TONSL p.Lys416=
c.1248A>G · rs144566958 · VCV1165061
Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
low-frequency (popmax 3.81%, sas)
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 0.3 | GERP -1.7, phastCons 0.98 |
| Overall | ||
| CADD | 6.044 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
3.81%
South Asian · 3,458/90,864 alleles
Filtering AF
3.7%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 3.66%
Overall
0.303%
4,863/1,607,524 alleles · low-frequency
exomes 4,444/1,455,396 · genomes 419/152,128 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 3.81% | 26 |
| Ashkenazi Jewishnot grpmax-eligible | 0.904% | 111 |
| African / African-American | 0.482% | 207 |
| Middle Eastern | 0.449% | 223 |
| Remaining individualsnot grpmax-eligible | 0.416% | 240 |
| Admixed American | 0.0485% | 2,062 |
| European (non-Finnish) | 0.0391% | 2,557 |
| East Asian | 0.00224% | 44,666 |
| Finnishnot grpmax-eligible | 0.00161% | 62,234 |
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.Lys416=
- Coding
- c.1248A>G
- MANE Select
- NM_013432
- dbSNP
- rs144566958
- Type
- single nucleotide variant
- Location
- chr8:144440393 (GRCh38)
- Gene constraint
- LOEUF 1.024 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.06 · 3 PDB
- Residue 416
- a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp)
Similar variants
- 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
- TONSL p.Ala1053Ser 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-lys416 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown