NFE2L2

Chr 2AD

NFE2 like bZIP transcription factor 2

Also known as: IMDDHH, NRF2, Nrf-2

NCBI Gene: 4780 ENSG00000116044 UniProt: Q16236 OMIM: 600492

The protein encoded by this gene is a transcription factor that regulates cellular antioxidant response by binding to antioxidant response elements and promoting expression of cytoprotective genes that neutralize oxidative stress. Mutations cause autosomal dominant developmental delay with seizures and reduced sensitivity to oxidative stress, typically presenting in infancy. The gene is highly constrained against loss-of-function variants, indicating that normal protein function is essential for development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.661 OMIM phenotype

Clinical Summary— NFE2L2

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Gene-Disease Validity (ClinGen)

immunodeficiency, developmental delay, and hypohomocysteinemia · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 229 VUS of 427 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.004

Z-score 2.74

OE 0.37 (0.21–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.81 (0.73–0.90)

252 obs / 312.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.21–0.66)

0≤0.351.4

Missense OE?0.81 (0.73–0.90)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 8 / 21.8Missense obs/exp: 252 / 312.1Syn Z: 0.84

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNFE2L2-related leukoencephalopathy, immune deficiency and hypohomocysteinaemiaGOFAD

This gene — mechanism propensity

0.5868th %ile

GOF

0.3986th %ile

LOF

0.4528th %ile

The Badonyi & Marsh model scores dominant-negative highest, but genomic evidence most strongly supports gain-of-function as the primary mechanism.

GOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFOverall, the findings suggested that the mutations increased NFE2L2 levels in the absence of stress and caused constitutive chronic activation of stress response genes, consistent with a gain-of-function effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 29018201 ↗

ClinVar Variant Classifications

427 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS229

Likely Benign137

Benign33

Conflicting13

Pathogenic

Likely Pathogenic

229

VUS

137

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	3	0	0	3
Likely Pathogenic	0	2	0	0	2
VUS	22	204	3	0	229
Likely Benign	2	15	21	99	137
Benign	0	26	4	3	33
Conflicting	—				13
Total	24	250	28	102	417

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap NFE2L2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →