Is ARSA p.Arg293Gln (c.878G>A) pathogenic?

ARSA p.Arg293Gln (c.878G>A) is classified Uncertain significance in ARSA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-18). Very rare (popmax 0.00668%, eas); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Arg293Gln (c.878G>A)?

ARSA p.Arg293Gln (c.878G>A) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg293Gln (c.878G>A) in the general population?

ARSA p.Arg293Gln (c.878G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

How is Metachromatic leukodystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ARSA p.Arg293Gln

c.878G>A · rs373866455 · VCV1383720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.349	indeterminate
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.83 · evaluated, not missing
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	15.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00192% 31/1,613,304 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
Finnishnot grpmax-eligible	0.00473%	21,155
Admixed American	0.00333%	29,992
European (non-Finnish)	0.00186%	53,634
African / African-American	0.00133%	74,938

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: ARSA
Protein: p.Arg293Gln
Coding: c.878G>A
MANE Select: NM_000487
dbSNP: rs373866455
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)

Full ARSA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

metachromatic leukodystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For 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.Arg293Leu Likely pathogenic 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-arg293gln (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown