ACER3

Chr 11

alkaline ceramidase 3

Also known as: APHC, PHCA, PLDECO

NCBI Gene: 55331 ENSG00000078124 UniProt: Q9NUN7

The ACER3 protein is an endoplasmic reticulum and Golgi ceramidase that hydrolyzes ceramides into sphingosine and fatty acids, regulating sphingolipid metabolism critical for cellular signaling, myelination, and neuronal function. Biallelic mutations cause progressive leukodystrophy with early childhood onset, inherited in an autosomal recessive pattern. The gene is highly constrained against loss-of-function variants (pLI 0.87, LOEUF 0.39), consistent with its essential role in brain sphingolipid homeostasis.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.39

Clinical Summary— ACER3

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 61 VUS of 126 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

1.80Z-score

OE missense 0.57 (0.47–0.68)

77 obs / 136.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.07–0.39)

0≤0.351.4

Missense OE?0.57 (0.47–0.68)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 3 / 20.0Missense obs/exp: 77 / 136.1Syn Z: 0.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongACER3-related leukodystrophyOTHERAR

This gene — mechanism propensity

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

0.6937th %ile

GOF

0.6151th %ile

LOF

0.3260th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

126 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS61

Likely Benign30

Benign13

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	1	0	0	0	1
VUS	2	55	3	1	61
Likely Benign	0	1	12	17	30
Benign	0	1	8	4	13
Conflicting	—				1
Total	6	59	23	22	111

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap ACER3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →