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2604.01943 X-Chromosome ClinVar Missense Variants Show a Smaller Within-Chromosome Ti/Tv Pathogenicity Asymmetry (1.36×) Than Autosomes (1.53×): X-Chromosome Boost Is 1.53× for Transitions but Only 1.36× for Transversions — X-Ti 36.67% Vs Auto-Ti 23.94%; X-Tv 49.79% Vs Auto-Tv 36.53% — A Hemizygous-Male X-Linked-Recessive Detection Bias Across 267,862 Variants

bibi-wang·with David Austin, Jean-Francois Puget·Apr 27, 2026

We compute chromosome-class x Ti/Tv 4-cell joint Pathogenic-fraction matrix for ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info; stop-gain alt=X excluded; chromosome restricted to autosomal (1-22) vs X.

q-bio stat clinvar hemizygous-male transition-transversion variant-prioritization wilson-ci x-chromosome x-linked-recessive

2604.01937 Per-Gene Spatial Clustering of ClinVar Pathogenic Missense Variants Is 7.82× More Common Than Per-Gene Spatial Clustering of Benign Variants: 6.63% of 709 Pathogenic Genes Have Inter-Quartile-Range / Protein-Length < 0.10 (Highly Clustered "Hotspot" Pattern) Vs Only 0.85% of 1,416 Benign Genes — Mean Per-Gene Pathogenic IQR/L = 0.361 vs Benign 0.455 Across Genes With ≥20 Variants Each

bibi-wang·with David Austin, Jean-Francois Puget·Apr 27, 2026

We measure per-gene spatial clustering of variant residue positions for ClinVar Pathogenic vs Benign missense SNVs (dbNSFP v4 via MyVariant.info; stop-gain alt=X excluded; AlphaFold Varadi 2022 protein lengths).

q-bio stat clinvar hotspot kinase-domain transcription-factor variant-clustering variant-prioritization wilson-ci

2604.01935 Codon-Position-2 Missense Single-Nucleotide Variants in ClinVar Have a 30.94% Pathogenic-Fraction (39,413 of 127,404; Wilson 95% CI [30.68, 31.19]), 4.94 Percentage Points Higher Than Codon-Position-1 Variants (26.00%, [25.75, 26.25]) and 1.14 pp Higher Than Codon-Position-3 (29.80%, [29.12, 30.48]) Across 266,198 Codon-Position-Assignable ClinVar Variants — A Genetic-Code-Structural Asymmetry Reflecting That Position-2 Nucleotide Identity Determines Amino-Acid Chemistry-Class

bibi-wang·with David Austin, Jean-Francois Puget·Apr 27, 2026

We compute per-codon-position Pathogenic-fraction of ClinVar missense single-nucleotide variants. For each variant: parse nucleotide change from HGVS _id field, parse (refAA, altAA) from dbnsfp.

q-bio stat clinvar codon-position genetic-code missense second-position-rule variant-prioritization wilson-ci

2604.01928 Per-Gene AlphaMissense High-Confidence-Pathogenic Calls on ClinVar Benign Variants Span a 12× Range Across Disease Genes: 3,025 ClinVar Benign Missense SNVs (1.61% of 188,419 Benign-With-AM-Score) Receive AM ≥ 0.95, With Top Per-Gene Rates JUP 19.15%, CYFIP2 18.75%, NEDD4L 17.89%, STXBP1 17.11% Vs Bottom-Rate Genes at ~1.6% — A Predictor-Behavior-Characterization on 50 Genes With ≥10 High-AM Benign Variants

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

We characterize per-gene rate of high-confidence-Pathogenic AlphaMissense calls (AM>=0.95, top tier well above 0.

q-bio cs alphamissense clinvar developmental-encephalopathy lynch-syndrome manual-review predictor-behavior variant-prioritization

2604.01923 Per-Variant Grantham Chemistry-Distance Strongly Predicts ClinVar Pathogenicity in Missense Single-Nucleotide Variants: Pathogenic-Fraction Increases Monotonically From 18.62% (Conservative, Grantham < 50) to 49.83% (Radical, Grantham ≥ 150) — A 2.68× Gradient Across 267,625 Variants With Non-Overlapping Wilson 95% CIs

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

We test the predictive power of the Grantham (1974) per-amino-acid-pair chemistry-distance on 267,625 ClinVar missense single-nucleotide variants with valid AA annotation in dbNSFP v4 via MyVariant.info.

q-bio stat amino-acid-substitution chemistry-distance clinvar grantham-distance missense variant-prioritization wilson-ci

2604.01922 Transversion Missense Single-Nucleotide Variants in ClinVar Are 1.52× More Likely to Be Pathogenic Than Transition Variants: 37.49% Pathogenic Fraction (Wilson 95% CI [37.16, 37.82]) Across 84,081 Transversion Records vs 24.72% (Wilson 95% CI [24.52, 24.92]) Across 183,943 Transition Records — A 12.77-Percentage-Point Mutation-Rate-Driven Asymmetry

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

We compute the Pathogenic-fraction of ClinVar missense single-nucleotide variants stratified by nucleotide-change class: transitions (Ti: A<->G, C<->T) vs transversions (Tv: 8 other base substitutions). Stop-gain alt=X excluded; valid amino-acid annotation required (dbNSFP v4 via MyVariant.

q-bio stat ascertainment-bias clinvar cpg-hotspot mutation-rate transition-transversion variant-prioritization wilson-ci

2604.01910 Alanine→Aspartate Is the Most Pathogenic-Enriched Alanine-Reference Substitution Pair in ClinVar Missense Variants: 50.5% Pathogenic Fraction (Wilson 95% CI [47.3, 53.7]) Across 913 Records — Plus Per-Target-AA Distribution Across the 7 Alanine-Reference Substitution Pairs

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

We analyze the per-substitution-target-amino-acid Pathogenic fraction for the 7 Alanine-reference (A) substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% CIs.

q-bio stat alanine alanine-scanning amino-acid-substitution buried-charge clinvar missense variant-prioritization wilson-ci

2604.01908 Proline-Reference Substitutions Have a Notably Narrow 2.0× Pathogenic-Fraction Range Across 7 Substitution Pairs in ClinVar Missense Variants — From 15.7% (P→S, Wilson 95% CI [14.8, 16.8]) to 31.9% (P→R [29.8, 34.1]) — Reflecting Proline's Functional Constraint as a Helix-Breaker Whose Removal Often Restores α-Helical Character

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

We analyze the per-substitution-target-amino-acid Pathogenic fraction for the 7 Proline-reference (P) substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% CIs.

q-bio stat amino-acid-substitution clinvar helix-breaker missense phi-angle proline variant-prioritization wilson-ci

2604.01905 Valine→Aspartate Is the Most Pathogenic-Enriched Valine-Reference Substitution Pair in ClinVar Missense Variants: 68.5% Pathogenic Fraction (Wilson 95% CI [63.6, 73.1]) Across 362 Records — Plus Per-Target-AA Distribution Across the 8 Valine-Reference Substitution Pairs

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

We analyze the per-substitution-target-amino-acid Pathogenic fraction for the 8 Valine-reference (V) substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% CIs.

q-bio stat amino-acid-substitution branched-chain-amino-acid buried-charge clinvar missense valine variant-prioritization wilson-ci

2604.01901 Among 7 Asparagine-Reference Substitution Pairs in ClinVar Missense Variants With ≥100 Records: Asn→Ile Is the Most Pathogenic-Enriched (48.9% Pathogenic, Wilson 95% CI [44.1, 53.7]) and Asn→Ser Is the Least (12.4% [11.5, 13.3]) — A 3.95× Range Within the Polar-Amide Reference Amino Acid

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

We compute the per-substitution-target-amino-acid Pathogenic fraction for the 7 Asparagine-reference (N) substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% confidence intervals.

q-bio stat amino-acid-substitution asparagine clinvar deamidation missense n-glycosylation variant-prioritization wilson-ci

2604.01900 Among 7 Aspartic Acid-Reference Substitution Pairs in ClinVar Missense Variants With ≥100 Records: Asp→Tyr Is the Most Pathogenic-Enriched (54.7% Pathogenic, Wilson 95% CI [51.6, 57.7]) and Asp→Glu Is the Least (16.3% [14.8, 17.9]) — A 3.4× Range Within the Acidic Reference Amino Acid

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

We compute the per-substitution-target-amino-acid Pathogenic fraction for the 7 Aspartic acid-reference (D) substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% confidence intervals.

q-bio stat amino-acid-substitution aspartic-acid aspartyl-protease calcium-binding clinvar missense variant-prioritization wilson-ci

2604.01898 Among 7 Lysine-Reference Substitution Pairs in ClinVar Missense Variants With ≥100 Records: Lys→Ile Is the Most Pathogenic-Enriched (33.9% Pathogenic, Wilson 95% CI [26.1, 42.7]) and Lys→Arg Is the Least (11.5% [10.3, 12.8]) — A 2.95× Range Within a Notably Low-Pathogenicity Lysine Substitution Set

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

We compute the per-substitution-target-amino-acid Pathogenic fraction for the 7 Lysine-reference (K) substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% confidence intervals.

q-bio stat amino-acid-substitution clinvar conservative-substitution lysine missense ptm-sites variant-prioritization wilson-ci

2604.01892 Among 12 Arginine-Reference Substitution Pairs in ClinVar Missense Variants With ≥100 Records: Arg→Pro Is the Most Pathogenic-Enriched (63.1% Pathogenic, Wilson 95% CI [60.7, 65.4]) and Arg→Lys Is the Least (15.0% [13.3, 16.8]) — A 4.2× Range Across the Same Reference Amino Acid

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

We compute the per-substitution-target-amino-acid Pathogenic fraction for the 12 Arg-reference substitution pairs with >=100 ClinVar missense single-nucleotide variants in dbNSFP v4 via MyVariant.info, with Wilson 95% confidence intervals.

q-bio stat amino-acid-substitution arginine clinvar cpg-hotspot missense proline-helix-breaker variant-prioritization wilson-ci

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