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GeneE
27 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
IRF6
interferon regulatory factor 6
Chromosome 1 Β· 1q32.2
NCBI Gene: 3664Ensembl: ENSG00000117595.14HGNC: HGNC:6121UniProt: G0Z349
201PubMed Papers
23Diseases
0Drugs
124Pathogenic Variants
FUNCTIONAL ROLE
Highly ConstrainedTranscription Factor
RESEARCH IMPACT
TrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
cytoplasmcytosolnegative regulation of cell population proliferationprotein bindingvan der Woude syndrome 1popliteal pterygium syndromevan der Woude syndromeautosomal dominant popliteal pterygium syndrome
✦AI Summary

IRF6 is a sequence-specific DNA-binding transcription factor that functions as a critical regulator of epithelial differentiation and development. As a member of the interferon regulatory factor family 1, IRF6 plays a key role in the keratinocyte proliferation-differentiation switch essential for epidermal development. Recent mechanistic studies reveal that glucose directly binds IRF6, enabling its dimerization, DNA binding, and transcriptional activation of pro-differentiation genes including GRHL1, GRHL3, HOPX, and PRDM1 2. Beyond skin, IRF6 regulates mammary epithelial cell differentiation and is autonomously required for osteoblast differentiation and bone mineralization in craniofacial tissues 3. IRF6 mutations cause non-syndromic orofacial clefts (NSOC), the most common craniofacial malformation, making it the best-documented NSOC susceptibility gene 4. Genetic studies identified a Finnish-enriched variant (rs570516915) that impairs IRF6 autoregulation through altered transcription factor binding in an upstream enhancer, specifically increasing cleft palate risk 5. Additionally, IRF6 mutations are frequently detected in head and neck squamous cell carcinoma, where dysregulation of genes controlling squamous differentiationβ€”including IRF6β€”drives carcinogenesis 6. Emerging evidence suggests IRF6 involvement in Alzheimer's disease pathology, where its expression is modulated by APOE-Ξ΅4 status 7.

Sources cited
1
Glucose directly binds IRF6, enabling dimerization, DNA binding, and activation of pro-differentiation target genes
PMID: 40120584
2
IRF6 is a member of the interferon regulatory factor transcription factor family
PMID: 11244049
3
IRF6 plays an autonomous role in osteoblast differentiation and bone mineralization in craniofacial tissues
PMID: 30684382
4
IRF6 is the best-documented susceptibility gene for non-syndromic orofacial clefts
PMID: 38546517
5
IRF6 variant rs570516915 impairs IRF6 autoregulation through altered enhancer activity, increasing cleft palate risk
PMID: 39500877
6
IRF6 mutations are frequent in head and neck squamous cell carcinoma, implicating squamous differentiation dysregulation in carcinogenesis
PMID: 21798893
7
IRF6 expression is modulated by APOE-Ξ΅4 status and associated with Alzheimer's disease
PMID: 39169269
Disease Associationsβ“˜23
van der Woude syndrome 1Open Targets
0.82Strong
popliteal pterygium syndromeOpen Targets
0.80Strong
van der Woude syndromeOpen Targets
0.75Strong
autosomal dominant popliteal pterygium syndromeOpen Targets
0.69Moderate
cleft palateOpen Targets
0.65Moderate
IRF6-related conditionOpen Targets
0.62Moderate
cleft lipOpen Targets
0.60Moderate
genetic disorderOpen Targets
0.48Moderate
orofacial cleftOpen Targets
0.42Moderate
tooth agenesisOpen Targets
0.39Weak
OligodontiaOpen Targets
0.38Weak
Lip pitOpen Targets
0.37Weak
orofacial cleft 1Open Targets
0.35Weak
dental cariesOpen Targets
0.27Weak
orofacial cleft 10Open Targets
0.16Weak
Selective tooth agenesisOpen Targets
0.14Weak
neoplasmOpen Targets
0.10Suggestive
nonpapillary renal cell carcinomaOpen Targets
0.10Suggestive
breast cancerOpen Targets
0.09Suggestive
androgenetic alopeciaOpen Targets
0.09Suggestive
Non-syndromic orofacial cleft 6UniProt
Popliteal pterygium syndromeUniProt
Van der Woude syndrome 1UniProt
Pathogenic Variants124
NM_006147.4(IRF6):c.749G>A (p.Arg250Gln)Pathogenic
Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome;Van der Woude syndrome|IRF6-related condition|Van der Woude syndrome
β˜…β˜…β˜†β˜†2026β†’ Residue 250
NM_006147.4(IRF6):c.1234C>T (p.Arg412Ter)Pathogenic
Van der Woude syndrome 1|Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome;Van der Woude syndrome|not provided|Van der Woude syndrome
β˜…β˜…β˜†β˜†2025β†’ Residue 412
NM_006147.4(IRF6):c.748C>T (p.Arg250Ter)Pathogenic
Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome;Van der Woude syndrome|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 250
NM_006147.4(IRF6):c.250C>T (p.Arg84Cys)Pathogenic
Popliteal pterygium syndrome|not provided|Autosomal dominant popliteal pterygium syndrome|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to|IRF6-related condition|Van der Woude syndrome
β˜…β˜…β˜†β˜†2025β†’ Residue 84
NM_006147.4(IRF6):c.16dup (p.Arg6fs)Pathogenic
Inborn genetic diseases|Van der Woude syndrome 1
β˜…β˜…β˜†β˜†2025β†’ Residue 6
NM_006147.4(IRF6):c.889G>A (p.Val297Ile)Likely pathogenic
Van der Woude syndrome;Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome|Van der Woude syndrome 1
β˜…β˜…β˜†β˜†2025β†’ Residue 297
NM_006147.4(IRF6):c.1060+1G>APathogenic
Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome;Van der Woude syndrome|Inborn genetic diseases|not provided
β˜…β˜…β˜†β˜†2025
NM_006147.4(IRF6):c.16C>T (p.Arg6Cys)Pathogenic
Van der Woude syndrome 1|Cleft palate|not provided|Popliteal pterygium syndrome;Van der Woude syndrome 1;Orofacial cleft 6, susceptibility to|IRF6-related condition|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to
β˜…β˜…β˜†β˜†2025β†’ Residue 6
NM_006147.4(IRF6):c.1198C>T (p.Arg400Trp)Pathogenic
Van der Woude syndrome 1|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to
β˜…β˜…β˜†β˜†2025β†’ Residue 400
NM_006147.4(IRF6):c.25C>T (p.Arg9Trp)Pathogenic
not provided|Van der Woude syndrome 1|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to|IRF6-related condition
β˜…β˜…β˜†β˜†2024β†’ Residue 9
NM_006147.4(IRF6):c.859C>T (p.Gln287Ter)Pathogenic
not provided|Van der Woude syndrome 1;Orofacial cleft 6, susceptibility to;Autosomal dominant popliteal pterygium syndrome
β˜…β˜…β˜†β˜†2024β†’ Residue 287
NM_006147.4(IRF6):c.1210G>A (p.Glu404Lys)Pathogenic
Van der Woude syndrome 1|not provided|Van der Woude syndrome;Popliteal pterygium syndrome;Orofacial cleft 6, susceptibility to|Van der Woude syndrome 1;Orofacial cleft 6, susceptibility to;Autosomal dominant popliteal pterygium syndrome
β˜…β˜…β˜†β˜†2024β†’ Residue 404
NM_006147.4(IRF6):c.454C>T (p.Gln152Ter)Pathogenic
not provided|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to|IRF6-related condition
β˜…β˜…β˜†β˜†2023β†’ Residue 152
NM_006147.4(IRF6):c.251G>A (p.Arg84His)Pathogenic
Popliteal pterygium syndrome|not provided|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to|Van der Woude syndrome 1|Autosomal dominant popliteal pterygium syndrome
β˜…β˜…β˜†β˜†2023β†’ Residue 84
NM_006147.4(IRF6):c.226C>T (p.Pro76Ser)Pathogenic
not provided|Popliteal pterygium syndrome;Van der Woude syndrome;Orofacial cleft 6, susceptibility to
β˜…β˜…β˜†β˜†2022β†’ Residue 76
NM_006147.4(IRF6):c.133del (p.Arg45fs)Pathogenic
Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome;Van der Woude syndrome|IRF6-related condition
β˜…β˜…β˜†β˜†2022β†’ Residue 45
NM_006147.4(IRF6):c.119G>A (p.Trp40Ter)Pathogenic
Van der Woude syndrome
β˜…β˜†β˜†β˜†2026β†’ Residue 40
NM_006147.4(IRF6):c.691C>T (p.Gln231Ter)Pathogenic
Van der Woude syndrome
β˜…β˜†β˜†β˜†2026β†’ Residue 231
NM_006147.4(IRF6):c.365C>A (p.Ser122Ter)Pathogenic
Orofacial cleft 6, susceptibility to;Popliteal pterygium syndrome;Van der Woude syndrome
β˜…β˜†β˜†β˜†2026β†’ Residue 122
NM_006147.4(IRF6):c.797T>C (p.Phe266Ser)Pathogenic
Van der Woude syndrome 1
β˜…β˜†β˜†β˜†2025β†’ Residue 266
View on ClinVar β†—
Related Genes
MSX1Protein interaction98%GRHL3Protein interaction83%MAFBProtein interaction81%VAX1Protein interaction79%RIPK4Protein interaction78%NECTIN1Protein interaction76%
Tissue Expression6 tissues
Heart
100%
Brain
99%
Liver
72%
Bone Marrow
33%
Lung
13%
Ovary
5%
Gene Interaction Network
Click a node to explore
IRF6MSX1GRHL3MAFBVAX1RIPK4NECTIN1
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt O14896
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.21Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.10 [0.05–0.21]
RankingsWhere IRF6 stands among ~20K protein-coding genes
  • #2,096of 20,598
    Most Researched201 Β· top quartile
  • #634of 5,498
    Most Pathogenic Variants124 Β· top quartile
  • #533of 17,882
    Most Constrained (LOEUF)0.21 Β· top 5%
Genes detectedIRF6
Sources retrieved27 papers
Response timeβ€”
πŸ“„ Sources
27β–Ό
1
The mutational landscape of head and neck squamous cell carcinoma.
PMID: 21798893
Science Β· 2011
1.00
2
PMID: 20301581
0.90
3
IRF family of transcription factors as regulators of host defense.
PMID: 11244049
Annu Rev Immunol Β· 2001
0.80
4
Identification of functional non-coding variants associated with orofacial cleft.
PMID: 40670354
Nat Commun Β· 2025
0.76
5
Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation.
PMID: 40120584
Cell Stem Cell Β· 2025
0.70