Is ARSA p.Arg290Cys (c.868C>T) pathogenic?

ARSA p.Arg290Cys (c.868C>T) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-25). Very rare (popmax 0.00223%, eas); Associated with spastic ataxia.

What condition is associated with ARSA p.Arg290Cys (c.868C>T)?

ARSA p.Arg290Cys (c.868C>T) is associated with spastic ataxia, metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg290Cys (c.868C>T) in the general population?

ARSA p.Arg290Cys (c.868C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

ARSA p.Arg290Cys

c.868C>T · rs74315473 · VCV3077

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

spastic ataxia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.878	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.79, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000682% 11/1,612,944 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,884
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,470
South Asian	0.0011%	90,992
European (non-Finnish)	0.000593%	168,565

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.Arg290Cys
Coding: c.868C>T
MANE Select: NM_000487
dbSNP: rs74315473
Type: single nucleotide variant
Location: chr22:50626265 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 290: an α-helix

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

Disease context

spastic ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: metachromatic leukodystrophy

Similar variants

ARSA p.Arg290His Pathogenic/Likely pathogenic ★★ same residue
ARSA p.Arg290Gly Likely pathogenic ★ same residue
ARSA p.Arg290Pro Likely pathogenic ★ same residue
ARSA p.Arg290Leu Conflicting classifications of pathogenicity ★ same residue
ARSA p.Arg290= Likely benign ★ same residue
ARSA p.Arg290_Met291del Conflicting classifications of pathogenicity ★ same residue
ARSA c.1107+1G>A Pathogenic/Likely pathogenic ★★ same condition
ARSA c.1107+1G>T 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-arg290cys (accessed [today's date]).

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