ARSA

Chr 22AR

arylsulfatase A

Also known as: ASA, MLD

NCBI Gene: 410ENSG00000100299UniProt: O43681

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]

Primary Disease Associations & Inheritance

Metachromatic leukodystrophyMIM #250100
AR
UniProtCardiomyopathy, dilated, 2H
1467
ClinVar variants
0
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— ARSA
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
1467 total variants — no pathogenic classifications of 1467 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.38Z-score
OE missense 0.94 (0.85–1.03)
298 obs / 317.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.90 (0.62–1.34)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.85–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 18 / 19.9Missense obs/exp: 298 / 317.0Syn Z: -0.16

ClinVar Variant Classifications

1467 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

ARSA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ARSA-related arylsulfatase A deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ARYLSULFATASE A; ARSA
MIM #607574 · *

Metachromatic leukodystrophy

MIM #250100

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy.
Cesani M et al.·Hum Mutat
2016Review
Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.
Adang LA et al.·Cytotherapy
2024Review
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix.
Trinidad M et al.·Genome Biol
2023
Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy.
Fumagalli F et al.·N Engl J Med
2025Clinical trial
Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access.
Fumagalli F et al.·Lancet
2022Clinical trial
Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs.
Mullagulova A et al.·Int J Mol Sci
2023
Dysphagia lusoria: problem or incidentaloma?
Epperson MV et al.·Curr Opin Otolaryngol Head Neck Surg
2019Review
ARSA Variants Associated With Cognitive Decline and Long-Term Preservation of Motor Function in Metachromatic Leukodystrophy.
Beerepoot S et al.·J Inherit Metab Dis
2025
Arylsulfatases A and B: From normal tissues to malignant tumors.
Kovacs Z et al.·Pathol Res Pract
2019Review
Variant anatomy of non-recurrent laryngeal nerve: when and how should it be taught in surgical residency?
Zheng V et al.·Langenbecks Arch Surg
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Lysosomal Storage DiseaseMetachromatic Leukodystrophy

A Safety and Efficacy Study of Cryopreserved OTL-200 for Treatment of Metachromatic Leukodystrophy (MLD)

ACTIVE NOT RECRUITING
NCT03392987Phase PHASE2Orchard TherapeuticsStarted 2018-01-25
OTL-200
Metachromatic Leukodystrophy (MLD)

Direct Lentiviral Injection Gene Therapy for MLD

RECRUITING
NCT03725670Phase NAShenzhen Geno-Immune Medical InstituteStarted 2025-05-31
Intrathecal and intravenous LV gene therapy
Metachromatic Leukodystrophy (MLD)

Lentiviral Hematopoietic Stem Cell Gene Therapy for MLD

RECRUITING
NCT07046338Phase NAShenzhen Geno-Immune Medical InstituteStarted 2025-06-01
Lentiviral TYF-ARSA correction of patient's autologous HSCs
Lysosomal Storage DiseasesMetachromatic Leukodystrophy

OTL-200 in Patients With Late Juvenile Metachromatic Leukodystrophy (MLD)

ACTIVE NOT RECRUITING
NCT04283227Phase PHASE3Orchard TherapeuticsStarted 2022-01-17
OTL-200

External Resources

Links to major genomics databases and tools