Natural genetic diversity modulates structural stability changes caused by pathogenic variants in small proteins

Natural haplotype backgrounds significantly change predicted structural stability effects of ClinVar pathogenic variants in small human proteins, with 62% of 271 variants showing haplotype-dependent ΔΔG.

• Why it matters: Reference genomes can miss how natural sequence diversity alters variant expressivity, and variant interpretation increasingly needs biophysical evidence of protein disruption that accounts for genetic context.
• What they did: The authors built a physics-based computational pipeline using reconstructed DNA haplotypes from 1000 Genomes Project data, modeled ≤100-residue proteins, and energetically relaxed both natural and pathogenic protein haplotypes.
• The result: Across 271 variants in 46 genes, ΔΔG changes differed by haplotype background for 168 variants (Kruskal-Wallis, Bonferroni-adjusted p < 0.01), spanning 43 of 46 genes (93%).

AI summary of the abstract · may contain errors · not medical advice · read the paper.