ASPA

Chr 17AR

aspartoacylase

Also known as: ACY2, ASP

NCBI Gene: 443 ENSG00000108381 UniProt: P45381 OMIM: 608034

The protein catalyzes the hydrolysis of N-acetyl-L-aspartic acid to aspartate and acetate, which is essential for maintaining white matter in the brain. Mutations cause Canavan disease, an autosomal recessive leukodystrophy. The pathogenic mechanism involves loss of enzyme function leading to toxic accumulation of N-acetyl-L-aspartic acid in the brain.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.101 OMIM phenotype

Clinical Summary— ASPA

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Gene-Disease Validity (ClinGen)

Canavan disease · 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

203 unique Pathogenic / Likely Pathogenic· 127 VUS of 539 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 — ASPA

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?

1.10LOEUF

pLI 0.000

Z-score 1.33

OE 0.59 (0.33–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.48Z-score

OE missense 0.90 (0.79–1.03)

154 obs / 171.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.33–1.10)

0≤0.351.4

Missense OE?0.90 (0.79–1.03)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 7 / 12.0Missense obs/exp: 154 / 171.6Syn Z: 0.40

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveASPA-related Canavan diseaseLOFAR

This gene — mechanism propensity

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

0.6358th %ile

GOF

0.4382th %ile

LOF

0.3067th %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

539 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59

Likely Pathogenic144

VUS127

Likely Benign181

Benign13

Conflicting13

Pathogenic

144

Likely Pathogenic

127

VUS

181

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	8	14	0	59
Likely Pathogenic	82	57	4	1	144
VUS	1	107	11	8	127
Likely Benign	0	5	54	122	181
Benign	0	1	12	0	13
Conflicting	—				13
Total	120	178	95	131	537

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

View in ClinVar →

42 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap ASPA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →