Is ARSA p.Arg498His (c.1493G>A) pathogenic?

ARSA p.Arg498His (c.1493G>A) is classified Benign/Likely benign in ARSA (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-04). Common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Arg498His (c.1493G>A)?

ARSA p.Arg498His (c.1493G>A) is associated with metachromatic leukodystrophy (ClinVar).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Arg498His

Q: How common is ARSA p.Arg498His (c.1493G>A) in the general population?

ARSA p.Arg498His (c.1493G>A) is common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1493G>A · rs6151428 · VCV93120

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

gnomAD v4.1

Common

common (popmax 10.3%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.229	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.094	GERP -2
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	9.384	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.3% African / African-American · 7,670/74,754 alleles

Filtering AF 10.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.99%

Overall 3.88% 61,811/1,594,468 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	12.9%	8
African / African-Americangrpmax	10.3%	10
European (non-Finnish)	4.09%	24
Remaining individualsnot grpmax-eligible	3.83%	26
Admixed American	3.22%	31
Middle Eastern	2.24%	45
Ashkenazi Jewishnot grpmax-eligible	1.95%	51
Finnishnot grpmax-eligible	1.01%	99
South Asian	0.643%	155
East Asian	0.00902%	11,089

Amish 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.Arg498His
Coding: c.1493G>A
MANE Select: NM_000487
dbSNP: rs6151428
Type: single nucleotide variant
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

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.Arg498Cys Uncertain significance ★★ same residue
ARSA p.Arg498Leu Conflicting classifications of pathogenicity ★ same residue
ARSA p.Arg498Ser Uncertain significance ★ same residue
ARSA p.Arg498fs Pathogenic/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

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-arg498his (accessed [today's date]).

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