TONSL p.Ala622=
c.1866G>A · rs112282581 · VCV1626326
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
rare (popmax 0.197%, mid)
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 -16 | GERP -3 |
| Overall | ||
| CADD | 0.351 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.197%
Middle Eastern · 12/6,084 alleles
Filtering AF
0.114%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0892%
Overall
0.00528%
85/1,611,014 alleles · rare
exomes 71/1,458,802 · genomes 14/152,212 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.197% | 507 |
| Ashkenazi Jewishnot grpmax-eligible | 0.0203% | 4,930 |
| African / African-American | 0.0147% | 6,812 |
| Remaining individualsnot grpmax-eligible | 0.0128% | 7,805 |
| Admixed American | 0.01% | 9,996 |
| European (non-Finnish) | 0.00356% | 28,088 |
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.Ala622=
- Coding
- c.1866G>A
- MANE Select
- NM_013432
- dbSNP
- rs112282581
- Type
- single nucleotide variant
- Location
- chr8:144436781 (GRCh38)
- Gene constraint
- LOEUF 1.024 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 76.06 · 3 PDB
- Residue 622
- a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp)
Similar variants
- TONSL p.Ala622Pro Uncertain significance ★ ⚠ same residue
- TONSL p.Ala622Thr Uncertain significance ★ ⚠ same residue
- TONSL p.Ala622fs 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
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-ala622 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown