IRF6

Summary

IRF6 (interferon regulatory factor 6, HGNC:6121) is a protein-coding gene on chromosome 1q32.2, encoding Interferon regulatory factor 6 (O14896). Probable DNA-binding transcriptional activator. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly-conserved N-terminal helix-turn-helix DNA-binding domain and a less conserved C-terminal protein-binding domain. The encoded protein may be a transcriptional activator. Mutations in this gene can cause van der Woude syndrome and popliteal pterygium syndrome. Mutations in this gene are also associated with non-syndromic orofacial cleft type 6. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 3664 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IRF6-related condition (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 385 total — 79 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 101
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 270 downstream targets (CollecTRI)
• MANE Select transcript: NM_006147

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6121
Approved symbol	IRF6
Name	interferon regulatory factor 6
Location	1q32.2
Locus type	gene with protein product
Status	Approved
Aliases	OFC6, VWS1
Ensembl gene	ENSG00000117595
Ensembl biotype	protein_coding
OMIM	607199
Entrez	3664

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000367021, ENST00000456314, ENST00000464698, ENST00000542854, ENST00000643798, ENST00000696134, ENST00000863915, ENST00000863916, ENST00000863917, ENST00000863918, ENST00000927431, ENST00000950196, ENST00000950197, ENST00000950198

RefSeq mRNA: 2 — MANE Select: NM_006147 NM_001206696, NM_006147

CCDS: CCDS1492, CCDS55681

Canonical transcript exons

ENST00000367021 — 9 exons

Exon	Start	End
ENSE00000792130	209789667	209789785
ENSE00000792131	209790495	209790887
ENSE00000792132	209792269	209792427
ENSE00000792133	209795290	209795418
ENSE00001010326	209801972	209802043
ENSE00001443262	209785617	209788644
ENSE00001443263	209801240	209801416
ENSE00001443264	209805947	209806142
ENSE00003549011	209796348	209796552

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 98.72.

FANTOM5 (CAGE): breadth broad, TPM avg 11.5321 / max 440.4409, expressed in 701 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17314	8.2765	674
17312	2.5809	267
17313	0.3069	158
17311	0.2436	78
17308	0.0569	21
17310	0.0440	16
17309	0.0234	9

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.72	gold quality
upper leg skin	UBERON:0004262	98.26	gold quality
esophagus squamous epithelium	UBERON:0006920	97.78	gold quality
squamous epithelium	UBERON:0006914	97.62	gold quality
gingival epithelium	UBERON:0001949	97.30	gold quality
skin of abdomen	UBERON:0001416	97.03	gold quality
cervix squamous epithelium	UBERON:0006922	96.95	silver quality
gingiva	UBERON:0001828	96.83	gold quality
skin of leg	UBERON:0001511	96.61	gold quality
skin of hip	UBERON:0001554	96.51	gold quality
pancreatic ductal cell	CL:0002079	96.43	gold quality
zone of skin	UBERON:0000014	96.37	gold quality
tongue squamous epithelium	UBERON:0006919	96.36	gold quality
hair follicle	UBERON:0002073	96.30	gold quality
epithelium of esophagus	UBERON:0001976	96.23	gold quality
lower esophagus mucosa	UBERON:0035834	96.19	gold quality
esophagus mucosa	UBERON:0002469	95.88	gold quality
oocyte	CL:0000023	95.85	gold quality
oviduct epithelium	UBERON:0004804	95.54	gold quality
upper arm skin	UBERON:0004263	95.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.55	gold quality
ileal mucosa	UBERON:0000331	94.32	gold quality
cervix epithelium	UBERON:0004801	94.20	gold quality
epithelium of nasopharynx	UBERON:0001951	93.93	gold quality
epithelium of mammary gland	UBERON:0003244	93.30	gold quality
mammalian vulva	UBERON:0000997	93.01	gold quality
mammary duct	UBERON:0001765	92.87	gold quality
corpus epididymis	UBERON:0004359	92.71	gold quality
colonic mucosa	UBERON:0000317	92.61	gold quality
rectum	UBERON:0001052	92.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	1377.05
E-GEOD-86618	yes	402.67
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

270 targets.

