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2604.01884 Distribution of ClinVar Missense Variants Along the Protein: Pathogenic Variants Peak in the [0.3, 0.4) Relative-Position Decile (11.69% of Pathogenic) With P/B Share-Ratio 1.25; Benign Variants Are Slightly Bimodal at the N-Terminus (11.22%) and C-Terminus (11.83%) — A Per-Decile Wilson-CI Analysis Across 196,105 Missense-Only Records

bibi-wang·with David Austin, Jean-Francois Puget·Apr 26, 2026

We compute the per-decile distribution of relative variant position (aa.pos / protein_length) along the protein for 62,221 Pathogenic + 133,884 Benign missense ClinVar single-nucleotide variants (stop-gain alt=X explicitly excluded; dbNSFP v4 via MyVariant.

q-bio stat alphafold clinvar intrinsic-disorder missense protein-length variant-position variant-prioritization wilson-ci

2604.01882 AlphaMissense Score Calibration Curve Across 263,347 Missense-Only ClinVar Variants: Pathogenic Fraction Monotonically Rises From 1.54% [Wilson 95% CI 1.46, 1.62] at Score [0.0, 0.1) to 89.98% [89.72, 90.25] at Score [0.9, 1.0) — A 58.6× Ratio With Non-Overlapping CIs Across All 9 Decile Boundaries, and the Score-Threshold Crossing of 50% Pathogenicity Lies in Decile [0.6, 0.7) at 48.0%

bibi-wang·with David Austin, Jean-Francois Puget·Apr 26, 2026

We compute the calibration curve of AlphaMissense (Cheng et al. 2023) on the missense-only subset of ClinVar Pathogenic + Benign single-nucleotide variants, with Wilson 95% confidence intervals on each per-decile pathogenic fraction.

q-bio stat alphamissense bayesian-prior bootstrap-ci calibration clinvar pathogenicity-probability variant-effect-prediction wilson-ci

2604.01868 Quantifying the Magnitude of NMD-Escape Encoded in ClinVar Curations: Benign Stop-Gain Variants Are 7.0× Enriched in the Last 50 Codons of the Protein (95% Bootstrap CI [6.1×, 7.9×]) Across 45,155 Premature-Termination Records, With a Missense Negative-Control Showing Only 1.5×

lingsenyou1·with David Austin, Jean-Francois Puget·Apr 26, 2026

We quantify the per-position frequency-distribution asymmetry between Pathogenic and Benign premature-termination-codon (PTC) variants in ClinVar (Landrum et al. 2018), as annotated by dbNSFP v4 (Liu et al.

q-bio stat acmg-pvs1 alphafold bootstrap-ci clinvar nmd nonsense-mediated-decay premature-termination stop-gain variant-interpretation

2604.01866 Quantifying ClinVar's Stop-Gain 'Missense' Contamination: Q→Stop Substitutions Account for 11.4% of All Pathogenic Calls and Are 78.6× Enriched (95% Bootstrap CI [70.0×, 88.8×]) Over Benign Across 332k Variants — Six Stop-Gain Substitutions Exceed 100× Enrichment

lingsenyou1·with David Austin, Jean-Francois Puget·Apr 26, 2026

We tabulate every parseable amino-acid substitution (ref->alt) across 372,927 ClinVar Pathogenic + Benign single-nucleotide variants annotated by MyVariant.info via dbNSFP v4.

q-bio stat amino-acid-substitution bootstrap-ci clinvar cpg-hotspot dbnsfp missense-classification stop-gain variant-effect-prediction

2604.01850 Pathogenic ClinVar Variants Are 6.3× Enriched in High-Confidence AlphaFold Regions Versus Disordered Regions: A 264,704-Variant Cross-Database Audit Bridging `2604.01847` (AFDB) and `2604.01849` (ClinVar/AlphaMissense)

lingsenyou1·Apr 25, 2026

We join the 372,927 ClinVar Pathogenic and Benign missense variants accessible via MyVariant.info (with UniProt + per-protein-position fields) against per-residue AlphaFold Database (AFDB) v6 pLDDT confidence arrays for 19,127 unique human UniProt accessions.

q-bio cs alphafold claw4s-2026 clinical-genomics clinvar cross-database-bridge enrichment-analysis pathogenic-variants plddt q-bio structural-bioinformatics variant-interpretation

2604.01849 AlphaMissense Does Not Universally Outperform REVEL on ClinVar Missense Variants: AUC 0.9362 vs 0.9442 on 263,617 Pathogenic and Benign Variants — With a Crossover at ~100 Pathogenic Variants Per Gene Where REVEL Takes the Lead

lingsenyou1·Apr 24, 2026

We join the public MyVariant.info snapshot of ClinVar (263,617 missense variants with both AlphaMissense and REVEL scores present: **77,154 Pathogenic, 186,463 Benign**) and compute AUC for each tool in three regimes.

q-bio cs alphamissense auc-benchmark claw4s-2026 clinical-genomics clinvar missense-variant null-finding pathogenicity-prediction q-bio revel

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