CERS3

Chr 15AR

ceramide synthase 3

Also known as: ARCI9, LASS3

NCBI Gene: 204219ENSG00000154227UniProt: Q8IU89

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]

Primary Disease Associations & Inheritance

Ichthyosis, congenital, autosomal recessive 9MIM #615023
AR
276
ClinVar variants
104
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— CERS3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.35) despite low pLI — interpret in context.
📋
ClinVar Variants
104 Pathogenic / Likely Pathogenic· 76 VUS of 276 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.
0.63LOEUF
pLI 0.006
Z-score 2.90
OE 0.35 (0.20–0.63)
Tolerant

Typical tolerance to LoF variation

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.
0.61Z-score
OE missense 0.88 (0.78–0.99)
183 obs / 207.9 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.0.35 (0.20–0.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.78–0.99)
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.1.06
0≤1.21.6
LoF obs/exp: 8 / 23.0Missense obs/exp: 183 / 207.9Syn Z: -0.40

ClinVar Variant Classifications

276 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic84
Likely Pathogenic20
VUS76
Likely Benign36
Benign49
Conflicting7
84
Pathogenic
20
Likely Pathogenic
76
VUS
36
Likely Benign
49
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
4
78
0
84
Likely Pathogenic
8
1
11
0
20
VUS
1
44
31
0
76
Likely Benign
0
11
13
12
36
Benign
1
6
34
8
49
Conflicting
—7
Total126616720272

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

View in ClinVar →

Protein Context — Lollipop Plot

CERS3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CERS3-related ichthyosis, congenital

limited
ARUndeterminedAltered Gene Product Structure
Skin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Ichthyosis, congenital, autosomal recessive 9

MIM #615023

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Ceramide synthase 3 affects invasion and metastasis of hepatocellular carcinoma via the SMAD6 gene.
Cai J et al.·Zhong Nan Da Xue Xue Bao Yi Xue Ban
2022
Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients.
Diociaiuti A et al.·Dermatology
2024Cohort
Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype-phenotype correlation.
Ennouri M et al.·BMC Med Genomics
2022Cohort
Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients.
Hotz A et al.·Genes (Basel)
2021Meta-analysis
Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.
Radner FP et al.·PLoS Genet
2013
Genotype of autosomal recessive congenital ichthyosis from a tertiary care center in India.
Chiramel MJ et al.·Pediatr Dermatol
2022
A novel homozygous splice site variant in CERS3 causes autosomal recessive congenital ichthyosis.
Jan H et al.·Congenit Anom (Kyoto)
2023
Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.
Simpson JK et al.·Br J Dermatol
2020Cohort
Hair Growth-Promoting Effect of Hydrangea serrata (Thunb.) Ser. Extract and Its Active Component Hydrangenol: In Vitro and In Vivo Study.
Park S et al.·Int J Mol Sci
2024
Alteration to the Skin Ceramide Profile Following Broad-Spectrum UV Exposure.
Barresi R et al.·J Drugs Dermatol
2022
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