CYP26B1

Summary

CYP26B1 (cytochrome P450 family 26 subfamily B member 1, HGNC:20581) is a protein-coding gene on chromosome 2p13.2, encoding Cytochrome P450 26B1 (Q9NR63). A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals.

This gene encodes a member of the cytochrome P450 superfamily. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The encoded protein is localized to the endoplasmic reticulum, and functions as a critical regulator of all-trans retinoic acid levels by the specific inactivation of all-trans retinoic acid to hydroxylated forms. Mutations in this gene are associated with radiohumeral fusions and other skeletal and craniofacial anomalies, and increased levels of the encoded protein are associated with atherosclerotic lesions. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 56603 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal occipital encephalocele-skeletal dysplasia syndrome (Strong, GenCC)
• GWAS associations: 13
• Clinical variants (ClinVar): 178 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_019885

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20581
Approved symbol	CYP26B1
Name	cytochrome P450 family 26 subfamily B member 1
Location	2p13.2
Locus type	gene with protein product
Status	Approved
Aliases	P450RAI-2
Ensembl gene	ENSG00000003137
Ensembl biotype	protein_coding
OMIM	605207
Entrez	56603

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000001146, ENST00000412253, ENST00000461519, ENST00000474509, ENST00000546307

RefSeq mRNA: 2 — MANE Select: NM_019885 NM_001277742, NM_019885

CCDS: CCDS1919, CCDS62934

Canonical transcript exons

ENST00000001146 — 6 exons

Exon	Start	End
ENSE00000401861	72147631	72147862
ENSE00000761362	72133023	72133307
ENSE00000761363	72134761	72134916
ENSE00000846592	72129238	72132619
ENSE00000846593	72143989	72144213
ENSE00003623778	72135144	72135419

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 92.31.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7163 / max 43.9804, expressed in 199 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29074	0.2693	114
29071	0.2676	88
29073	0.0927	46
29075	0.0868	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	92.31	gold quality
upper arm skin	UBERON:0004263	91.49	gold quality
cerebellar vermis	UBERON:0004720	90.93	gold quality
cerebellar cortex	UBERON:0002129	90.33	gold quality
cerebellum	UBERON:0002037	90.21	gold quality
cerebellar hemisphere	UBERON:0002245	90.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.60	gold quality
skin of leg	UBERON:0001511	89.28	gold quality
zone of skin	UBERON:0000014	88.19	gold quality
adipose tissue	UBERON:0001013	87.75	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.59	gold quality
decidua	UBERON:0002450	87.55	gold quality
skin of abdomen	UBERON:0001416	87.53	gold quality
connective tissue	UBERON:0002384	87.10	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.99	gold quality
pericardium	UBERON:0002407	85.60	gold quality
omental fat pad	UBERON:0010414	85.58	gold quality
peritoneum	UBERON:0002358	85.49	gold quality
skin of hip	UBERON:0001554	85.19	gold quality
cartilage tissue	UBERON:0002418	84.64	gold quality
tendon of biceps brachii	UBERON:0008188	84.55	silver quality
cortical plate	UBERON:0005343	84.27	gold quality
upper leg skin	UBERON:0004262	84.03	gold quality
thymus	UBERON:0002370	83.38	gold quality
prefrontal cortex	UBERON:0000451	82.90	gold quality
tibia	UBERON:0000979	82.54	gold quality
right lobe of thyroid gland	UBERON:0001119	82.13	gold quality
left lobe of thyroid gland	UBERON:0001120	82.01	gold quality
synovial joint	UBERON:0002217	81.70	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	80.67	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	31.23
E-ANND-3	no	2.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXL2, NR5A1, PAX6, PPARG, SOX9

miRNA regulators (miRDB)

205 targeting CYP26B1, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034

Literature-anchored findings (GeneRIF, showing 31)

• Mouse studies identified different expression patterns of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during development. (PMID:11744378)
• CYP26B1 mRNA levels were approximately twice the level in adult cerebellum compared to adult whole brain samples. CYP26B1 levels were 10x higher in earlier gestational times than in later gestational times. (PMID:12101034)
• Studies in mice found that regulation of retinoid levels, affected by the retinoid-degrading enzyme CYP26B1, during fetal gonad development determined whether germ cells would become oocytes or spermatogonia. (PMID:16574820)
• The predominant expression of CYP26A1 in the liver is in agreement with previous reports of tissue distribution of CYP26 mRNA in adult humans. (PMID:19884280)
• role of CYP26 in the regulation of all trans retinoic acid levels in human aortic smooth muscle cells (PMID:20606468)
• The presence of CYP26B1 in normal lung development (A549 cell line), & the capacity to convert retinol to retinoic acid, indicates that fetal human lung has the ability to regulate the supply of vitamin A from the pseudoglandular stage. (PMID:21482329)
• Increased expression of the CYP26B1 gene was observed in tumor tissue compared with adjacent normal tissue and it plays a novel role in the betel dependent pathogenesis of oral squamous cell carcinoma. (PMID:21641851)
• Detection of the methylation prevalence of KCNA4 and CYP26B1 together in serum demonstrated the good sensitivity and specificityin gastric cancer (PMID:21945024)
• Human null and hypomorphic mutations were identified in the gene encoding the retinoic acid degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis (PMID:22019272)
• The mRNA expression of CYP26A1 and CYP26B1 correlated between human tissues except for human cerebellum in which CYP26B1 was the predominant CYP26 and liver in which CYP26A1 dominated. (PMID:22020119)
• CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis. (PMID:22415012)
• Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions (PMID:22666329)
• Single nucleotide polymorphisms in CYP26B1, NANOS1 and STRA8 genes support involvement of meiotic program initiation genes in modifying the risk of azoospermia and oligozoospermia in a Han-Chinese population (PMID:23320086)
• We report a 2p13.2 microdeletion in 2 subjects encompasing 2 genes, EXOC6B and CYP26B12 with clinical effects on cognitive function, and craniofacial and skeletal development. (PMID:23837398)
• homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of Crohn’s disease. (PMID:23977348)
• inhibits fibroblasts-induced activation of mast cells and dermatitis (PMID:24726878)
• Our results suggested that the CYP26B1 splice variant is associated with the occurrence of BQ-related oral cancer. (PMID:25114974)
• SNPs in three genes CYP26B1 rs2241057, CISD1 rs2251039, rs2590370, and TBX1 rs4819522 were involved in six potential pathways to influence serum prostate-specific antigen levels. (PMID:25168891)
• There was increased expression of mRNA CYP26B1 in oral cancer tissue compared to adjacent noncancerous tissues. (PMID:25839051)
• Study investigated the distribution of Cyp26a1 and Cyp26b1 transcripts in the rat and human brain, identifying several novel regions of expression, including the cerebral cortex for both enzymes and striatum for Cyp26b1. (PMID:26374207)
• we provide the third family affected by the disorder and the first affected individual to survive beyond infancy. This woman homozygous for c.1303G>A; p.(Gly435Ser) in CYP26B1, which was associated with multisutural synostosis, radiohumeral synostosis, normal bone mineral density, and apparent intellectual disability, a phenotype with significant similarities to Antley-Bixler and Pfeiffer syndromes. (PMID:27410456)
• Holo-CRABPs had higher affinity for CYP26B1 than free atRA, but both apo-CRABPs(CRABP-I and CRABP-II ) inhibited the formation of 4-OH-RA by CYP26B1. (PMID:27416800)
• Individuals with the rs138478634-GA genotype had significantly lower levels of serum all-trans retinoic acid, an anticancer nutrient, than those with the rs138478634-GG genotype (P = 0.0004), most likely due to an enhanced capacity of variant CYP26B1 to catabolize this agent. These findings emphasize the important role of rare coding variants in the development of Esophageal squamous cell carcinoma. (PMID:29379198)
• Data reported the pathogenic missense mutations of NAGLU and CYP26B1 concurrent in one patient, which not only expands the phenotype and genotype spectra of NAGLU and CYP26B1, but more importantly indicates the possibility of simultaneous occurrence of two rare diseases in one patient. (PMID:29606097)
• This review highlights the current knowledge of structure-function of CYP26 enzymes and focuses on their role in human retinoid metabolism in different tissues. (PMID:31419517)
• CYP26B1 and its implications in lymphangiogenesis: Literature review and study of rare variants in two families. (PMID:32521127)
• Polymorphisms in Vitamin A-Related Genes and Their Functions in Autoimmune Thyroid Disease. (PMID:34470463)
• A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis. (PMID:36769350)
• A variant in CYP26B1 associated with esophageal squamous cell carcinoma risk by affecting retinoic acid metabolism. (PMID:37042568)
• Familial monoallelic CYP26B1 truncating variant causes a syndromic craniosynostosis due to haploinsufficiency ? (PMID:37100236)
• CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence. (PMID:37755482)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cyp26b1	ENSDARG00000077121
mus_musculus	Cyp26b1	ENSMUSG00000063415
rattus_norvegicus	Cyp26b1	ENSRNOG00000015076

Paralogs (2): CYP26A1 (ENSG00000095596), CYP26C1 (ENSG00000187553)

Protein

Protein identifiers

Cytochrome P450 26B1 — Q9NR63 (reviewed: Q9NR63)

Alternative names: Cytochrome P450 26A2, Cytochrome P450 retinoic acid-inactivating 2, Retinoic acid-metabolizing cytochrome

All UniProt accessions (4): Q9NR63, E5RHM2, E5RHN4, E7ER08

UniProt curated annotations — full annotation on UniProt →

Function. A cytochrome P450 monooxygenase involved in the metabolism of retinoates (RAs), the active metabolites of vitamin A, and critical signaling molecules in animals. RAs exist as at least four different isomers: all-trans-RA (atRA), 9-cis-RA, 13-cis-RA, and 9,13-dicis-RA, where atRA is considered to be the biologically active isomer, although 9-cis-RA and 13-cis-RA also have activity. Catalyzes the hydroxylation of atRA primarily at C-4 and C-18, thereby contributing to the regulation of atRA homeostasis and signaling. Hydroxylation of atRA limits its biological activity and initiates a degradative process leading to its eventual elimination. Involved in the convertion of atRA to all-trans-4-oxo-RA. Can oxidize all-trans-13,14-dihydroretinoate (DRA) to metabolites which could include all-trans-4-oxo-DRA, all-trans-4-hydroxy-DRA, all-trans-5,8-epoxy-DRA, and all-trans-18-hydroxy-DRA. Shows preference for the following substrates: atRA > 9-cis-RA > 13-cis-RA. Plays a central role in germ cell development: acts by degrading RAs in the developing testis, preventing STRA8 expression, thereby leading to delay of meiosis. Required for the maintenance of the undifferentiated state of male germ cells during embryonic development in Sertoli cells, inducing arrest in G0 phase of the cell cycle and preventing meiotic entry. Plays a role in skeletal development, both at the level of patterning and in the ossification of bone and the establishment of some synovial joints. Essential for postnatal survival. Also has a significant activity in oxidation of tazarotenic acid and may therefore metabolize that xenobiotic in vivo.

Subcellular location. Endoplasmic reticulum membrane. Microsome membrane.

Tissue specificity. Highly expressed in brain, particularly in the cerebellum and pons.

Disease relevance. Radiohumeral fusions with other skeletal and craniofacial anomalies (RHFCA) [MIM:614416] A disease characterized by craniofacial malformations, occipital encephalocele, radiohumeral fusions, oligodactyly, advanced osseous maturation, and calvarial mineralization defects. The disease is caused by variants affecting the gene represented in this entry.

Induction. By retinoic acid.

Similarity. Belongs to the cytochrome P450 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NR63-1	1	yes
Q9NR63-2	2
Q9NR63-3	3

RefSeq proteins (2): NP_001264671, NP_063938* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001128	Cyt_P450	Family
IPR002403	Cyt_P450_E_grp-IV	Family
IPR017972	Cyt_P450_CS	Conserved_site
IPR036396	Cyt_P450_sf	Homologous_superfamily

Pfam: PF00067

Catalyzed reactions (Rhea), 2 shown:

• all-trans-retinoate + reduced [NADPH–hemoprotein reductase] + O2 = all-trans-4-hydroxyretinoate + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:51984)
• all-trans-retinoate + reduced [NADPH–hemoprotein reductase] + O2 = all-trans-18-hydroxyretinoate + oxidized [NADPH–hemoprotein reductase] + H2O + H(+) (RHEA:55856)

UniProt features (17 total): sequence variant 12, splice variant 2, chain 1, binding site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR63-F1	90.99	0.82

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 (1): 441 (axial binding residue)

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-211916	Vitamins
R-HSA-5365859	RA biosynthesis pathway
R-HSA-5579015	Defective CYP26B1 causes RHFCA

MSigDB gene sets: 394 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, AHRARNT_01, GOBP_POSITIVE_REGULATION_OF_MYOTUBE_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, STAEGE_EWING_FAMILY_TUMOR, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (27): cell fate determination (GO:0001709), establishment of T cell polarity (GO:0001768), kidney development (GO:0001822), vitamin metabolic process (GO:0006766), xenobiotic metabolic process (GO:0006805), inflammatory response (GO:0006954), male meiotic nuclear division (GO:0007140), spermatogenesis (GO:0007283), central nervous system development (GO:0007417), proximal/distal pattern formation (GO:0009954), positive regulation of gene expression (GO:0010628), embryonic limb morphogenesis (GO:0030326), response to vitamin A (GO:0033189), retinoic acid catabolic process (GO:0034653), retinoic acid metabolic process (GO:0042573), tongue morphogenesis (GO:0043587), regulation of T cell differentiation (GO:0045580), retinoic acid receptor signaling pathway (GO:0048384), negative regulation of retinoic acid receptor signaling pathway (GO:0048387), bone morphogenesis (GO:0060349), establishment of skin barrier (GO:0061436), cornification (GO:0070268), cellular response to retinoic acid (GO:0071300), positive regulation of tongue muscle cell differentiation (GO:2001037), lipid metabolic process (GO:0006629), response to retinoic acid (GO:0032526), regulation of retinoic acid receptor signaling pathway (GO:0048385)

GO Molecular Function (11): retinoic acid binding (GO:0001972), monooxygenase activity (GO:0004497), iron ion binding (GO:0005506), retinoic acid 4-hydroxylase activity (GO:0008401), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen (GO:0016709), heme binding (GO:0020037), all-trans retinoic acid 18-hydroxylase activity (GO:0062183), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cytochrome P450 - arranged by substrate type	1
Signaling by Retinoic Acid	1
Metabolic disorders of biological oxidation enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monooxygenase activity	3
male gamete generation	2
oxidoreductase activity	2
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	2
cellular anatomical structure	2
cell fate commitment	1
cellular developmental process	1
establishment of lymphocyte polarity	1
T cell activation	1
animal organ development	1
renal system development	1
small molecule metabolic process	1
metabolic process	1
cellular response to xenobiotic stimulus	1
defense response	1
meiotic cell cycle	1
meiotic nuclear division	1
developmental process involved in reproduction	1
nervous system development	1
system development	1
regionalization	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
response to vitamin	1
response to lipid	1
diterpenoid catabolic process	1
fat-soluble vitamin catabolic process	1
retinoic acid metabolic process	1
monocarboxylic acid catabolic process	1
retinoid metabolic process	1
monocarboxylic acid metabolic process	1
hormone metabolic process	1
tongue development	1
sensory organ morphogenesis	1
T cell differentiation	1
regulation of lymphocyte differentiation	1
regulation of T cell activation	1

Protein interactions and networks

STRING

2314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CYP26B1	NANOS2	P60321	956
CYP26B1	STRA8	Q7Z7C7	935
CYP26B1	ALDH1A2	O94788	876
CYP26B1	RDH10	Q8IZV5	701
CYP26B1	ALDH1A3	P47895	689
CYP26B1	LRAT	O95237	666
CYP26B1	RARS1	P54136	661
CYP26B1	STRA6	Q9BX79	648
CYP26B1	EXOC6B	Q9Y2D4	636
CYP26B1	RARB	P10826	620
CYP26B1	RARG	P13631	619
CYP26B1	ALDH1A1	P00352	614
CYP26B1	CRABP2	P29373	612
CYP26B1	RARA	P10276	604
CYP26B1	CRABP1	P29762	595

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CYP26B1	JPH3	psi-mi:“MI:0915”(physical association)	0.560
CYP26B1	SCARB2	psi-mi:“MI:0914”(association)	0.350
CYP26B1	ADCY3	psi-mi:“MI:0914”(association)	0.350

BioGRID (29): CYP26B1 (Affinity Capture-MS), CYP26B1 (Affinity Capture-RNA), CRELD1 (Affinity Capture-MS), PCYOX1 (Affinity Capture-MS), NDUFAF1 (Affinity Capture-MS), SCARB2 (Affinity Capture-MS), ECSIT (Affinity Capture-MS), FRMD5 (Affinity Capture-MS), CIB1 (Affinity Capture-MS), DCAKD (Affinity Capture-MS), PKMYT1 (Affinity Capture-MS), ESYT1 (Affinity Capture-MS), RETSAT (Affinity Capture-MS), GPRC5C (Affinity Capture-MS), EPHX1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1I9Q5Z0, A0A481NR20, A8WGA0, E1BHJ4, G3V7X8, O18635, O23051, O44220, O73853, P05093, P0DOX0, P11715, P48416, P82712, Q07973, Q09128, Q09660, Q2XVA1, Q4G0S4, Q64441, Q6JD68, Q6WG30, Q7KR10, Q811W2, Q8HYM9, Q8HYN0, Q8HYN1, Q8W4T9, Q91Z85, Q92045, Q92113, Q940V4, Q95328, Q9EPT4, Q9GLD2, Q9GMC8, Q9LUC5, Q9NGX9, Q9NR63, Q9SHG5

Diamond homologs: A0A068AA98, A0A068ACU3, A0A084API1, A0A0F7U0K0, A0A0P0ZEA9, A0A125QZE2, A0A1B4XBH0, A0A1L7VEQ6, A0A1L9WQK2, A0A1R3RGJ7, A0A1V1FNM9, A0A2K9RG08, A0A2P1DPA5, A0A3S9NM20, A0A411KUQ5, A0A455ZIK8, A0A481WPJ6, A0A831A9C9, A0A8K1AW54, A1C8C2, A1DA63, A2A974, A2R6G9, A2RRT9, B5BSX1, B6HFX9, B8NHD9, B8QHP1, C0SJS3, C8V7P3, C9K1X6, D1MX85, E1BHJ4, G0KYB2, G1XU01, G3V7X8, L0N063, L7HT17, M2UJ60, M2V933

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	89
Likely benign	50
Benign	14

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
30447	NM_019885.4(CYP26B1):c.1088G>T (p.Arg363Leu)	Pathogenic
30448	NM_019885.4(CYP26B1):c.436T>C (p.Ser146Pro)	Pathogenic
3393285	NM_019885.4(CYP26B1):c.3G>T (p.Met1Ile)	Pathogenic
1809805	NM_019885.4(CYP26B1):c.86C>A (p.Ser29Ter)	Likely pathogenic
432606	NM_019885.4(CYP26B1):c.1190G>A (p.Arg397Gln)	Likely pathogenic
432607	NM_019885.4(CYP26B1):c.1088G>A (p.Arg363His)	Likely pathogenic

SpliceAI

1170 predictions. Top by Δscore:

Variant	Effect	Δscore
2:72132616:AACC:A	acceptor_gain	1.0000
2:72132617:ACC:A	acceptor_gain	1.0000
2:72132618:CC:C	acceptor_gain	1.0000
2:72132618:CCC:C	acceptor_gain	1.0000
2:72132619:CC:C	acceptor_gain	1.0000
2:72133015:AG:A	donor_gain	1.0000
2:72133017:CCTCA:C	donor_loss	1.0000
2:72133018:CTCA:C	donor_loss	1.0000
2:72133019:TCACA:T	donor_loss	1.0000
2:72133020:CA:C	donor_loss	1.0000
2:72133021:A:AC	donor_gain	1.0000
2:72133021:AC:A	donor_loss	1.0000
2:72133022:C:CA	donor_gain	1.0000
2:72133022:CAT:C	donor_gain	1.0000
2:72133024:T:TA	donor_gain	1.0000
2:72133090:T:TA	donor_gain	1.0000
2:72133303:CCGTC:C	acceptor_gain	1.0000
2:72133304:CGTC:C	acceptor_gain	1.0000
2:72133304:CGTCC:C	acceptor_gain	1.0000
2:72133305:GTCCT:G	acceptor_loss	1.0000
2:72133306:TCC:T	acceptor_loss	1.0000
2:72133307:CCTGC:C	acceptor_loss	1.0000
2:72133308:C:CC	acceptor_gain	1.0000
2:72133309:T:A	acceptor_loss	1.0000
2:72134768:T:TA	donor_gain	1.0000
2:72134787:T:TA	donor_gain	1.0000
2:72134788:C:A	donor_gain	1.0000
2:72134914:GCCC:G	acceptor_loss	1.0000
2:72134915:CC:C	acceptor_gain	1.0000
2:72134916:CC:C	acceptor_gain	1.0000

AlphaMissense

3341 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:72133051:C:G	R373P	0.999
2:72133254:G:C	S305R	0.999
2:72133254:G:T	S305R	0.999
2:72133256:T:G	S305R	0.999
2:72132464:G:C	F434L	0.998
2:72132464:G:T	F434L	0.998
2:72132466:A:G	F434L	0.998
2:72132515:G:C	F417L	0.998
2:72132515:G:T	F417L	0.998
2:72132517:A:G	F417L	0.998
2:72132591:A:T	V392D	0.998
2:72132598:A:G	W390R	0.998
2:72132598:A:T	W390R	0.998
2:72133052:G:T	R373S	0.998
2:72133082:G:T	R363S	0.998
2:72144137:A:T	I94K	0.998
2:72132303:A:T	V488D	0.997
2:72132393:A:G	L458P	0.997
2:72132438:C:T	G443D	0.997
2:72132439:C:A	G443C	0.997
2:72133090:T:A	E360V	0.997
2:72133234:A:G	L312P	0.997
2:72133246:A:G	L308P	0.997
2:72135335:A:G	W172R	0.997
2:72135335:A:T	W172R	0.997
2:72144166:G:C	F84L	0.997
2:72144166:G:T	F84L	0.997
2:72144168:A:G	F84L	0.997
2:72132438:C:A	G443V	0.996
2:72132439:C:G	G443R	0.996

dbSNP variants (sampled 300 via entrez): RS1000293467 (2:72149736 AC>A,ACC), RS1000305768 (2:72135689 G>A), RS1000375653 (2:72147200 T>G), RS1000665068 (2:72145710 C>A), RS1000665624 (2:72146860 C>G,T), RS1001115429 (2:72141407 G>A,T), RS1001116921 (2:72147514 C>A,G), RS1001304716 (2:72136087 G>A), RS1001555595 (2:72140678 G>A), RS1001585321 (2:72145457 G>A), RS1001609328 (2:72135990 A>G), RS1001618022 (2:72145290 G>A), RS1001725438 (2:72136130 G>A), RS1001877231 (2:72140854 A>G), RS1002120453 (2:72147924 A>G,T)

Disease associations

OMIM: gene MIM:605207 | disease phenotypes: MIM:614416, MIM:123100

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal occipital encephalocele-skeletal dysplasia syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
lethal occipital encephalocele-skeletal dysplasia syndrome	Moderate	AR

Mondo (2): lethal occipital encephalocele-skeletal dysplasia syndrome (MONDO:0013740), craniosynostosis (MONDO:0015469)

Orphanet (2): Lethal occipital encephalocele-skeletal dysplasia syndrome (Orphanet:293925), Craniosynostosis (Orphanet:1531)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000248	Brachycephaly
HP:0001166	Arachnodactyly
HP:0001363	Craniosynostosis
HP:0002085	Occipital encephalocele
HP:0003041	Humeroradial synostosis
HP:0012165	Oligodactyly
HP:0030674	Antenatal onset

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002539_37	Schizophrenia	7.000000e-09
GCST006979_13	Heel bone mineral density	7.000000e-16
GCST008568_12	IgA levels	2.000000e-20
GCST008839_245	Height	3.000000e-13
GCST008839_4	Height	3.000000e-14
GCST010482_1	Cardiovascular death or myocardial infarction in response to clopidogrel treatment	2.000000e-06
GCST010725_60	Malaria	7.000000e-06
GCST010725_79	Malaria	5.000000e-06
GCST011878_20	Mitochondrial heteroplasmy measurement	5.000000e-08
GCST012020_585	Serum metabolite levels	3.000000e-12
GCST012021_33	Serum metabolite levels	3.000000e-12
GCST012484_14	Cerebral amyloid angiopathy x APOEe4 status interaction in Alzheimer’s disease	4.000000e-06
GCST90000015_17	Parkinson’s disease motor subtype (tremor to postural instability/gait difficulty score ratio)	7.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0006919	cardiovascular event measurement
EFO:0600008	mitochondrial heteroplasmy measurement
EFO:0007659	APOE carrier status
EFO:0600011	Parkinson’s disease symptom measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3713687 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 131,137 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1023	BEXAROTENE	4	40,951
CHEMBL157101	KETOCONAZOLE	4	75,361
CHEMBL389433	LIAROZOLE	2	14,636
CHEMBL459505	TALAROZOLE	2	189

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — CYP24, CYP26 and CYP27 families

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[4-[2-(dimethylamino)-1-imidazol-1-ylpropyl]phenyl]-1,3-benzothiazol-2-amine	IC50	4.3 nM	US-9963439: Specific inhibitors of cytochrome P450 26 retinoic acid hydroxylase
R115866	EC50	5 nM
1-[4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone	IC50	127 nM	US-9394290: Selective CYP11B1 inhibitors for the treatment of cortisol dependent diseases
Liazal	IC50	1900 nM	US-9963439: Specific inhibitors of cytochrome P450 26 retinoic acid hydroxylase

ChEMBL bioactivities

32 potent at pChembl≥5 of 54 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.34	IC50	0.46	nM	TALAROZOLE
8.51	IC50	3.1	nM	CHEMBL5785788
7.75	IC50	18	nM	LIAROZOLE
6.85	IC50	140	nM	KETOCONAZOLE
6.70	IC50	200	nM	CHEMBL5934332
6.54	IC50	290	nM	CHEMBL5961796
6.30	IC50	500	nM	CHEMBL5972108
6.28	IC50	520	nM	CHEMBL309282
6.26	IC50	550	nM	CHEMBL5850367
6.17	IC50	680	nM	CHEMBL3787323
6.03	IC50	930	nM	CHEMBL3787564
5.99	IC50	1030	nM	CHEMBL3786620
5.99	IC50	1030	nM	CHEMBL3786184
5.96	IC50	1100	nM	CHEMBL323626
5.85	IC50	1400	nM	CHEMBL3785511
5.85	IC50	1400	nM	CHEMBL3787691
5.77	IC50	1700	nM	CHEMBL3786324
5.69	IC50	2061	nM	CHEMBL5785529
5.64	IC50	2300	nM	CHEMBL5744932
5.36	IC50	4400	nM	CHEMBL3785701
5.23	IC50	5900	nM	BEXAROTENE
5.21	IC50	6200	nM	CHEMBL3786340
5.06	IC50	8800	nM	CHEMBL5912888
5.05	IC50	8807	nM	CHEMBL5803577
5.04	IC50	9066	nM	CHEMBL5894941

PubChem BioAssay actives

14 with measured affinity, of 25 total; 14 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
N-[4-[2-ethyl-1-(1,2,4-triazol-1-yl)butyl]phenyl]-1,3-benzothiazol-2-amine	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	0.0005	uM
6-[(3-chlorophenyl)-imidazol-1-ylmethyl]-1H-benzimidazole	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	0.0180	uM
6-(5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)naphthalene-2-carboxylic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	0.5200	uM
3-[4-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl]propanoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	0.6800	uM
4-[2-oxo-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethoxy]benzoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	0.9300	uM
6-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1,3-dithiolan-2-yl]naphthalene-2-carboxylic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	1.0300	uM
6-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1,3-dioxolan-2-yl]naphthalene-2-carboxylic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	1.0300	uM
4-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1,3-dithiolan-2-yl]benzoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	1.1000	uM
4-[(2Z)-2-hydroxyimino-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethoxy]benzoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	1.4000	uM
4-[2-hydroxy-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)ethoxy]benzoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	1.4000	uM
3-[4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)methyl]phenyl]propanoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	1.7000	uM
(E)-3-[4-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)-1,3-dithiolan-2-yl]phenyl]prop-2-enoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	4.4000	uM
Bexarotene	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	5.9000	uM
3-[4-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)sulfonyl]phenyl]propanoic acid	1290555: Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	ic50	6.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases abundance, increases activity, increases reaction, decreases reaction, affects degradation (+4 more)	11
Estradiol	affects cotreatment, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	2
Calcitriol	increases expression	2
Cisplatin	decreases expression, affects expression, affects cotreatment	2
Ketoconazole	decreases activity, decreases reaction, increases metabolic processing	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	increases expression	2
Isotretinoin	increases expression, increases reaction	2
aristolochic acid I	increases expression	1
CD2665	decreases reaction, increases expression	1
sotorasib	affects cotreatment, increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
ascorbate-2-phosphate	affects binding, affects cotreatment, increases expression	1
kojic acid	increases expression	1
quercitrin	increases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
fipronil	affects cotreatment, increases expression	1
azoxystrobin	decreases expression	1
CGP 52608	increases reaction, affects binding	1
deguelin	decreases expression	1
R 115866	decreases activity, increases activity	1
R116010	increases expression, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
Chir 99021	affects cotreatment, increases expression, affects binding	1
abrine	decreases expression	1
bisphenol S	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3789262	Binding	Inhibition of microsomal fraction of human CYP26B1 expressed in Sf9 cells using 9-cis-RA as substrate at 20 uM preincubated for 5 mins followed by NADPH addition measured after 5 mins by HPLC analysis in presence of rat P450 reductase	Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0WX	Ubigene KYSE-30 CYP26B1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT00077831	Not specified	COMPLETED	Child and Infant Learning Project
NCT00106977	Not specified	COMPLETED	Clinical Study of Muenke Syndrome (FGFR3-Related Craniosynostosis)
NCT00367796	Not specified	COMPLETED	Genetic Analysis of Craniosynostosis, Philadelphia Type
NCT00769847	Not specified	WITHDRAWN	Endoscopic Treatment for Isolated, Single Suture Craniosynostosis
NCT00773643	Not specified	COMPLETED	Osteogenic Profiling of Tissue From Children With Craniosynostosis
NCT01898650	Not specified	COMPLETED	MRI for Non-invasive Evaluation of Brain Stress
NCT02287805	Not specified	COMPLETED	Qualitative and Quantitative Study Which Aims to Determine the Specifics of the Announcement for the Diagnosis of Patients With Craniosynostosis and Their Parents to Better Support Them in Their Care
NCT02561728	Not specified	WITHDRAWN	Hanger Helmet Study
NCT03025763	Not specified	ACTIVE_NOT_RECRUITING	Network Of Clinical Research Studies On Craniosynostosis, Skull Malformations With Premature Fusion Of Skull Bones
NCT03231085	Not specified	COMPLETED	Comparison of the Rate of Preoperative Haemoglobin After Administration of Epoetin Alpha Associated With an Oral Medical Supplementation Versus Intravenous Before Surgery of Craniosynostosis at the Child
NCT04704284	Not specified	COMPLETED	Comparing MRI to CT on Pediatric Craniosynostosis.
NCT05911139	Not specified	ENROLLING_BY_INVITATION	Influence of General Anesthesia on the Dynamic Changes in Brain Damage Markers During and After Craniosynostosis Operations in Infancy
NCT06928727	Not specified	RECRUITING	Ocular Characteristics in Patients With Craniosynostosis