NFE2L1

Chr 17

NFE2 like bZIP transcription factor 1

Also known as: LCR-F1, NRF-1, NRF1, TCF11

NCBI Gene: 4779ENSG00000082641UniProt: Q14494

This gene encodes an endoplasmic reticulum membrane sensor that translocates to the nucleus in response to cellular stresses including cholesterol excess, oxidative stress, and proteasome inhibition, where it functions as the transcription factor NRF1 to regulate proteasome homeostasis and cholesterol metabolism. Loss-of-function mutations cause an autosomal dominant disorder due to the gene's extreme intolerance to loss-of-function variants. The pathogenic mechanism involves haploinsufficiency of this essential transcriptional regulator.

Summary from RefSeq, UniProt, Mechanism
0
Active trials
36
Pubs (1 yr)
9
P/LP submissions
0%
P/LP missense
0.25
LOEUF· LoF intol.
LOF
Mechanism· predicted
Clinical Summary— NFE2L1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
9 unique Pathogenic / Likely Pathogenic· 107 VUS of 128 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.25LOEUF
pLI 0.998
Z-score 4.65
OE 0.10 (0.04–0.25)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.76Z-score
OE missense 0.77 (0.70–0.84)
343 obs / 447.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.10 (0.04–0.25)
0≤0.351.4
Missense OE0.77 (0.70–0.84)
0≤0.61.4
Synonymous OE1.01
0≤1.21.6
LoF obs/exp: 3 / 30.9Missense obs/exp: 343 / 447.5Syn Z: -0.12
DN
0.4091th %ile
GOF
0.3789th %ile
LOF
0.80top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.25

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

128 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic1
VUS107
Likely Benign2
Benign1
8
Pathogenic
1
Likely Pathogenic
107
VUS
2
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
105
2
0
107
Likely Benign
0
1
1
0
2
Benign
0
0
0
1
1
Total0106121119

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

View in ClinVar →

Protein Context — Lollipop Plot

NFE2L1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients