Is ARSA p.Cys158Ter (c.474C>A) pathogenic?

ARSA p.Cys158Ter (c.474C>A) is classified Pathogenic in ARSA (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Ultra-rare (popmax 0.015%, amr); Associated with metachromatic leukodystrophy.

What condition is associated with ARSA p.Cys158Ter (c.474C>A)?

ARSA p.Cys158Ter (c.474C>A) is associated with metachromatic leukodystrophy (ClinVar).

How common is ARSA p.Cys158Ter (c.474C>A) in the general population?

ARSA p.Cys158Ter (c.474C>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

How is Metachromatic leukodystrophy inherited?

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

ARSA p.Cys158Ter

c.474C>A · rs768028181 · VCV265461

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

metachromatic leukodystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.023, phastCons 1
Overall
CADD	37.0	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 0.015% Admixed American · 9/59,856 alleles

Filtering AF 0.00775% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0058%

Overall 0.000619% 9/1,454,404 alleles · ultra-rare

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.Cys158Ter
Coding: c.474C>A
MANE Select: NM_000487
dbSNP: rs768028181
Type: single nucleotide variant
Location: chr22:50627044 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 158: 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.Cys158Ser 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
ARSA c.225-1G>C 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-cys158ter (accessed [today's date]).

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