ALOX12B

Chr 17AR

arachidonate 12-lipoxygenase, 12R type

Also known as: 12R-LOX, ARCI2

NCBI Gene: 242 ENSG00000179477 UniProt: O75342 OMIM: 603741

The protein catalyzes the incorporation of oxygen into polyunsaturated fatty acids and plays a crucial role in skin barrier formation by acting on ceramides to synthesize the corneocyte lipid envelope. Mutations cause autosomal recessive congenital ichthyosiform erythroderma, a severe skin disorder present from birth characterized by scaling and redness. The gene shows low constraint against loss-of-function variants (pLI 0.0008, LOEUF 0.55), consistent with the recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme involved in the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid. Mutations in this gene are associated with nonbullous congenital ichthyosiform erythroderma. [provided by RefSeq, Sep 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.551 OMIM phenotype

Clinical Summary— ALOX12B

⚡

Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

📋

ClinVar Variants

150 unique Pathogenic / Likely Pathogenic· 163 VUS of 440 total submissions

Explore recent and relevant literature in Research Assistant →

📖

GeneReview available — ALOX12B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.001

Z-score 3.63

OE 0.34 (0.22–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.40Z-score

OE missense 0.80 (0.73–0.88)

326 obs / 405.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.22–0.55)

0≤0.351.4

Missense OE?0.80 (0.73–0.88)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 12 / 35.2Missense obs/exp: 326 / 405.6Syn Z: 0.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveALOX12B-related congenital ichthyosisLOFAR

This gene — mechanism propensity

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

0.6260th %ile

GOF

0.7028th %ile

LOF

0.2679th %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.

ClinVar Variant Classifications

440 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic105

Likely Pathogenic45

VUS163

Likely Benign51

Benign38

Conflicting31

105

Pathogenic

Likely Pathogenic

163

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	48	4	0	105
Likely Pathogenic	17	26	2	0	45
VUS	0	138	17	8	163
Likely Benign	0	4	22	25	51
Benign	0	1	33	4	38
Conflicting	—				31
Total	70	217	78	37	433

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap ALOX12B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →