IRF8

Chr 16ADAR

interferon regulatory factor 8

Also known as: H-ICSBP, ICSBP, ICSBP1, IMD32A, IMD32B, IRF-8

NCBI Gene: 3394 ENSG00000140968 UniProt: Q02556 OMIM: 601565

The IRF8 protein is a transcription factor that regulates interferon and interferon-inducible genes and is essential for the development and function of immune cells including dendritic cells and macrophages. Mutations cause immunodeficiency with susceptibility to mycobacterial infections, with autosomal dominant mutations causing mycobacteriosis and autosomal recessive mutations causing monocyte and dendritic cell deficiency. IRF8 is highly constrained against loss-of-function mutations in the general population, reflecting its critical role in immune system development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Interferon consensus sequence-binding protein (ICSBP) is a transcription factor of the interferon (IFN) regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta. IRF family proteins also control expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.342 OMIM phenotypes

Clinical Summary— IRF8

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.95). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

4 unique Pathogenic / Likely Pathogenic· 221 VUS of 441 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.34LOEUF

pLI 0.948

Z-score 3.81

OE 0.13 (0.06–0.34)

Highly constrained

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

Missense Constraint?

1.19Z-score

OE missense 0.80 (0.71–0.89)

220 obs / 275.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.34)

0≤0.351.4

Missense OE?0.80 (0.71–0.89)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 3 / 22.5Missense obs/exp: 220 / 275.5Syn Z: -1.67

This gene — mechanism propensity

0.4190th %ile

GOF

0.3392th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.34

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

441 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic2

VUS221

Likely Benign184

Benign22

Conflicting7

Pathogenic

Likely Pathogenic

221

VUS

184

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	0	2	0	0	2
VUS	10	191	13	7	221
Likely Benign	0	4	61	119	184
Benign	0	0	11	11	22
Conflicting	—				7
Total	11	198	85	137	438

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

View in ClinVar →

45 pathogenic / likely-pathogenic (of 57) ClinVar copy-number / structural variants overlap IRF8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →