CERS3

Chr 15AR

ceramide synthase 3

Also known as: ARCI9, LASS3

NCBI Gene: 204219 ENSG00000154227 UniProt: Q8IU89 OMIM: 615276

This protein functions as a ceramide synthase that catalyzes the formation of ultra-long-chain ceramides from sphingoid bases and acyl-CoA substrates, which are essential for maintaining epidermal lipid homeostasis and the skin's protective barrier function. Mutations cause autosomal recessive congenital ichthyosis, characterized by epidermal defects due to impaired skin barrier formation. The gene shows low constraint against loss-of-function variants (pLI 0.006), consistent with its recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the ceramide synthase family of genes. The ceramide synthase enzymes regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid base and acyl-coA substrates. This family member is involved in the synthesis of ceramides with ultra-long-chain acyl moieties (ULC-Cers), important to the epidermis in its role in creating a protective barrier from the environment. The protein encoded by this gene has also been implicated in modification of the lipid structures required for spermatogenesis. Mutations in this gene have been associated with male fertility defects, and epidermal defects, including ichthyosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Ichthyosis, congenital, autosomal recessive 9MIM #615023

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Ichthyosis, congenital, autosomal recessive 9; no ClinGen or GenCC tier

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.63

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — CERS3

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?

0.63LOEUF

pLI 0.006

Z-score 2.90

OE 0.35 (0.20–0.63)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.61Z-score

OE missense 0.88 (0.78–0.99)

183 obs / 207.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.20–0.63)

0≤0.351.4

Missense OE?0.88 (0.78–0.99)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 8 / 23.0Missense obs/exp: 183 / 207.9Syn Z: -0.40

Background carrier burden — how many people carry a rare variant somewhere in CERS3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

504 rare PASS variants

Rare truncating (LoF)

1 in 3,800

64 rare PASS variants

Rare synonymous (reference)

1 in 170

181 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CERS3. 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 170	1 in 5,000
South Asian	~43k	1 in 110	1 in 3,800
Remaining (unassigned)	~30k	1 in 150	1 in 6,000
European (Finnish)	~27k	1 in 1,100	≈ 1 in 8,900
Admixed American	~22k	1 in 170	1 in 2,400
African / African American	~21k	1 in 120	1 in 1,800
East Asian	~20k	1 in 120	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,600	none seen
Middle Eastern	~2,884	1 in 100	≈ 1 in 2,900

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): 8 of 10 coding exons well covered in gnomAD exomes; exons 4, 8 marginal. Genomes: all 10.? see exons ↓