ALOXE3

Chr 17AR

arachidonate epidermal lipoxygenase 3

Also known as: ARCI3, E-LOX, LI5, eLOX-3, eLOX3

NCBI Gene: 59344 ENSG00000179148 UniProt: Q9BYJ1 OMIM: 607206

The protein is a hydroperoxide isomerase that synthesizes epoxy-alcohol derivatives from fatty acid precursors and plays a crucial role in establishing the skin barrier by modifying ceramides in the lipid envelope of skin cells. Mutations cause congenital ichthyosis with autosomal recessive inheritance, presenting as scaling and erythroderma from birth due to impaired skin barrier function. The gene shows low constraint against loss-of-function variants (LOEUF 1.055), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a member of the lipoxygenase family, which are catabolized by arachidonic acid-derived compounds. The encoded enzyme is a hydroperoxide isomerase that synthesizes a unique type of epoxy alcohol (8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid) from 12R-hydroperoxyeicosatetraenoic acid (12R-HPETE). This epoxy alcohol can activate the the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), which is implicated in epidermal differentiation. Loss of function of the enzyme encoded by this gene results in ichthyosis, implicating the function of this gene in the differentiation of human skin. This gene is part of a cluster of lipoxygenase genes on 17p13.1. Mutations in this gene result in nonbullous congenital ichthyosiform erythroderma (NCIE). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.051 OMIM phenotype

Clinical Summary— ALOXE3

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

71 unique Pathogenic / Likely Pathogenic· 161 VUS of 369 total submissions

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GeneReview available — ALOXE3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.05LOEUF

pLI 0.000

Z-score 1.26

OE 0.80 (0.61–1.05)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.98 (0.91–1.06)

471 obs / 480.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.80 (0.61–1.05)

0≤0.351.4

Missense OE?0.98 (0.91–1.06)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 35 / 44.0Missense obs/exp: 471 / 480.2Syn Z: 0.41

ClinVar Variant Classifications

369 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic47

Likely Pathogenic24

VUS161

Likely Benign55

Benign51

Conflicting27

Pathogenic

Likely Pathogenic

161

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	32	11	3	1	47
Likely Pathogenic	17	5	2	0	24
VUS	1	134	20	6	161
Likely Benign	0	8	28	19	55
Benign	0	6	40	5	51
Conflicting	—				27
Total	50	164	93	31	365

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap ALOXE3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →