AnnotateMissense: a genome-wide annotation and benchmarking framework for missense pathogenicity prediction

• URL: http://arxiv.org/abs/2605.24520v1
• Date: Sat, 23 May 2026 11:15:53 GMT
• Title: AnnotateMissense: a genome-wide annotation and benchmarking framework for missense pathogenicity prediction
• Abstract summary: AnnotateMissense is a scalable annotation, benchmarking and genome-wide prediction framework for missense variant interpretation.<n>It integrates hg38 missense variants derived from dbNSFP v5.1 with ANNOVAR annotations, transcript/protein descriptors, AlphaMissense scores, ESM-derived features, conservation metrics, population-frequency variables, established pathogenicity predictors and engineered amino acid/codon-labelled features.
• Score: 0.0
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: Missense variant interpretation remains challenging because pathogenicity depends on heterogeneous evidence from population frequency, evolutionary conservation, transcript context, amino acid substitution severity, prior pathogenicity predictors and protein-language-model-derived features. We present AnnotateMissense, a scalable annotation, benchmarking and genome-wide prediction framework for missense variant interpretation. AnnotateMissense integrates hg38 missense variants derived from dbNSFP v5.1 with ANNOVAR annotations, dbNSFP transcript/protein descriptors, AlphaMissense scores, ESM-derived features, conservation metrics, population-frequency variables, established pathogenicity predictors and engineered amino acid/codon-context features. Using 132,714 ClinVar-labelled missense variants, we benchmarked machine-learning and deep-learning models under controlled feature configurations. The full 303-feature benchmark set achieved the strongest performance with XGBoost, reaching mean MCC = 0.9411 and ROC-AUC = 0.9950 across stratified five-fold cross-validation. Restricted naive and location-oriented feature sets achieved lower best MCC values of 0.4989 and 0.5113, respectively. Circularity-controlled ablations showed that removing prior-predictor, population-frequency and clinically overlapping evidence reduced performance, whereas excluding AlphaMissense and ESM-derived features alone had minimal effect. Temporal ClinVar validation on newly observed pathogenic/benign variants achieved MCC = 0.7613, accuracy = 0.8798 and F1-score = 0.8750. The final model was applied to 90,643,830 hg38 missense variants to generate AnnotateMissense pathogenicity scores and binary prediction labels. Code and outputs are available at https://github.com/MuhammadMuneeb007/CAGI7_Annotate_All_Missense and https://doi.org/10.5281/zenodo.19981867.

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