TONSL p.Ala964=
c.2892G>A · rs758921156 · VCV2063528
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0325%, amr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -9 | GERP -3.3 |
| Overall | ||
| CADD | 5.483 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0325%
Admixed American · 18/55,340 alleles
Filtering AF
0.0281%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0271%
Overall
0.0246%
388/1,576,884 alleles · ultra-rare
exomes 379/1,424,656 · genomes 9/152,228 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0325% | 3,074 |
| European (non-Finnish) | 0.0307% | 3,255 |
| Remaining individualsnot grpmax-eligible | 0.0115% | 8,669 |
| African / African-American | 0.00542% | 18,462 |
| South Asian | 0.00228% | 43,883 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- TONSL
- Protein
- p.Ala964=
- Coding
- c.2892G>A
- MANE Select
- NM_013432
- dbSNP
- rs758921156
- Type
- single nucleotide variant
- Location
- chr8:144435131 (GRCh38)
- Gene constraint
- LOEUF 1.024 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.06 · 3 PDB
- Residue 964
- a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); a UniProt-annotated variant site (in semdsp; disease phenotype includes primary aphakia and absent pupils)
Similar variants
- TONSL p.Ala964Val Uncertain significance ★★ same residue
- TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same type
- TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same type
- TONSL p.Arg934Trp Pathogenic ★★ ⚠ same type
- TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same type
- TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same type
- TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
- TONSL c.2775+5G>T Uncertain significance ★★ same type
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/tonsl-p-ala964 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown