ACER2

Chr 9

alkaline ceramidase 2

Also known as: ALKCDase2, ASAH3L

NCBI Gene: 340485 ENSG00000177076 UniProt: Q5QJU3 OMIM: 613492

The ACER2 protein is a Golgi ceramidase that hydrolyzes ceramides into sphingosine and fatty acids, regulating the balance of bioactive sphingolipids that control cell proliferation, apoptosis, and autophagy. Mutations cause progressive leukodystrophy, which follows autosomal recessive inheritance and typically presents in early childhood with developmental regression and neurological deterioration. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.695), consistent with recessive disease where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

The sphingolipid metabolite sphingosine-1-phosphate promotes cell proliferation and survival, whereas its precursor, sphingosine, has the opposite effect. The ceramidase ACER2 hydrolyzes very long chain ceramides to generate sphingosine (Xu et al., 2006 [PubMed 16940153]).[supplied by OMIM, Jul 2010]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.69

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.040

Z-score 2.41

OE 0.33 (0.17–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.37Z-score

OE missense 1.08 (0.95–1.23)

166 obs / 153.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.33 (0.17–0.69)

0≤0.351.4

Missense OE?1.08 (0.95–1.23)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 5 / 15.1Missense obs/exp: 166 / 153.0Syn Z: -0.57

Background carrier burden — how many people carry a rare variant somewhere in ACER2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 160

379 rare PASS variants

Rare truncating (LoF)

1 in 3,000

52 rare PASS variants

Rare synonymous (reference)

1 in 330

144 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ACER2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 290	1 in 3,400
South Asian	~43k	1 in 190	1 in 6,100
Remaining (unassigned)	~30k	1 in 260	1 in 4,300
European (Finnish)	~27k	1 in 450	none seen
Admixed American	~22k	1 in 160	1 in 1,800
African / African American	~21k	1 in 200	1 in 3,100
East Asian	~20k	1 in 220	1 in 1,400
Ashkenazi Jewish	~13k	1 in 690	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 170	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 6 coding exons well covered in gnomAD exomes and genomes.? see exons ↓