KVarPredDB

KVarPredDB predicts the pathogenicity of missense variants in ten keratin genes (K1, K2, K5, K6A, K6B, K9, K10, K14, K16, and K17) to assess their potential contribution to autosomal dominant genodermatoses.

Key Features:

• Curated variant dataset: Contains annotations for 400 known pathogenic missense variants and 4,629 variants of uncertain significance (VUS) in the ten keratin genes.
• Physico-chemical property analysis: Assesses differences between wild-type and substituted amino acids to infer potential functional disruptions.
• Inter/intra-chain interaction analysis: Evaluates loss or alteration of critical inter- and intra-chain interactions that may affect protein stability.
• Evolutionary conservation assessment: Considers evolutionary conservation of wild-type residues to infer their functional importance.
• Heptad repeat impact analysis: Examines how substitutions affect heptad repeat organization required for keratin coiled-coil formation and stability.
• Molecular docking simulations: Uses resolved crystal structures to compare binding energies between wild-type and mutant keratin coiled-coil heterodimers for protein stability assessment.

Scientific Applications:

• Variant pathogenicity interpretation: Supports interpretation of missense variants in keratin genes for genodermatoses diagnosis and research.
• Prioritization for experimental validation: Enables prioritization of novel missense variants for functional studies based on predicted structural and energetic impacts.
• Genotype–phenotype correlation studies: Facilitates analysis of genotype–phenotype relationships in autosomal dominant keratin-associated dermatological conditions.
• Structural and mechanistic investigation: Provides computational assessments of coiled-coil heterodimer stability to inform structural studies of keratin proteins.

Methodology:

Curates variant data and applies four explicit criteria—physico-chemical property differences, inter/intra-chain interaction evaluation, evolutionary conservation analysis, and heptad repeat impact—combined with molecular docking simulations using resolved crystal structures to compare binding energies of wild-type and mutant keratin coiled-coil heterodimers.