CYP26B1

protein-coding

cytochrome P450 family 26 subfamily B member 1, the group of Cytochrome P450 family 26

Gene summary

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. [provided by RefSeq, Apr 2013]

MANE transcript

NM_019885.4

Inheritance

ClinVar variants

P:8U:92B:53

Top phenotype

Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomalies

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr2:72,129,238-72,147,862

External References & Databases

Ensembl (ENSG00000003137)

Transcript & Mutation Effects

hg38 • Region Span ~18.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lethal occipital encephalocele-skeletal dysplasia syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013740

Submitter: Labcorp Genetics (formerly Invitae)

lethal occipital encephalocele-skeletal dysplasia syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013740

Submitter: Ambry Genetics

lethal occipital encephalocele-skeletal dysplasia syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013740

Submitter: ClinGen

*CYP26B1* was first reported in relation to autosomal recessive lethal occipital encephalocele-skeletal dysplasia syndrome in 2011 (Laue et al., PMID: 22019272). This condition is often associated with intrauterine fetal demise, stillbirth, or neonatal death. However, probands may survive into adolescence or adulthood. Features of this condition include craniosynostosis (such as coronal, lambdoid, or sagittal); facial anomalies (like midface retrusion, frontal bossing, brachycephaly, and small ears); delayed ossification; digit anomalies (like oligodactyly or long/slender fingers and toes); narrow thorax; radiohumeral fusions; hearing loss; and respiratory issues. Nine variants (missense, splicing) that have been reported in at least seven probands in four publications (PMIDs: 22019272, 27410456, 34160123, 37755482) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function (PMID: 22019272). This gene-disease relationship is also supported by experimental evidence (mouse and zebrafish models; PMIDs: 15030763, 22019272). Mouse and zebrafish models show that CYP26B1 deficiency leads to skeletal anomalies like short limbs and inappropriate joint fusion; improper skeletal patterning during development; reduced body size; and craniosynostosis. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 2/19/2026 (SOP Version 12).

lethal occipital encephalocele-skeletal dysplasia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013740

Submitter: Orphanet

Clinical Genomic Database (CGD)

Craniosynostosis with radiohumeral fusions and other skeletal and craniofacial anomaliesAR

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22019272

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP26B1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 98

Inborn genetic diseasesTotal: 72

CYP26B1-related disorderTotal: 11

Lethal occipital encephalocele-skeletal dysplasia syndromeTotal: 11

Craniosynostosis syndromeTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019885.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				31 clinvar	7 clinvar	38
missense	2 clinvar	3 clinvar	89 clinvar	13 clinvar	2 clinvar	109
nonsense		1 clinvar				1
start loss	1 clinvar					1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	4	4	92	44	9	153

Highest pathogenic variant AF is 0.000004117768

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019885.4	RefSeq	NP_063938.1	6	MANE Select
ENST00000001146.7	Ensembl	ENSP00000001146.2	6	MANE Select
NM_001277742.2	RefSeq	NP_001264671.1	5	Standard
ENST00000412253.1	Ensembl	ENSP00000401465.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cyp26b1	Danio rerio	Structure: osteoblast Quality: star shaped abnormal

Gene / Model

Organism

Observed Phenotype

cyp26b1

Danio rerio

Structure: osteoblast

Quality: star shaped

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retinol metabolism - Homo sapiens (human)
Adipogenesis
Oxidation by Cytochrome P450
Metapathway biotransformation Phase I and II
Vitamin A and Carotenoid Metabolism

Biological Process

cell fate determination
establishment of T cell polarity
kidney development
vitamin metabolic process
xenobiotic metabolic process

Molecular Function

retinoic acid binding
iron ion binding
retinoic acid 4-hydroxylase activity
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
heme binding

Cellular Component

cytoplasm
endoplasmic reticulum membrane
organelle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000001146
Coding exons: 6
Length: 18801
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125745
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.05	275	329	0.837	0.0000219	3299
Missense (PolyPhen)		79	136.7	0.57792		1322
Synonymous	-0.663	161	151	1.07	0.0000102	1070
Loss of Function	3.52	1	16.3	0.0612	7.11e-7	191

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00069	0.00068	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00083	0.00082	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00038	0.00036	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the metabolism of retinoic acid (RA), rendering this classical morphogen inactive through oxidation. Involved in the specific inactivation of all-trans-retinoic acid (all-trans-RA), with a preference for the following substrates: all-trans-RA > 9-cis-RA > 13-cis-RA. Generates several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA, and 18-OH- RA. Essential for postnatal survival. Plays a central role in germ cell development: acts by degrading RA 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. {ECO:0000269|PubMed:10823918, ECO:0000269|PubMed:22019272}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:22019272}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.462
RVIS EVS: 0
RVIS percentile EVS: 54.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.363

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium