IREB2

Chr 15AR

iron responsive element binding protein 2

Also known as: ACO3, IRE-BP 2, IRE-BP2, IRP2, IRP2AD, NDCAMA

NCBI Gene: 3658ENSG00000136381UniProt: P48200

The protein encoded by this gene is an RNA-binding protein that acts to regulate iron levels in the cells by regulating the translation and stability of mRNAs that affect iron homeostasis under conditions when iron is depleted. When iron levels are low, this protein binds to iron-responsive elements (IRES), stem-loop structures located either in the 5' or 3' UTRs. Binding to the 5' UTR represses translation, while binding to the 3' UTR inhibits mRNA degradation. When iron is found in the cell, this protein is degraded in a F-box and leucine rich repeat protein 5-dependent manner. Variants in this gene have been associated with lung cancer and chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

Primary Disease Associations & Inheritance

Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemiaMIM #618451
AR
0
Active trials
21
Pathogenic / LP
306
ClinVar variants
33
Pubs (1 yr)
2.0
Missense Z
0.22
LOEUF· LoF intolerant
Clinical Summary— IREB2
⚡
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
21 Pathogenic / Likely Pathogenic· 152 VUS of 306 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.22LOEUF
pLI 1.000
Z-score 5.98
OE 0.11 (0.06–0.22)
Highly constrained

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

Missense Constraint
2.03Z-score
OE missense 0.75 (0.69–0.81)
378 obs / 506.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.11 (0.06–0.22)
0≤0.351.4
Missense OE0.75 (0.69–0.81)
0≤0.61.4
Synonymous OE1.02
0≤1.21.6
LoF obs/exp: 6 / 53.0Missense obs/exp: 378 / 506.8Syn Z: -0.22
LOF
DN
0.4587th %ile
GOF
0.4677th %ile
LOF
0.64top 25%

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

LOFprediction above median · LOEUF 0.22

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

306 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic4
VUS152
Likely Benign109
Benign23
Conflicting1
17
Pathogenic
4
Likely Pathogenic
152
VUS
109
Likely Benign
23
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
4
0
4
VUS
2
139
10
1
152
Likely Benign
0
10
44
55
109
Benign
0
3
16
4
23
Conflicting
—1
Total21529160306

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

View in ClinVar →

IREB2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

IREB2-related neurodevelopmental disorder

moderate
ARUndeterminedAbsent Gene Product, Altered Gene Product Structure, Decreased Gene Product Level
Dev. Disorders
G2P ↗
stop gainedmissense variantinframe deletion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
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
Inhibiting ubiquitin-specific protease 38 safeguards against diabetic nephropathy by limiting tubular epithelial cell ferroptotic death through the suppression of IREB2-mediated iron overload.
Gao S et al.·Int Immunopharmacol
2026
The D826V point mutation in IREB2 induces lipogenesis in adipose tissues.
Lv Y et al.·Front Cell Dev Biol
2026Open Access
Integrative GWAS and Mendelian Randomization Analysis Identifies IREB2 and CD27+ Memory B Cells as Core Drivers of COPD to Lung Cancer Progression.
Yi E et al.·MedComm (2020)
2025Open Access
The D826V point mutation in IREB2 causes early-onset neurodegeneration in mice.
Guo Z et al.·Acta Biochim Biophys Sin (Shanghai)
2025
Exploring the Associations Between CHRNA5 and IREB2 Gene Polymorphisms and COPD in the Kazakhstan Population.
Akparova A et al.·Biomedicines
2025Open Access
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