Is ARSA p.Ile181Ser (c.542T>G) pathogenic?

ARSA p.Ile181Ser (c.542T>G) is classified Pathogenic/Likely pathogenic in ARSA (ClinVar, Multiple submitters, 28 submitters; last evaluated 2026-09-17). Ultra-rare (popmax 0.0232%, nfe); Associated with ARSA-related disorder.

What condition is associated with ARSA p.Ile181Ser (c.542T>G)?

ARSA p.Ile181Ser (c.542T>G) is associated with ARSA-related disorder, metachromatic leukodystrophy, juvenile form, metachromatic leukodystrophy, adult form (ClinVar).

How common is ARSA p.Ile181Ser (c.542T>G) in the general population?

ARSA p.Ile181Ser (c.542T>G) is ultra-rare (popmax 0.0232%, nfe) (gnomAD).

ARSA p.Ile181Ser

c.542T>G · rs74315457 · VCV3057

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 28 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, nfe)

Conditions

ARSA-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.794	moderately pathogenic-leaning
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,631 bp · p 0.96 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0232% European (non-Finnish) · 274/1,179,918 alleles

Filtering AF 0.021% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.0197% 317/1,612,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,959
Finnishnot grpmax-eligible	0.0334%	2,994
European (non-Finnish)grpmax	0.0232%	4,306
Remaining individualsnot grpmax-eligible	0.0128%	7,807
Admixed American	0.005%	20,000
African / African-American	0.00134%	74,894

Ashkenazi Jewish 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.Ile181Ser
Coding: c.542T>G
MANE Select: NM_000487
dbSNP: rs74315457
Type: single nucleotide variant
Location: chr22:50626976 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.43 · 10 PDB
Residue 181: a β-strand; a UniProt-annotated variant site (in mld; infantile form)

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

Disease context

ARSA-related disorder

Also linked: metachromatic leukodystrophy, juvenile form metachromatic leukodystrophy, adult form metachromatic leukodystrophy

Similar variants

ARSA p.Ile181= Likely benign ★ 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-ile181ser (accessed [today's date]).

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