TONSL p.Pro1014=
c.3042G>C · rs34180657 · VCV2084636
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00797%, nfe)
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 -20 | GERP -3.3 |
| Overall | ||
| CADD | 0.012 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00797%
European (non-Finnish) · 94/1,179,956 alleles
Filtering AF
0.00664%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00616%
Overall
0.00614%
99/1,613,290 alleles · very rare
exomes 80/1,461,074 · genomes 19/152,216 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00797% | 12,553 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00676% | 14,796 |
| Remaining individualsnot grpmax-eligible | 0.0032% | 31,236 |
| African / African-American | 0.00133% | 74,934 |
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.Pro1014=
- Coding
- c.3042G>C
- MANE Select
- NM_013432
- dbSNP
- rs34180657
- Type
- single nucleotide variant
- Location
- chr8:144434854 (GRCh38)
- Gene constraint
- LOEUF 1.024 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.06 · 3 PDB
- Residue 1014
- 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.Pro1014Leu Uncertain significance ★ ⚠ same residue
- TONSL p.Pro1014fs Pathogenic ★ 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
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-pro1014 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown