Architecture of the SynMall database and its annotation-based analyses. (A) An overview of SynMall, including integrated resources for both human and non-human sSNVs. (B) SynMall assembles three core modules: the annotation module offers 79 universal annotations; the feature module provides more than 100 contextual features for each variant; and the analysis module focuses on four sSNV-specific biological mechanisms with predictive algorithms and visualizations. (LLMs) Large language models. (C) Variants are aggregated from four resources: transcript-generated, CADD v1.7, synVep, and FAVOR. (All sources) sSNVs recorded in all four data sets, (single/dual/triple sources) variants present in only some of them. (D) Genome-wide minor allele frequency (MAF) landscape of sSNVs, integrated from multiple population sequencing projects. (E) Comparison of SynScore with other variant effect predictors (VEPs) on an independent test set. (F) SynScore patterns of sSNVs in ACMG-actionable genes. (G) Z(SynScore): gene-level enrichment of high-score sSNVs across loss-of-function observed/expected upper-bound fraction (LoEUF) groups. Significance (two-sided Mann–Whitney U test) is indicated by asterisks: (***) P < 0.001, (****) P < 0.0001. (H) Top 10 overrepresented KEGG pathways for genes with high SynScores in COSMIC. (I) Positional distribution of SynScore along the coding sequence of MYH7. (J) Spatial clustering of MYH11 sSNVs with SynScore > 0.5 across protein domains.