GeneBe

CYP3A4

protein-coding

cytochrome P450 family 3 subfamily A member 4, the group of Cytochrome P450 family 3

Gene summary

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, and chloroquine. The enzyme also metabolizes some steroids and carcinogens. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2020]

Previous symbols:
  • CYP3A3

MANE transcript

NM_017460.6

Inheritance

AD

ClinVar variants

P:1U:23B:14

Top phenotype

Vitamin D-dependent rickets, type 3; Drug metabolism, CYP3A4-related

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr7:99,756,960-99,784,248

External References & Databases

Ensembl (ENSG00000160868)NCBI Gene (1576)OMIM (124010)HGNC:2637GenCCUniProt (P08684)AlphaFoldClinVar (CYP3A4)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~27.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vitamin D-dependent rickets, type 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033640

Submitter: Labcorp Genetics (formerly Invitae)

vitamin D-dependent rickets, type 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033640

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Vitamin D-dependent rickets, type 3; Drug metabolism, CYP3A4-relatedAD

Manifestation: General

Intervention: Pharmacogenomic

Rationale: In Vitamin D-dependent rickets, medical management (eg, with high-dose calcitriol or vitamin D3) has been reporteed as beneficial; For Drug metabolism, CYP3A4-related, selection and dosing of medications (eg,colchicine) may be affected by the presence of variants

Refs: 9789061; 18973929; 19337788; 19802823; 19907160; 20386561; 21047202; 20437462; 20440227; 21902501; 21902502; 21903774; 21946898; 29461981Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP3A4 variants in ClinVar

5 Conditions Cataloged
not specifiedTotal: 22
not providedTotal: 9
Vitamin D-dependent rickets, type 3Total: 7
CYP3A4-related disorderTotal: 6
Familial hypercholesterolemiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017460.6. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
7
clinvar
2
clinvar
 10
missense
1
clinvar
19
clinvar
4
clinvar
 24
nonsense
0
start loss
0
frameshift
2
clinvar
1
clinvar
 3
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total102312238
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_017460.6RefSeqNP_059488.213MANE Select
ENST00000651514.1EnsemblENSP00000498939.113MANE Select
NM_001202855.3RefSeqNP_001189784.113Standard
ENST00000336411.7EnsemblENSP00000337915.314Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Citalopram Pathway, Pharmacokinetics
  • Artemisinin and Derivatives Pathway, Pharmacokinetics
  • Celecoxib Pathway, Pharmacokinetics
  • Benzodiazepine Pathway, Pharmacokinetics
  • Retinol metabolism - Homo sapiens (human)

Biological Process

  • lipid hydroxylation
  • lipid metabolic process
  • steroid catabolic process
  • xenobiotic metabolic process
  • steroid metabolic process

Molecular Function

  • monooxygenase activity
  • steroid binding
  • iron ion binding
  • steroid hydroxylase activity
  • oxidoreductase activity

Cellular Component

  • cytoplasm
  • endoplasmic reticulum membrane
  • integral component of membrane
  • organelle membrane
  • intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000336411
Coding exons
13
Length
27285
Individuals with no LoFs
125514
Homozygous LoFs
0
Heterozygous LoFs
233
Defined
125747
p
0.000927
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.3522812651.060.00001293320
Missense (PolyPhen)7889.4040.872441160
Synonymous0.3828993.70.9500.00000461944
Loss of Function1.091924.80.7650.00000123314

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000490.00049rare
Latino/Admixed American0.000640.00064rare
Ashkenazi Jewish0.00360.0036notable
East Asian0.00260.0026notable
Finnish0.0000460.000046rare
European (Non-Finnish)0.000320.00032rare
South Asian0.00260.0026notable
Other0.000650.00065rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2- exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599). {ECO:0000269|PubMed:11159812, ECO:0000269|PubMed:21576599}.;

Recessive Scores

pRec
0.582

Intolerance Scores

LoFtool
0.930
RVIS EVS
-0.49
RVIS percentile EVS
22.65

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.00151

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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