KEAP1
protein-codingkelch like ECH associated protein 1, the group of BTB domain containing|Kelch like
Gene summary
This gene encodes a cytoplasmic regulatory protein that plays a role in the cellular response to oxidative and electrophilic stress. The encoded protein regulates NRF2, a transcription factor that controls the expression of antioxidant and cytoprotective genes. Under non-stress conditions, KEAP1 binds NRF2 and promotes its ubiquitination and proteasomal degradation, thereby maintaining low NRF2 levels. During oxidative or electrophilic stress, conformational changes in KEAP1 impair its ability to promote NRF2 degradation, allowing NRF2 to activate genes that protect cells from oxidative damage and toxic insults. [provided by RefSeq, Mar 2026]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007681
Submitter: Orphanet
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KEAP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_203500.2. 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 | 2 | 7 | 9 | |||
| missense | 60 | 3 | 63 | |||
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 6 | 6 | ||||
| Total | 0 | 0 | 72 | 10 | 0 | 82 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_987096.1 | 5 | MANE Select | |
| Ensembl | ENSP00000171111.4 | 5 | MANE Select | |
| RefSeq | NP_036421.2 | 5 | Standard | |
| Ensembl | ENSP00000377245.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Hepatocellular carcinoma - Homo sapiens (human)
- Fluid shear stress and atherosclerosis - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Quercetin and Nf-kB- AP-1 Induced Cell Apoptosis
Biological Process
- in utero embryonic development
- proteasomal ubiquitin-independent protein catabolic process
- viral process
- protein ubiquitination
- protein deubiquitination
Molecular Function
- protein binding
- transcription factor binding
- protein homodimerization activity
- disordered domain specific binding
Cellular Component
- nucleoplasm
- cytoplasm
- endoplasmic reticulum
- microtubule organizing center
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000171111
- Coding exons
- 5
- Length
- 17622
- Individuals with no LoFs
- 125727
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 21
- Defined
- 125748
- p
- 0.0000835
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.80 | 206 | 427 | 0.483 | 0.0000300 | 4071 |
| Missense (PolyPhen) | 45 | 165.03 | 0.27268 | 1571 | ||
| Synonymous | 0.733 | 176 | 189 | 0.932 | 0.0000148 | 1246 |
| Loss of Function | 3.10 | 11 | 29.1 | 0.379 | 0.00000195 | 244 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000061 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00031 | 0.00030 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000082 | 0.000079 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. Retains NFE2L2/NRF2 and may also retain BPTF in the cytosol. Targets PGAM5 for ubiquitination and degradation by the proteasome. {ECO:0000269|PubMed:14585973, ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:15572695, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:17046835}.;
Recessive Scores
- pRec
- 0.209
Intolerance Scores
- LoFtool
- 0.303
- RVIS EVS
- -1.13
- RVIS percentile EVS
- 6.43
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.942
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |