NFKBIE

Chr 6

NFKB inhibitor epsilon

Also known as: IKBE

NCBI Gene: 4794ENSG00000146232UniProt: O00221

The protein encoded by this gene binds to components of NF-kappa-B, trapping the complex in the cytoplasm and preventing it from activating genes in the nucleus. Phosphorylation of the encoded protein targets it for destruction by the ubiquitin pathway, which activates NF-kappa-B by making it available to translocate to the nucleus. [provided by RefSeq, Sep 2011]

74
ClinVar variants
9
Pathogenic / LP
0.77
pLI score
0
Active trials
Clinical Summary— NFKBIE
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.77) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
9 Pathogenic / Likely Pathogenic· 59 VUS of 74 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.43LOEUF
pLI 0.771
Z-score 3.28
OE 0.17 (0.07–0.43)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.47Z-score
OE missense 0.75 (0.67–0.84)
213 obs / 282.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.07–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.67–0.84)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 3 / 18.0Missense obs/exp: 213 / 282.3Syn Z: -0.97

ClinVar Variant Classifications

74 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic1
VUS59
Likely Benign5
Benign1
8
Pathogenic
1
Likely Pathogenic
59
VUS
5
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
0
0
1
0
1
VUS
0
28
31
0
59
Likely Benign
0
1
3
1
5
Benign
0
0
1
0
1
Total02944174

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NFKBIE · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
High-risk MCL: recognition and treatment.
Jain P et al.·Blood
2025Review
NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia.
Bonato A et al.·Leukemia
2024
IκBε deficiency accelerates disease development in chronic lymphocytic leukemia.
Bordini J et al.·Leukemia
2024
Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.
Hawe JS et al.·Nat Genet
2022Functional
Distinct genetic alterations in CD10-negative MUM1-positive follicular lymphoma.
Yang Y et al.·Pathology
2025
Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials.
Khouja M et al.·Leukemia
2024
Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.
Shain AH et al.·Nat Genet
2015
BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib.
Bonfiglio S et al.·Blood Adv
2023Cohort
FTO promotes the progression of triple-negative breast cancer by regulating the m6A methylation of NFKBIE.
Zhang J et al.·Clin Exp Med
2025
Acquired initiating mutations in early hematopoietic cells of CLL patients.
Damm F et al.·Cancer Discov
2014Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools