IRF4

Chr 6ADAR

interferon regulatory factor 4

Also known as: IMD131, LSIRF, MUM1, NF-EM5, SHEP8

NCBI Gene: 3662ENSG00000137265UniProt: Q15306

The protein encoded by this gene belongs to the IRF (interferon regulatory factor) family of transcription factors, characterized by an unique tryptophan pentad repeat DNA-binding domain. The IRFs are important in the regulation of interferons in response to infection by virus, and in the regulation of interferon-inducible genes. This family member is lymphocyte specific and negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of innate and adaptive immune systems. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2010]

Primary Disease Associations & Inheritance

[Skin/hair/eye pigmentation, variation in, 8]MIM #611724
Immunodeficiency 131MIM #621097
ADAR
UniProtMultiple myeloma
419
ClinVar variants
63
Pathogenic / LP
0.86
pLI score
3
Active trials
Clinical Summary— IRF4
🧬
Gene-Disease Validity (ClinGen)
combined immunodeficiency · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
63 Pathogenic / Likely Pathogenic· 158 VUS of 419 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.38LOEUF
pLI 0.857
Z-score 3.78
OE 0.17 (0.08–0.38)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.85Z-score
OE missense 0.52 (0.45–0.59)
144 obs / 277.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.08–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.45–0.59)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 4 / 24.0Missense obs/exp: 144 / 277.9Syn Z: 0.31

ClinVar Variant Classifications

419 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic4
VUS158
Likely Benign156
Benign37
Conflicting5
59
Pathogenic
4
Likely Pathogenic
158
VUS
156
Likely Benign
37
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
3
56
0
59
Likely Pathogenic
0
0
4
0
4
VUS
5
126
25
2
158
Likely Benign
0
19
35
102
156
Benign
0
5
28
4
37
Conflicting
—5
Total5153148108419

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

View in ClinVar →

Protein Context — Lollipop Plot

IRF4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

[Skin/hair/eye pigmentation, variation in, 8]

MIM #611724

Molecular basis of disorder known

Immunodeficiency 131

MIM #621097

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Human dendritic cell subsets: an update.
Collin M et al.·Immunology
2018Review
Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies.
Nicosia L et al.·Cancer Cell
2023
Simplified algorithm for genetic subtyping in diffuse large B-cell lymphoma.
Shen R et al.·Signal Transduct Target Ther
2023
Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers.
Paus R et al.·J Invest Dermatol
2024Review
Follicular lymphoma and marginal zone lymphoma: how many diseases?
Laurent C et al.·Virchows Arch
2023Review
BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells.
Seo H et al.·Nat Immunol
2021
Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis.
Tavasolian F et al.·Ann Rheum Dis
2023Cohort
A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.
IRF4 International Consortium et al.·Sci Immunol
2023
Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.
Byun J et al.·Nat Genet
2022Meta-analysis
Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.
Mandula JK et al.·Immunity
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Immunometabolism of IRF4 in Adipose, Muscle, and Immune Cells Influences Obesity and MASLD.
Marko DM et al.·Am J Physiol Endocrinol Metab
2026
HTLV-1 Tax Reshapes the DNA-Binding Pattern of Transcription Factor IRF4 and Disrupts Host Gene Regulation.
Tosaka S et al.·Cancer Sci
2026
Insulin and adipocyte IRF4 promote fat retention over muscle preservation during intermittent fasting in obesity.
Marko DM et al.·Cell Rep
2026
Dexamethasone-loaded glycyrrhiza protein nanoparticles reprogram macrophages to an anti-inflammatory phenotype via STAT6/IRF4 activation for alleviating sepsis-induced acute respiratory distress syndrome.
Wang X et al.·Nanotechnology
2026
Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma.
Tang K et al.·Adv Sci (Weinh)
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Diffuse Large B-Cell Lymphoma Associated With Chronic InflammationEBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise SpecifiedHigh Grade B-Cell Lymphoma, Not Otherwise Specified

Zanubrutinib and CAR T-cell Therapy for the Treatment of Recurrent or Refractory Aggressive B-cell Non-Hodgkin's Lymphoma or Transformed Indolent B-cell Lymphoma

ACTIVE NOT RECRUITING
NCT05202782Phase PHASE2Northwestern UniversityStarted 2022-03-21
Chimeric Antigen Receptor T-Cell TherapyQuality-of-Life AssessmentQuestionnaire Administration
Mature B-Cell NeoplasmNon Hodgkin LymphomaDLBCL

Study of SGR-1505 in Mature B-Cell Neoplasms

RECRUITING
NCT05544019Phase PHASE1Schrödinger, Inc.Started 2023-04-10
SGR-1505
Diffuse Large B Cell Lymphoma

Mixed Molecular Clinical Index (MMCI) in Diffuse Large B-cell Lymphoma (DLBCL)

RECRUITING
NCT04300101Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCSStarted 2020-05-14
Prospective cohortRetrospective cohort

External Resources

Links to major genomics databases and tools