ALOX12B

Summary

ALOX12B (arachidonate 12-lipoxygenase, 12R type, HGNC:430) is a protein-coding gene on chromosome 17p13.1, encoding Arachidonate 12-lipoxygenase, 12R-type (O75342). Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species.

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.

Source: NCBI Gene 242 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive congenital ichthyosis 2 (Definitive, GenCC) — +3 more curated relationships
• Clinical variants (ClinVar): 449 total — 108 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 47
• MANE Select transcript: NM_001139

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:430
Approved symbol	ALOX12B
Name	arachidonate 12-lipoxygenase, 12R type
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	12R-LOX
Ensembl gene	ENSG00000179477
Ensembl biotype	protein_coding
OMIM	603741
Entrez	242

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 2 protein_coding_CDS_not_defined, 2 retained_intron, 2 protein_coding

ENST00000577351, ENST00000583276, ENST00000584116, ENST00000647874, ENST00000649809, ENST00000650441

RefSeq mRNA: 1 — MANE Select: NM_001139 NM_001139

CCDS: CCDS11129

Canonical transcript exons

ENST00000647874 — 15 exons

Exon	Start	End
ENSE00001239726	8073148	8073318
ENSE00001239731	8073657	8073757
ENSE00001239738	8075595	8075716
ENSE00001239772	8079769	8079941
ENSE00001239775	8080235	8080338
ENSE00001239784	8080658	8080780
ENSE00001239795	8080884	8080976
ENSE00001239804	8081106	8081187
ENSE00001239810	8086016	8086220
ENSE00001483924	8072636	8072950
ENSE00003468250	8076990	8077193
ENSE00003477287	8079396	8079539
ENSE00003505084	8076657	8076743
ENSE00003539006	8076175	8076344
ENSE00003833237	8087296	8087716

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 96.39.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5599 / max 188.2506, expressed in 183 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164355	0.1693	37
164348	0.1234	65
164349	0.0759	28
164357	0.0667	16
164356	0.0408	10
164351	0.0303	16
164353	0.0212	7
164352	0.0166	8
164354	0.0157	7

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	96.39	gold quality
skin of abdomen	UBERON:0001416	95.05	gold quality
zone of skin	UBERON:0000014	93.79	gold quality
penis	UBERON:0000989	91.97	gold quality
upper leg skin	UBERON:0004262	87.99	gold quality
mammalian vulva	UBERON:0000997	87.88	gold quality
upper arm skin	UBERON:0004263	87.36	gold quality
gingival epithelium	UBERON:0001949	87.30	gold quality
cervix epithelium	UBERON:0004801	86.32	gold quality
gingiva	UBERON:0001828	85.43	gold quality
lower esophagus mucosa	UBERON:0035834	84.40	gold quality
cervix squamous epithelium	UBERON:0006922	83.89	silver quality
tongue squamous epithelium	UBERON:0006919	81.38	gold quality
squamous epithelium	UBERON:0006914	75.02	silver quality
skin of hip	UBERON:0001554	72.37	gold quality
esophagus mucosa	UBERON:0002469	71.09	gold quality
nipple	UBERON:0002030	70.93	silver quality
vagina	UBERON:0000996	70.68	gold quality
oviduct epithelium	UBERON:0004804	68.17	silver quality
body of tongue	UBERON:0011876	66.73	silver quality
esophagus squamous epithelium	UBERON:0006920	66.24	silver quality
uterine cervix	UBERON:0000002	66.18	gold quality
prefrontal cortex	UBERON:0000451	66.08	gold quality
tonsil	UBERON:0002372	65.53	gold quality
right frontal lobe	UBERON:0002810	65.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	64.13	gold quality
frontal cortex	UBERON:0001870	62.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	62.35	gold quality
cerebellar hemisphere	UBERON:0002245	62.03	gold quality
islet of Langerhans	UBERON:0000006	61.99	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.10
E-GEOD-124858	no	0.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting ALOX12B, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-655-5P	98.74	65.93	888
HSA-MIR-3921	97.81	67.45	1431
HSA-MIR-4653-5P	97.22	67.72	1429

Literature-anchored findings (GeneRIF, showing 23)

• Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13.1. (PMID:11773004)
• Isoenzyme is characterized. (PMID:12664578)
• 12R-LOX hydrolase functions in the normal process of skin differentiation, and that the loss of function mutations are the basis of the LOX-dependent form of Non-bullous congenital ichthyosiform erythroderma. (PMID:15629692)
• Our data contribute to an enlargement of the spectrum of mutations for the development of efficient molecular genetic tests for analysis of at risk individuals whose carrier status is unknown. (PMID:17139268)
• Formation of a ligand for the nuclear receptor PPARalpha may be one possibility by which 12R-LOX and eLOX3 contribute to epidermal differentiation. (PMID:17436029)
• presented a novel form of ichthyosis in a patient, termed hepoxilin A(3) synthase-linked ichthyosis (HXALI), whose scales expressed high levels of 12R-LOX, but were deficient of HXA(3) synthase [hepoxilin A3 synthase] (PMID:18086569)
• clinical & molecular features of 2 cases of self-healing collodion phenotype that developed mild ichthyosiform erythroderma; both patients were compound heterozygous for novel ALOX12B mutations (PMID:18347291)
• mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B may have roles in autosomal recessive congenital ichthyosis (PMID:19131948)
• 12-R-LOX and COX-2 play critical roles in the regulation of growth in epidermoid carcinoma (PMID:19558494)
• ALOX12B mutations are the leading cause of self-improving collodion ichthyosis in Scandinavia, followed by ALOXE3 mutations, and TGM1 mutations (PMID:19890349)
• co-overproduction of the two chaperones with 12R-LOX resulted in increased solubility of 12R-LOX and allowed the purification of milligram amounts of active enzyme for structural studies by X-ray diffraction (PMID:21821891)
• It was shown that 12R-lipoxygenase is involved in MUC5AC expression via ERK- and Sp1-signalling pathways. (PMID:22441738)
• Autosomal recessive congenital ichthyosis patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. (PMID:22622417)
• We found that the contribution of the ALOX12B gene to the pathogenesis of Autosomal Recessive Congenital Ichthyosis to be as important as that of TGM1 in families of Arab Muslim origin (PMID:23621129)
• Loss-of-function mutations in the LOX genes ALOX12B and ALOXE3 have been found to represent the second most common cause of autosomal recessive congenital ichthyosis. [review] (PMID:23954555)
• This review covers the background to discovery of the two key lipoxygenases (LOX) involved in epidermal barrier function, 12R-LOX and eLOX3. [review] (PMID:24021977)
• report adds information on the clinical picture of autosomal recessive congenital ichthyosis caused by ALOX12B mutations (PMID:26575587)
• The rare homozygous ALOX12B mutation found in Patient 5 causes a change in a conserved residue; Leu315 into a proline in the catalytic domain of 12R-LOX. (PMID:28236338)
• A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree. (PMID:32253496)
• Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients. (PMID:33435499)
• Unbound Corneocyte Lipid Envelopes in 12R-Lipoxygenase Deficiency Support a Specific Role in Lipid-Protein Cross-Linking. (PMID:33607042)
• Survival-related indicators ALOX12B and SPRR1A are associated with DNA damage repair and tumor microenvironment status in HPV 16-negative head and neck squamous cell carcinoma patients. (PMID:35768785)
• Whole exome sequencing identifies novel pathogenic variants in TGM1 and ALOX12B in patients with hereditary ichthyosis. (PMID:38060040)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Alox12b	ENSMUSG00000032807
rattus_norvegicus	Alox12b	ENSRNOG00000022210

Paralogs (5): ALOX5 (ENSG00000012779), ALOX12 (ENSG00000108839), ALOX15 (ENSG00000161905), ALOXE3 (ENSG00000179148), ALOX15B (ENSG00000179593)

Protein

Protein identifiers

Arachidonate 12-lipoxygenase, 12R-type — O75342 (reviewed: O75342)

Alternative names: Epidermis-type lipoxygenase 12

All UniProt accessions (2): A0A3B3IRK2, O75342

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species. In the skin, acts upstream of ALOXE3 on the lineolate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins. Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss. May also play a role in the regulation of the expression of airway mucins.

Subcellular location. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed in B-cells, hair follicles, foreskin keratinocytes and adult skin. Also expressed in psoriatic tissue.

Disease relevance. Ichthyosis, congenital, autosomal recessive 2 (ARCI2) [MIM:242100] A form of autosomal recessive congenital ichthyosis, a disorder of keratinization with abnormal differentiation and desquamation of the epidermis, resulting in abnormal skin scaling over the whole body. The main skin phenotypes are lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur. Lamellar ichthyosis is a condition often associated with an embedment in a collodion-like membrane at birth; skin scales later develop, covering the entire body surface. Non-bullous congenital ichthyosiform erythroderma characterized by fine whitish scaling on an erythrodermal background; larger brownish scales are present on the buttocks, neck and legs. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Increased by calcium.

Cofactor. Binds 1 Fe cation per subunit.

Pathway. Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis. Lipid metabolism; sphingolipid metabolism.

Similarity. Belongs to the lipoxygenase family.

RefSeq proteins (1): NP_001130* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000907	LipOase	Family
IPR001024	PLAT/LH2_dom	Domain
IPR001885	LipOase_mml	Family
IPR013819	LipOase_C	Domain
IPR020833	LipOase_Fe_BS	Binding_site
IPR020834	LipOase_CS	Conserved_site
IPR036226	LipOase_C_sf	Homologous_superfamily
IPR036392	PLAT/LH2_dom_sf	Homologous_superfamily
IPR042062	PLAT_LOX_verte	Domain

Pfam: PF00305, PF01477

Enzyme classification (BRENDA):

• EC 1.13.11.31 — arachidonate 12-lipoxygenase (BRENDA: 25 organisms, 141 substrates, 194 inhibitors, 60 Km, 34 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ARACHIDONIC ACID	0.004–0.08	14
ARACHIDONATE	0.0009–0.232	8
LINOLEIC ACID	0.0125–0.0312	8
O2	0.0052–7	8
5,8,11,14,17-EICOSAPENTAENOIC ACID	0.003–0.427	4
4Z,7Z,10Z,12E,16Z,19Z-DOCOSAHEXAENOIC ACID	0.0009–0.0067	2
5S-HYDROPEROXY-6E,8Z,10E,14Z-EICOSATETRAENOIC AC	0.0017–0.0078	2
5S-HYDROXY-6E,8Z,10E,14Z-EICOSATETRAENOIC ACID	0.0017–0.0049	2
8,11,14-EICOSATRIENOIC ACID	0.0035–0.079	2
METHYL ARACHIDONATE	0.0114–0.018	2
(Z,Z,Z,E)-5,8,11,13-EICOSATETRAENOIC ACID	0.0039	1
1-LINOLEOYL LYSOPHOSPHATIDIC ACID	0.0355	1
1-LINOLEOYL LYSOPHOSPHATIDYLCHOLINE	0.0151	1
5(S)-HYDROXY-6E,8Z,11Z,14Z-EICOSATETRAENOIC ACID	0.0045	1
5S,15S-DIHYDROPEROXYEICOSATETRAENOIC ACID	—	0

Catalyzed reactions (Rhea), 12 shown:

• N-[omega-(9Z,12Z)-octadecadienoyloxy]acyl-beta-D-glucosyl-(1<->1)-octadecasphing-4E-enine + O2 = N-[omega-(9R)-hydroperoxy-(10E,12Z)-octadecadienoyloxy]acyl-beta-D-glucosyl-(1<->1)-octadecasphing-4E-enine (RHEA:40495)
• a N-[omega-(9Z,12Z)-octadecadienoyloxy]-acylsphin-4E-enine + O2 = a N-[omega-(9R)-hydroperoxy-(10E,12Z)-octadecadienoyloxy]-acylsphin-4E-enine (RHEA:41239)
• 1-O-methyl-(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = 1-O-methyl (5Z,8Z,10E,12R,14Z)-hydroperoxyiecosatetraenoate (RHEA:41311)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (12R)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate (RHEA:41336)
• (6Z,9Z,12Z)-octadecatrienoate + O2 = 10R-hydroperoxy-(6Z,8E,12Z)-octadecatrienoate (RHEA:41340)
• (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 = (5Z,7Z,8Z,10E,14Z,17Z)-12-hydroperoxyeicosapentaenoate (RHEA:41344)
• 1-O-methyl-(9Z,12Z)-octadecadienoate + O2 = 1-O-methyl-(13S)-hydroperoxy-(9Z,11E)-octadecadienoate (RHEA:41756)
• (8Z,11Z,14Z)-eicosatrienoate + O2 = (8Z,10E,14Z)-12-hydroperoxyeicosatrienoate (RHEA:43468)
• (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 = 14-hydroperoxy-(4Z,7Z,10Z,12E,16Z,19Z)-docosahexaenoate (RHEA:43472)
• (6Z,9Z,12Z)-octadecatrienoate + O2 = 10-hydroperoxy-(6Z,8E,12Z)-octadecatrienoate (RHEA:43476)
• 1-O-methyl-(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = 1-O-methyl-8-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate (RHEA:43480)
• 1-O-methyl-(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = 1-O-methyl-(8R)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatrienoate (RHEA:61868)

UniProt features (27 total): sequence variant 19, binding site 5, domain 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75342-F1	92.07	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 398; 403; 578; 582; 701

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-2142712	Synthesis of 12-eicosatetraenoic acid derivatives
R-HSA-1430728	Metabolism
R-HSA-2142753	Arachidonate metabolism
R-HSA-556833	Metabolism of lipids
R-HSA-8978868	Fatty acid metabolism

MSigDB gene sets: 232 (showing top): GOBP_LIPID_MODIFICATION, GOBP_EPITHELIUM_DEVELOPMENT, MODULE_451, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_LONG_CHAIN_FATTY_ACID_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CERAMIDE_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_LIPOXYGENASE_PATHWAY, GOBP_SPHINGOLIPID_METABOLIC_PROCESS, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_AMIDE_BIOSYNTHETIC_PROCESS, GOBP_LIPOPROTEIN_BIOSYNTHETIC_PROCESS

GO Biological Process (14): protein lipidation (GO:0006497), sphingolipid metabolic process (GO:0006665), positive regulation of gene expression (GO:0010628), arachidonate metabolic process (GO:0019369), lipoxygenase pathway (GO:0019372), lipid oxidation (GO:0034440), positive regulation of MAPK cascade (GO:0043410), linoleic acid metabolic process (GO:0043651), ceramide biosynthetic process (GO:0046513), hepoxilin biosynthetic process (GO:0051122), establishment of skin barrier (GO:0061436), positive regulation of mucus secretion (GO:0070257), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631)

GO Molecular Function (12): arachidonate 12(S)-lipoxygenase activity (GO:0004052), iron ion binding (GO:0005506), oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen (GO:0016702), lyase activity (GO:0016829), isomerase activity (GO:0016853), arachidonate 8(R)-lipoxygenase activity (GO:0047677), arachidonate 12(R)-lipoxygenase activity (GO:0106237), linoleate 9S-lipoxygenase activity (GO:1990136), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (4): cytosol (GO:0005829), membrane (GO:0016020), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Arachidonate metabolism	1
Fatty acid metabolism	1
Metabolism	1
Metabolism of lipids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen	4
cellular anatomical structure	4
catalytic activity	3
lipid metabolic process	2
long-chain fatty acid metabolic process	2
icosanoid metabolic process	2
unsaturated fatty acid metabolic process	2
olefinic compound metabolic process	2
cytoplasm	2
protein modification process	1
lipoprotein biosynthetic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
fatty acid metabolic process	1
lipid modification	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
ceramide metabolic process	1
sphingolipid biosynthetic process	1
long-chain fatty acid biosynthetic process	1
skin epidermis development	1
positive regulation of secretion	1
positive regulation of multicellular organismal process	1
mucus secretion	1
regulation of mucus secretion	1
primary metabolic process	1
monocarboxylic acid metabolic process	1
transition metal ion binding	1
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen	1
dioxygenase activity	1
binding	1
cation binding	1
oxidoreductase activity	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALOX12B	NIPAL4	Q0D2K0	917
ALOX12B	TGM1	P22735	871
ALOX12B	ABHD5	Q8WTS1	859
ALOX12B	CYP4F22	Q6NT55	830
ALOX12B	ABCA12	Q86UK0	794
ALOX12B	PNPLA1	Q8N8W4	788
ALOX12B	LOX	P28300	773
ALOX12B	CERS3	Q8IU89	695
ALOX12B	LIPN	Q5VXI9	659
ALOX12B	SDR9C7	Q8NEX9	655
ALOX12B	TINCR	A0A2R8Y7D0	604
ALOX12B	SULT2B1	O00204	578
ALOX12B	CASP14	P31944	554
ALOX12B	SLC27A4	Q6P1M0	479
ALOX12B	KRT80	Q6KB66	400

IntAct

121 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
ZSCAN12	A2ML1	psi-mi:“MI:0914”(association)	0.530
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
GMCL1	A2ML1	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
DNAAF19	KLK10	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
KIR3DS1	PPL	psi-mi:“MI:0914”(association)	0.530
AIRE	ALOX12B	psi-mi:“MI:0914”(association)	0.530
GPANK1	ALOX12B	psi-mi:“MI:0914”(association)	0.530
CCDC27	ALOX12B	psi-mi:“MI:0914”(association)	0.530
DPPA4	ALOX12B	psi-mi:“MI:0914”(association)	0.530
MMRN1	CTSV	psi-mi:“MI:0914”(association)	0.530
ZIC1	CTSV	psi-mi:“MI:0914”(association)	0.530
TOX4	ALOX12B	psi-mi:“MI:0914”(association)	0.530

BioGRID (123): ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), ALOX12B (Affinity Capture-MS)

ESM2 similar proteins: A6H603, D3ZBP4, D3ZKX9, D3ZQF9, F1LQ70, O00329, O00411, O15296, O35936, O43548, O70582, O75342, O95932, P09917, P0C869, P0C871, P12527, P12530, P16050, P16452, P16469, P18054, P27479, P39654, P39655, P48999, P49222, P51399, P52630, P55249, Q02759, Q149M9, Q2KMM4, Q2TB18, Q4R7D0, Q50L43, Q5R5N9, Q5RBE8, Q5RCY5, Q68DD2

Diamond homologs: C8YR32, D3ZKX9, D3ZQF9, F1LQ70, O15296, O16025, O22507, O22508, O24371, O24379, O35936, O70582, O75342, P08170, P09186, P09439, P09917, P09918, P12527, P12530, P16050, P16469, P18054, P24095, P27479, P27480, P27481, P37831, P38414, P38417, P38418, P39654, P39655, P48999, P51399, P55249, Q02759, Q2KMM4, Q41238, Q43190

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

449 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	27
Uncertain significance	169
Likely benign	47
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1050787	NM_001139.3(ALOX12B):c.88C>T (p.Gln30Ter)	Pathogenic
1191903	NM_001139.3(ALOX12B):c.759C>A (p.Tyr253Ter)	Pathogenic
1438249	NM_001139.3(ALOX12B):c.1785_1790del (p.Phe595_Ala597delinsLeu)	Pathogenic
1526047	NM_001139.3(ALOX12B):c.1625_1626del (p.Lys542fs)	Pathogenic
2030744	NM_001139.3(ALOX12B):c.1463G>C (p.Arg488Pro)	Pathogenic
2052334	NM_001139.3(ALOX12B):c.1273A>T (p.Lys425Ter)	Pathogenic
2423280	NC_000017.10:g.(?7571752)(8285628_?)del	Pathogenic
2797660	NM_001139.3(ALOX12B):c.1018dup (p.Leu340fs)	Pathogenic
280119	NM_001139.3(ALOX12B):c.252C>A (p.Cys84Ter)	Pathogenic
2816422	NM_001139.3(ALOX12B):c.1517G>A (p.Trp506Ter)	Pathogenic
2832883	NM_001139.3(ALOX12B):c.1693del (p.Arg565fs)	Pathogenic
3374962	NM_001139.3(ALOX12B):c.324C>G (p.Tyr108Ter)	Pathogenic
3382516	NM_001139.3(ALOX12B):c.1693C>T (p.Arg565Ter)	Pathogenic
3384712	NM_001139.3(ALOX12B):c.1662dup (p.Arg555Ter)	Pathogenic
3619195	NM_001139.3(ALOX12B):c.311G>A (p.Trp104Ter)	Pathogenic
3626525	NM_001139.3(ALOX12B):c.1924_1925del (p.Arg642fs)	Pathogenic
373376	NM_001139.3(ALOX12B):c.530G>A (p.Trp177Ter)	Pathogenic
39540	NM_001139.3(ALOX12B):c.2036G>T (p.Arg679Leu)	Pathogenic
39541	NM_001139.3(ALOX12B):c.1180G>A (p.Glu394Lys)	Pathogenic
39544	NM_001139.3(ALOX12B):c.353-1G>A	Pathogenic
39546	NM_001139.3(ALOX12B):c.1562A>G (p.Tyr521Cys)	Pathogenic
39547	NM_001139.3(ALOX12B):c.199A>T (p.Ile67Phe)	Pathogenic
437467	NM_001139.3(ALOX12B):c.353-2A>G	Pathogenic
4733395	NM_001139.3(ALOX12B):c.285dup (p.Ile96fs)	Pathogenic
59583	GRCh38/hg38 17p13.1(chr17:7478195-8435524)x1	Pathogenic
6082	NM_001139.3(ALOX12B):c.1389del (p.Phe463fs)	Pathogenic
6083	NM_001139.3(ALOX12B):c.1277T>C (p.Leu426Pro)	Pathogenic
6084	NM_001139.3(ALOX12B):c.1734C>A (p.His578Gln)	Pathogenic
633823	NM_001139.3(ALOX12B):c.149_353del (p.Val50fs)	Pathogenic
633825	NM_001139.3(ALOX12B):c.286_287dup (p.Tyr97fs)	Pathogenic

SpliceAI

2580 predictions. Top by Δscore:

Variant	Effect	Δscore
17:8073146:AC:A	donor_gain	1.0000
17:8073147:CC:C	donor_gain	1.0000
17:8073315:CCAT:C	acceptor_gain	1.0000
17:8073316:CAT:C	acceptor_gain	1.0000
17:8073316:CATC:C	acceptor_gain	1.0000
17:8073317:ATCTG:A	acceptor_loss	1.0000
17:8073319:CTG:C	acceptor_loss	1.0000
17:8073320:T:A	acceptor_loss	1.0000
17:8075633:T:TA	donor_gain	1.0000
17:8076156:A:AC	donor_gain	1.0000
17:8076157:C:CC	donor_gain	1.0000
17:8076169:G:C	donor_gain	1.0000
17:8076173:A:AC	donor_gain	1.0000
17:8076174:C:CT	donor_gain	1.0000
17:8076174:CTT:C	donor_gain	1.0000
17:8076174:CTTCT:C	donor_gain	1.0000
17:8076176:T:TA	donor_gain	1.0000
17:8076343:CC:C	acceptor_gain	1.0000
17:8076344:CC:C	acceptor_gain	1.0000
17:8076651:TCTTA:T	donor_loss	1.0000
17:8076652:CTTA:C	donor_loss	1.0000
17:8076653:TTAC:T	donor_loss	1.0000
17:8076654:TA:T	donor_loss	1.0000
17:8076655:A:AC	donor_gain	1.0000
17:8076656:C:A	donor_loss	1.0000
17:8076656:C:CC	donor_gain	1.0000
17:8076739:AGGAG:A	acceptor_gain	1.0000
17:8076740:GGAG:G	acceptor_gain	1.0000
17:8076741:GAG:G	acceptor_gain	1.0000
17:8076742:AG:A	acceptor_gain	1.0000

AlphaMissense

4582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8072783:G:C	S698R	0.996
17:8072783:G:T	S698R	0.996
17:8072785:T:G	S698R	0.996
17:8072784:C:A	S698I	0.995
17:8073724:A:G	L563P	0.995
17:8076705:G:C	N438K	0.995
17:8076705:G:T	N438K	0.995
17:8077056:G:C	H403Q	0.995
17:8077056:G:T	H403Q	0.995
17:8077119:C:A	K382N	0.995
17:8077119:C:G	K382N	0.995
17:8073666:G:C	N582K	0.994
17:8073666:G:T	N582K	0.994
17:8076694:C:G	R442P	0.994
17:8077069:A:G	L399P	0.994
17:8077071:G:C	H398Q	0.994
17:8077071:G:T	H398Q	0.994
17:8072871:A:G	L669P	0.993
17:8075643:A:G	W536R	0.993
17:8075643:A:T	W536R	0.993
17:8080690:C:A	K206N	0.993
17:8080690:C:G	K206N	0.993
17:8081141:T:A	R133S	0.993
17:8081141:T:G	R133S	0.993
17:8072786:G:C	N697K	0.992
17:8072786:G:T	N697K	0.992
17:8077058:G:C	H403D	0.992
17:8077073:G:C	H398D	0.992
17:8077108:C:G	R386P	0.992
17:8080290:C:A	W233C	0.992

dbSNP variants (sampled 300 via entrez): RS1000038349 (17:8085712 T>C), RS1000070874 (17:8085507 A>T), RS1000301526 (17:8083266 TAAA>T), RS1000938448 (17:8088617 C>T), RS1001107118 (17:8075102 C>T), RS1001141773 (17:8072681 CTG>C), RS1001254303 (17:8078719 C>T), RS1001939948 (17:8082061 G>T), RS1002002902 (17:8083158 G>T), RS1002381957 (17:8086704 G>A,C,T), RS1002411787 (17:8086497 G>A), RS1002600879 (17:8084278 G>A), RS1002764192 (17:8078928 C>T), RS1002816855 (17:8078674 C>A), RS1002873668 (17:8085114 C>G,T)

Disease associations

OMIM: gene MIM:603741 | disease phenotypes: MIM:242100, MIM:204000, MIM:601777, MIM:151623, MIM:609266, MIM:242300, MIM:614561

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive congenital ichthyosis 2	Definitive	Autosomal recessive
congenital non-bullous ichthyosiform erythroderma	Strong	Autosomal recessive
self-healing collodion baby	Supportive	Autosomal recessive
lamellar ichthyosis	Supportive	Autosomal recessive

Mondo (10): autosomal recessive congenital ichthyosis 2 (MONDO:0009439), lamellar ichthyosis (MONDO:0017778), Leber congenital amaurosis 1 (MONDO:0008764), cone-rod dystrophy 6 (MONDO:0011143), Li-Fraumeni syndrome (MONDO:0018875), ichthyosis (MONDO:0019269), congenital non-bullous ichthyosiform erythroderma (MONDO:0019306), autosomal recessive congenital ichthyosis (MONDO:0017265), leukoencephalopathy with calcifications and cysts (MONDO:0013803), self-healing collodion baby (MONDO:0017267)

Orphanet (9): Self-improving collodion baby (Orphanet:281122), Congenital ichthyosiform erythroderma (Orphanet:79394), Lamellar ichthyosis (Orphanet:313), Cone rod dystrophy (Orphanet:1872), Leber congenital amaurosis (Orphanet:65), Li-Fraumeni syndrome (Orphanet:524), Ichthyosis (Orphanet:79354), Autosomal recessive congenital ichthyosis (Orphanet:281097), Leukoencephalopathy with calcifications and cysts (Orphanet:542310)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000164	Abnormality of the dentition
HP:0000232	Everted lower lip vermilion
HP:0000365	Hearing impairment
HP:0000389	Chronic otitis media
HP:0000491	Keratitis
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000966	Hypohidrosis
HP:0000970	Anhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001376	Limitation of joint mobility
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001792	Small nail
HP:0001816	Thin nail
HP:0001831	Short toe
HP:0001944	Dehydration
HP:0002205	Recurrent respiratory infections
HP:0003241	External genital hypoplasia
HP:0003470	Paralysis
HP:0003577	Congenital onset
HP:0004322	Short stature

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
D016864	Li-Fraumeni Syndrome	C04.700.600; C16.320.700.600; C18.452.284.520
C000598644	Leukoencephalopathy Brain Calcifications and Cysts (supp.)
C538363	Retinal cone dystrophy 2 (supp.)
C565473	Self-Healing Collodion Baby (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Lipoxygenases

PubChem BioAssay actives

1 with measured affinity, of 26 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4,4-dimethyl-2,6-dioxocyclohexyl)-[4-[(E)-2-phenylethenyl]phenyl]methyl]-5,5-dimethylcyclohexane-1,3-dione	1799689: Inhibition Assay from Article 10.1080/14756360701408754: “Mild and efficient synthesis of new tetraketones as lipoxygenase inhibitors and antioxidants.”	ic50	7.8000	uM

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation, affects methylation, decreases methylation	3
Endosulfan	increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
bisphenol A	affects cotreatment, increases expression	1
sodium arsenate	decreases expression, increases abundance	1
sodium arsenite	affects methylation	1
hydroquinone	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Arsenic	decreases expression, increases abundance	1
Camptothecin	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression, decreases reaction, increases reaction	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Ibuprofen	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Niclosamide	decreases response to substance, increases expression, decreases reaction	1
Valproic Acid	increases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Arachidonic Acid	increases expression, increases metabolic processing	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

54 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT01222000	PHASE3	UNKNOWN	Treatment of the Recessive Nonbullous Congenital Ichthyosis by the Epigallocatechine Cutaneous
NCT01464086	PHASE3	COMPLETED	LIFSCREEN : Evaluation of Whole Body MRI for Early Detection of Cancers in Subjects With P53 Mutation (Li-Fraumeni Syndrome)
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT03738800	PHASE2	TERMINATED	A Safety, Efficacy and Systemic Exposure Study of CD5789 Cream in Adults and Adolescents With Lamellar Ichthyosis
NCT06088030	PHASE2	RECRUITING	Arsenic Trioxide Combined With Chemotherapy for the Treatment of p53-mutated Pediatric Cancer
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT01014052	PHASE1	COMPLETED	Safety/Proof of Concept Study of Oral QLT091001 in Subjects With Leber Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) Due to Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT) Mutations
NCT01521793	PHASE1	COMPLETED	Repeated Treatments of QLT091001 in Subjects With Leber Congenital Amaurosis or Retinitis Pigmentosa (Extension of Study RET IRD 01)
NCT01981525	PHASE1	COMPLETED	A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome
NCT00001292	Not specified	COMPLETED	Study of Scaling Disorders and Other Inherited Skin Diseases
NCT03920007	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Subretinally Injected ATSN-101 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D
NCT00406445	Not specified	COMPLETED	Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome
NCT01143454	Not specified	RECRUITING	Characterization of Patients With Uncommon Presentations and/or Uncommon Diseases Associated With the Cardiovascular System
NCT01443468	Not specified	RECRUITING	Clinical and Genetic Studies of Li-Fraumeni Syndrome
NCT01737255	Not specified	COMPLETED	Magnetic Resonance Imaging Screening in Li Fraumeni Syndrome
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02950987	Not specified	ACTIVE_NOT_RECRUITING	Screening With Whole Body MRI For Detection Of Primary Tumors In Children And Adults With Li-Fraumeni Syndrome (LFS) And Other Cancer Predisposition Syndromes
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03176836	Not specified	ENROLLING_BY_INVITATION	Li-Fraumeni Syndrome Imaging Study
NCT04367246	Not specified	RECRUITING	Li-Fraumeni Syndrome/TP53 Biobank
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04966923	Not specified	COMPLETED	Phenotype and Prognosis of Patients With Breast Cancer and Pathogenic Variants of TP53
NCT04982744	Not specified	RECRUITING	Registry of Li Fraumeni and Li Fraumeni Like Syndromes
NCT05126810	Not specified	RECRUITING	Willingness to Participate in a Trial Comparing Standard Genetic Counseling Versus Personalized Genetic Counseling
NCT06163365	Not specified	UNKNOWN	Inherited Cancer Early Diagnosis (ICED) Study
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT06712095	Not specified	RECRUITING	Video Capsule Examination in Patients With Lynch Syndrome
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07032922	Not specified	COMPLETED	Exploring How to Adapt an Evidence-Based Mindful Self-Compassion Program for Young Adults With Li-Fraumeni Syndrome
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis