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…

Primary Disease Associations & Inheritance

Metachromatic leukodystrophyMIM #250100

UniProtCardiomyopathy, dilated, 2H

Clinical highlights

Management implications

ARSA has an approved disease-modifying therapy

Gene–disease validity (ClinGen · GenCC)

Definitive · metachromatic leukodystrophy · AR · ClinGen 2023
Definitive · metachromatic leukodystrophy, juvenile form · AR · Ambry Genetics

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

125

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.34

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — ARSA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

atidarsagene autotemcel (Lenmeldy)
ex-vivo gene therapyApproved · FDA 2024
Autologous CD34+ HSCs transduced with an ARSA lentivirus.
Delivery: One-time IV after myeloablative conditioningEligibility: Pre-/early-symptomatic late-infantile or early-juvenile MLD

Therapeutic landscape as of 2026-07. Educational only. Investigational ≠ available; not medical advice or eligibility. Approved entries are precise; investigational program names/phases are conservative and move fast. Curated from FDA/EMA approvals and the clinical-trial literature; verify against current labeling + ClinicalTrials.gov.

ClinicalTrials.gov

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

Background carrier burden — how many people carry a rare variant somewhere in ARSA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 80

735 rare PASS variants

Rare truncating (LoF)

1 in 400

100 rare PASS variants

Rare synonymous (reference)

1 in 150

325 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ARSA; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 1,300
South Asian	~43k	1 in 57	1 in 1,600
Remaining (unassigned)	~30k	1 in 78	1 in 510
European (Finnish)	~27k	1 in 190	1 in 470
Admixed American	~22k	1 in 85	1 in 760
African / African American	~21k	1 in 58	1 in 730
East Asian	~20k	1 in 67	1 in 1,600
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 85	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.