ACER3

Chr 11AR

alkaline ceramidase 3

Also known as: APHC, PHCA, PLDECO

NCBI Gene: 55331ENSG00000078124UniProt: Q9NUN7

Enables N-acylsphingosine amidohydrolase activity; calcium ion binding activity; and zinc ion binding activity. Involved in several processes, including myelination; positive regulation of cell population proliferation; and sphingolipid metabolic process. Located in Golgi membrane and endoplasmic reticulum membrane. Biomarker of hepatocellular carcinoma and metabolic dysfunction-associated steatohepatitis. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

?Leukodystrophy, progressive, early childhood-onsetMIM #617762
AR
120
ClinVar variants
14
Pathogenic / LP
0.87
pLI score
0
Active trials
Clinical Summary— ACER3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 63 VUS of 120 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.39LOEUF
pLI 0.875
Z-score 3.52
OE 0.15 (0.07–0.39)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.80Z-score
OE missense 0.57 (0.47–0.68)
77 obs / 136.1 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.0.15 (0.07–0.39)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.57 (0.47–0.68)
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.0.96
0≤1.21.6
LoF obs/exp: 3 / 20.0Missense obs/exp: 77 / 136.1Syn Z: 0.20

ClinVar Variant Classifications

120 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic1
VUS63
Likely Benign30
Benign13
13
Pathogenic
1
Likely Pathogenic
63
VUS
30
Likely Benign
13
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
11
0
13
Likely Pathogenic
0
0
1
0
1
VUS
2
56
4
1
63
Likely Benign
0
1
12
17
30
Benign
0
1
8
4
13
Total2603622120

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

View in ClinVar →

Protein Context — Lollipop Plot

ACER3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ACER3-related leukodystrophy

strong
ARUndeterminedAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Leukodystrophy, progressive, early childhood-onset

MIM #617762

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting the ceramidase ACER3 attenuates cholestasis in mice by mitigating bile acid overload via unsaturated ceramide-mediated LXRβ signaling transduction.
Liao L et al.·Nat Commun
2025
Ceramide(d18:1/18:1)-NDUFA6 interaction inactivates respiratory complex I to attenuate oxidative-stress-driven pathogenesis in liver ischemia/reperfusion injury.
Wang K et al.·JCI Insight
2025
ACER3-related leukoencephalopathy: expanding the clinical and imaging findings spectrum due to novel variants.
Dehnavi AZ et al.·Hum Genomics
2021
LINC01087 indicates a poor prognosis of glioma patients with preoperative MRI.
Chen W et al.·Funct Integr Genomics
2022Cohort
Sphingolipid metabolism-related genes as diagnostic markers in pneumonia-induced sepsis: the AUG model.
Wu J et al.·Sci Rep
2025Functional
Overview of genetic variants in a cohort of Iranian patients with leukodystrophy.
Fathi M et al.·Sci Rep
2025Review
Profile of sphingolipid-related genes and its association with prognosis highlights sphingolipid metabolism in oral cancer.
da Silva G et al.·Cancer Biomark
2021
Key Risk Genes Identified From the Postmortem Brain of Patients With Major Depressive Disorder and Their Potential Clinical Applications.
Zhuang Q et al.·Int J Neuropsychopharmacol
2023Cohort
The impact of BMI on the causal relationship between NAFLD and OA: A 2-sample Mendelian randomization study exploring gene interactions and metabolic pathways.
Yu S et al.·Medicine (Baltimore)
2025
Identification of the biomarkers associated with lipid metabolism and endoplasmic reticulum stress in pediatric sepsis through bioinformatics analysis and quantitative reverse transcriptase PCR (qRT-PCR) assay.
Shan B et al.·Eur J Med Res
2026
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