Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 3.2 | GERP 2.1, phastCons 1 |
| Overall | ||
| CADD | 11.32 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Amishnot grpmax-eligible | 81% | 1 |
| Admixed Americangrpmax | 77.7% | 1 |
| European (non-Finnish) | 76.4% | 1 |
| Ashkenazi Jewishnot grpmax-eligible | 75.7% | 1 |
| Remaining individualsnot grpmax-eligible | 71.4% | 1 |
| Finnishnot grpmax-eligible | 70.5% | 1 |
| Middle Eastern | 69% | 1 |
| South Asian | 68.3% | 1 |
| African / African-American | 50.7% | 2 |
| East Asian | 43.6% | 2 |
Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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
- AARS2
- Protein
- p.Lys869=
- Coding
- c.2607G>A
- MANE Select
- NM_020745
- dbSNP
- rs498512
- Type
- single nucleotide variant
- Location
- chr6:44301456 (GRCh38)
- Gene constraint
- LOEUF 0.752 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 88.05 · 3 PDB
- Residue 869
- an α-helix
Disease context
leukoencephalopathy, progressive, with ovarian failure — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: combined oxidative phosphorylation defect type 8
For CACH syndrome (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Childhood
Similar variants
- AARS2 c.2146-2A>G Pathogenic/Likely pathogenic ★★ same condition
- AARS2 c.2255+1G>A Pathogenic ★★ same condition
- AARS2 p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
- AARS2 p.Arg521Ter Pathogenic ★★ same condition
- AARS2 p.Arg592Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
- AARS2 p.Arg958Ter Pathogenic/Likely pathogenic ★★ same condition
- AARS2 p.Thr782Ile Likely pathogenic ★★ same condition
- AARS2 c.*718C>A Uncertain significance ★★ same condition
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/aars2-p-lys869 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown