ARSA

Chr 22AR

arylsulfatase A

Also known as: ASA, MLD

NCBI Gene: 410 ENSG00000100299 UniProt: O43681 OMIM: 607574

The protein hydrolyzes cerebroside sulfate to cerebroside and sulfate, functioning as a lysosomal enzyme essential for sulfatide metabolism. Mutations cause metachromatic leukodystrophy, a progressive demyelinating disease that presents with neurological deterioration and is ultimately fatal. This condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.341 OMIM phenotype

Clinical Summary— ARSA

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Gene-Disease Validity (ClinGen)

metachromatic leukodystrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

395 unique Pathogenic / Likely Pathogenic· 378 VUS of 1354 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ARSA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.000

Z-score 0.40

OE 0.90 (0.62–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.38Z-score

OE missense 0.94 (0.85–1.03)

298 obs / 317.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.90 (0.62–1.34)

0≤0.351.4

Missense OE?0.94 (0.85–1.03)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 18 / 19.9Missense obs/exp: 298 / 317.0Syn Z: -0.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveARSA-related arylsulfatase A deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6356th %ile

GOF

0.6051th %ile

LOF

0.3164th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1354 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic166

Likely Pathogenic229

VUS378

Likely Benign437

Benign47

Conflicting65

166

Pathogenic

229

Likely Pathogenic

378

VUS

437

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	98	55	13	0	166
Likely Pathogenic	66	158	4	1	229
VUS	6	269	90	13	378
Likely Benign	0	7	143	287	437
Benign	0	4	39	4	47
Conflicting	—				65
Total	170	493	289	305	1,322

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

151 pathogenic / likely-pathogenic (of 167) ClinVar copy-number / structural variants overlap ARSA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →