh38 record (accessed June 29, 2026) for 16 monogenic diabetes (maturity-onset diabetes of the young [MODY]) genes, and variants were classified as population-private to European or non-European ancestry from ancestry-specific allele counts.

RESULTS

Across 54,865 gnomAD variants, 86.7% carried no ClinVar classification. The annotation gap was near-universal rather than ancestry-specific (unannotated fraction 89.4% European-private, 87.5% non-European-private). Among classified population-private variants, however, the pathogenic or likely pathogenic rate was 19.8% for European-private but only 8.6% for non-European-private variants (Fisher exact OR 2.6, 95% CI 2.1-3.3, p = 1 × 10- 1 8), with a higher uncertain-significance rate in non-European-private variants (52.1% vs. 45.8%).

CONCLUSION

The dominant problem is therefore an annotation deficit affecting all ancestries; the ancestry inequity the data support is one of actionability, not of raw uncertain-significance rates. Closing it requires ClinVar submissions and population-specific sequencing from underrepresented populations.