IREB2

Chr 15

iron responsive element binding protein 2

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

NCBI Gene: 3658 ENSG00000136381 UniProt: P48200

This protein binds to iron-responsive elements in mRNAs to regulate cellular iron homeostasis by controlling translation of ferritin and stability of transferrin receptor mRNA. Biallelic mutations cause autosomal recessive neurodegeneration with early-onset choreoathetoid movements and microcytic anemia. The gene is highly constrained against loss-of-function variants (pLI 0.999), suggesting that complete loss of protein function is poorly tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.22

Clinical Summary— IREB2

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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.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 149 VUS of 300 total submissions

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.11 (0.06–0.22)

0≤0.351.4

Missense OE?0.75 (0.69–0.81)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 6 / 53.0Missense obs/exp: 378 / 506.8Syn Z: -0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateIREB2-related neurodevelopmental disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4587th %ile

GOF

0.4677th %ile

LOF

0.64top 25%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

300 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS149

Likely Benign108

Benign23

Conflicting1

Likely Pathogenic

149

VUS

108

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	2	0	0	0	2
VUS	2	141	5	1	149
Likely Benign	0	10	43	55	108
Benign	0	3	16	4	23
Conflicting	—				1
Total	4	154	64	60	283

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap IREB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →