AARS1 p.Gln449=
c.1347G>A · rs200557581 · VCV576369
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00475%, nfe)
Conditions
1
Charcot-Marie-Tooth disease type 2
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.27 | donor loss at this position · masked 0 · deltas |
|---|---|---|
| Pangolin | Δ0.72 | loss · gain 0.02 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 1.7, phastCons 1 |
| Overall | ||
| CADD | 21.7 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00475%
European (non-Finnish) · 56/1,179,858 alleles
Filtering AF
0.00375%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00337%
Overall
0.00366%
59/1,613,744 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00475% | 21,069 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,602 |
| Admixed American | 0.00167% | 59,982 |
| African / African-American | 0.00134% | 74,894 |
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
- AARS1
- Protein
- p.Gln449=
- Coding
- c.1347G>A
- MANE Select
- NM_001605
- dbSNP
- rs200557581
- Type
- single nucleotide variant
- Location
- chr16:70265538 (GRCh38)
- Gene constraint
- LOEUF 0.772 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 90.66 · 10 PDB
- Residue 449
- an α-helix
Similar variants
- AARS1 c.2177+1G>A Pathogenic/Likely pathogenic ★★ same condition
- AARS1 p.Arg13Ter Pathogenic ★★ same condition
- AARS1 p.Arg246Ter Pathogenic/Likely pathogenic ★★ same condition
- AARS1 p.Arg329Cys Likely pathogenic ★★ same condition
- AARS1 p.Arg329His Pathogenic/Likely pathogenic ★★ same condition
- AARS1 p.Arg330Ter Pathogenic/Likely pathogenic ★★ same condition
- AARS1 p.Arg333Ter Pathogenic/Likely pathogenic ★★ same condition
- AARS1 p.Arg598Ter Pathogenic/Likely pathogenic ★★ 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/aars1-p-gln449 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown