ASAH1

Chr 8AR

N-acylsphingosine amidohydrolase 1

Also known as: AC, ACDase, ASAH, PHP, PHP32, SMAPME

NCBI Gene: 427ENSG00000104763UniProt: Q13510

This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

Primary Disease Associations & Inheritance

Farber lipogranulomatosisMIM #228000
AR
Spinal muscular atrophy with progressive myoclonic epilepsyMIM #159950
AR
580
ClinVar variants
77
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ASAH1
🧬
Gene-Disease Validity (ClinGen)
ASAH1-related sphingolipidosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
77 Pathogenic / Likely Pathogenic· 182 VUS of 580 total submissions

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.
1.18LOEUF
pLI 0.000
Z-score 0.85
OE 0.82 (0.58–1.18)
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.
-2.21Z-score
OE missense 1.42 (1.29–1.56)
310 obs / 218.2 exp
Tolerant

Tolerant to missense variation

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.0.82 (0.58–1.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.42 (1.29–1.56)
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.1.01
0≤1.21.6
LoF obs/exp: 21 / 25.6Missense obs/exp: 310 / 218.2Syn Z: -0.05

ClinVar Variant Classifications

580 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic28
VUS182
Likely Benign319
Conflicting2
49
Pathogenic
28
Likely Pathogenic
182
VUS
319
Likely Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
3
33
0
49
Likely Pathogenic
22
4
2
0
28
VUS
3
152
24
3
182
Likely Benign
0
2
194
123
319
Benign
0
0
0
0
0
Conflicting
—2
Total38161253126580

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

View in ClinVar →

Protein Context — Lollipop Plot

ASAH1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ASAH1-related Farber lipogranulomatosis

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

ASAH1-related spinal muscular atrophy with progressive myoclonic epilepsy

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

Farber lipogranulomatosis

MIM #228000

Molecular basis of disorder known

Autosomal recessive

Spinal muscular atrophy with progressive myoclonic epilepsy

MIM #159950

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ASAH1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.
Robak LA et al.·Brain
2017
Proteometabolomics of initial and recurrent glioblastoma highlights an increased immune cell signature with altered lipid metabolism.
Cosenza-Contreras M et al.·Neuro Oncol
2024
Broadening the mutational spectrum of ASAH1, as a susceptibility gene for keloids.
Hamzehlou S et al.·J Hum Genet
2025
ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.
Filosto M et al.·Eur J Hum Genet
2016
ASAH1-related disorders: Description of 15 novel pediatric patients and expansion of the clinical phenotype.
Mahmoud IG et al.·Clin Genet
2020Cohort
Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations.
Huang M et al.·Acta Neuropathol Commun
2020Functional
ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.
Elsea SH et al.·Hum Mutat
2020
The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile.
Lee MM et al.·Ann Clin Transl Neurol
2022Review
Functional analysis of a novel splice site variant in the ASAH1 gene.
Yan S et al.·Mol Genet Genomic Med
2024Functional
Pediatric ependymoma: GNAO1, ASAH1, IMMT and IPO7 protein expression and 5-year prognosis correlation.
Pérez-Ramírez M et al.·Clin Neurol Neurosurg
2019
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools