ARSA p.Arg293Leu
c.878G>T · VCV4850946
Likely pathogenic
No assertion criteria
Classification
Likely pathogenic
ClinVar
Review
No assertion criteria ☆☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Absent
absent from gnomAD v4.1
Conditions
1
metachromatic leukodystrophy
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| REVEL | 0.465 | indeterminate |
|---|---|---|
| Splicing | ||
| SpliceAI | Δ0.83 | acceptor gain · deltas |
| Pangolin | Δ0.69 | gain · loss 0.41 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -2 | GERP -3.7 |
| Regional constraint | o/e 1.00 | unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic |
| Overall | ||
| CADD | 22.5 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- ARSA
- Protein
- p.Arg293Leu
- Coding
- c.878G>T
- MANE Select
- NM_000487
- Type
- single nucleotide variant
- Location
- chr22:50626255 (GRCh38)
- Gene constraint
- LOEUF 1.166 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 96.43 · 10 PDB
- Residue 293
- a UniProt-annotated variant site (in mld; late-onset); a UniProt-annotated variant site (in mld; adult type; causes a severe reduction of enzyme activity)
Disease context
metachromatic leukodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Metachromatic leukodystrophy (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Adolescent, Adult, Childhood, Infancy
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- ARSA p.Arg293Ter Pathogenic ★★ same residue
- ARSA p.Arg293Gln Uncertain significance ★★ same residue
- ARSA c.1107+1G>A Pathogenic/Likely pathogenic ★★ same condition
- ARSA c.1107+1G>T Pathogenic ★★ same condition
- ARSA c.1108-2A>G Pathogenic ★★ same condition
- ARSA c.1108-3C>G Pathogenic/Likely pathogenic ★★ same condition
- ARSA c.1210+1G>A Pathogenic ★★ same condition
- ARSA c.224+1G>A 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/arsa-p-arg293leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown