Is ARSA p.Arg498fs (c.1489_1492dup) pathogenic?

ARSA p.Arg498fs (c.14891492dup) is classified Pathogenic/Likely pathogenic in ARSA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-06). Very rare (popmax 0.00268%, afr); Associated with ARSA-related disorder.

What condition is associated with ARSA p.Arg498fs (c.1489_1492dup)?

ARSA p.Arg498fs (c.1489_1492dup) is associated with ARSA-related disorder, metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Arg498fs (c.1489_1492dup) in the general population?

ARSA p.Arg498fs (c.1489_1492dup) is very rare (popmax 0.00268%, afr) (gnomAD).

ARSA p.Arg498fs

c.1489_1492dup · rs774153480 · VCV188843

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

ARSA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.094	GERP -2
Overall
CADD	19.74	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,646 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00194% 31/1,594,466 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00325%	30,773
African / African-Americangrpmax	0.00268%	37,323
European (non-Finnish)	0.00231%	43,359

Remaining individuals 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: ARSA
Protein: p.Arg498fs
Coding: c.1489_1492dup
MANE Select: NM_000487
dbSNP: rs774153480
Type: Duplication
Location: chr22:50625182 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 498: a turn; a disulfide bond

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

Disease context

ARSA-related disorder

Also linked: metachromatic leukodystrophy

Similar variants

ARSA p.Arg498Cys Uncertain significance ★★ same residue
ARSA p.Arg498His Benign/Likely benign ★★ same residue
ARSA p.Arg498Leu Conflicting classifications of pathogenicity ★ same residue
ARSA p.Arg498Ser Uncertain significance ★ same residue
ARSA p.Arg99fs Pathogenic ★★ same condition
ARSA p.Gly449fs Pathogenic ★★ same condition
ARSA p.Gly81fs Pathogenic/Likely pathogenic ★★ same condition
ARSA p.His140fs 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-arg498fs (accessed [today's date]).

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