Target	Regulation
ABCC3
ABCC8
ACOT11
ACSL1
ADAM2
ADIPOQ
ADM
AKT1
ALB
ALOX5
ALOX5AP
AP1
APC
APOE
AQP5
AR
AVP
BAG3
BAMBI
BCL2
BTK
CALCA
CARM1
CASP4
CAT
CBR3
CCL2
CCL3
CCL4
CCL5	Activation

JASPAR motifs

Motif	Name	Family
MA1509.1	IRF6	Interferon-regulatory factors

JASPAR matrix evidence (PMIDs): PMID:18604160

Upstream regulators (CollecTRI, top): AHR, AP1, ATF2, BCL3, CEBPB, CEBPD, CEBPG, EGR1, HIF1A, IRF1, IRF6, JUN, LITAF, NFKB1, NFKB, NFKBID, NONO, PARP1, RARA, RAX, REL, RELA, SP1, SPI1, TCF3, TFAP2A, TP53, TP63, TXK

miRNA regulators (miRDB)

132 targeting IRF6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-338-5P	99.92	72.34	2951

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes (PMID:12219090)
• An identification of three missense mutatins and one nonsense mutation in IRF6 (PMID:12920575)
• mutated IRF6 gene is associated with impaired morphogenesis of the lip and palate opf Van der Woude syndrome in a dominant-negative manner (PMID:12964020)
• six new van der Woude syndrome families with novel causative missense mutations in the IRF6 gene affecting the DNA binding domain or the protein binding domain. (PMID:14757865)
• A novel mutation (W217X) of the IRF6 gene in an Italian family with Van der Woude syndrome has been studied. (PMID:15013698)
• DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling. (PMID:15317890)
• there may be a dominant negative effect of the p.Arg84Gly mutation of the IRF6 gene in Van Der Woude syndrome (PMID:15647839)
• findings help to elucidate the molecular mechanisms of maspin and suggest an interactive role between maspin and IRF6 in regulating cellular phenotype, the loss of which can lead to neoplastic transformation (PMID:16049006)
• Our independent study group confirms that the IRF6 locus is associated with nonsyndromic cleft lip with or without palate and shows for the first time the implication of IRF6 in isolated CL/P in northern Europe. (PMID:16132054)
• A broad spectrum of IRF6 mutations is found in the Van der Woude and popliteal pterygium syndrome phenotypes originating in 17 kindreds from Finland, Sweden, Norway, Thailand and Singapore. (PMID:16160700)
• Three novel mutations (Y111H, S407fsX436, F165fsX166) as well as a recurrent mutation (R400W) were identified in the IRF6 gene from Chinese families with Van der Woude syndrome. (PMID:16211254)
• This study reports 11 Chinese families with variable clinical phenotypes of Van der Woude syndrome and identified mutations in all patients. Of the 11 mutations, 8 appeared to be novel: CC5.6GT, T342A, 566delA, C748T, C756A, C989A, C1209G, and 1316delT. (PMID:16998136)
• Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. (PMID:17041603)
• Data suggest that preferential premolar agenesis is associated with FGFR and IRF6. (PMID:17318851)
• the contribution of IRF6 gene to susceptibility of oral clefts across different populations; however, the specific single nucleotide polymorphisms showing statistical significance differed among ethnic groups (PMID:17438386)
• A novel codon nonsense mutation in IRF6 is reported in a German family with Van der Woude syndrome. (PMID:17549393)
• Screening for mutations at the IRF6 gene detected a pathogenic mutation (c.960G>C) in the propositus and in his mother; and a single nucleotide polymorphism (c.175-5C>G) in the propositus and in his father. (PMID:17551329)
• This review summarizes the variation in IRF6 as the most significant genetic contributor to cases of nonsyndromic oral facial cleft in the South American population. (PMID:17702008)
• an unidentified CL/P gene, or a non-coding IRF6 regulatory element in this linkage interval may have caused CL/P in this family. (PMID:17937438)
• mutations of the IRF6 gene are not a common cause for cleft predisposition in Swedish non-syndromic cleft lip and palate families (PMID:18209213)
• In quiescent cells, IRF6 is mostly nonphosphorylated. Cell proliferation leads to rapid IRF6 phosphorylation & proteasome-dependent IRF6 degradation. IRF6 & maspin, promote mammary epithelial cell differentiation by facilitating entry into the G(0) phase. (PMID:18212048)
• Mutation screening in the IRF6-gene in patients with apparently nonsyndromic orofacial clefts. (PMID:18247422)
• These findings support a role for IRF6 variants in clefting of the lip and provide specific risk estimates in a Norwegian population. (PMID:18278815)
• A haplotype involving the most 5’IRF6 markers was associated with sporadic tooth agenesis (p=0.006). (PMID:18452891)
• Several mutations in the interferon regulatory factor 6 (IRF6) gene have been found in families with Van der Woude syndrome, suggesting that this gene is the primary locus. (PMID:18506368)
• findings are consistent with the association of IRF6 gene variations in nonsyndromic cleft lip and palate (PMID:18798331)
• Novel IRF6 mutations in patients affected by Van der Woude syndrome were identified by screening 2 Brazilian families, sequencing the entire IRF6-coding region and flanking intronic boundaries. (PMID:18813858)
• These findings place IRF6 and AP-2alpha in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder. (PMID:18836445)
• The mutations found in the IRF6 of Van der Woude syndrome and popliteal pterygium syndrome patients inhibit its DNA binding and transcriptional activation functions. (PMID:19036739)
• present findings indicate that the 820A allele is more frequent in the Chinese cleft palate (without cleft lip) population and may confer an increased risk for cleft palate in these individuals (PMID:19115793)
• Results show that the type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. (PMID:19282774)
• Includes the study of a disease-related upstream ORF in this gene, and shows that it functions to reduce protein levels by ~96%. (PMID:19372376)
• Single nucleotide polymorphisms in IRF6 is associated with nonsyndromic orofacial clefts. (PMID:19388848)
• MTHFR 677TT alone and IRF6 820GG together with MTHFR 677CT, but not MTHFR A1298C, are risks for nonsyndromic cleft lip with or without cleft palate in an Indian population. (PMID:19419265)
• study presents mutations in IRF6 in nonsyndromic cleft lip with or without cleft palate without or with atypical lower lip pits (PMID:19449419)
• results support the hypothesis that IRF6 and Maspin are important for mammary epithelial cell differentiation. (PMID:19527266)
• The Van der Woude syndrome is a mendelian CL/P, accounting for about 2% of all cases and caused by mutations in the interferon regulatory factor 6 (IRF6) gene, located on 1q32.2 chromosome. (PMID:19536562)
• Study demonstrates that three candidate single nucleotide polymorphisms within IRF6 are significantly associated with nonsyndromic cleft lip with or without cleft palate in the Honduran population. (PMID:19536891)
• Strong evidence of over- and under-transmission of the C allele (the Val allele) at rs2235371, and the C allele at rs2235375 in cleft case-parent trios. Five specific haplotypes showed significant over- and under-transmission. (PMID:19734457)
• findings are consistent with a lack of involvement of IRF6 rs2235371 and rs642961 polymorphisms in the NSCL/P pathogenesis in the Brazilian population. (PMID:19780991)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	irf6	ENSDARG00000101986
mus_musculus	Irf6	ENSMUSG00000026638
rattus_norvegicus	Irf6	ENSRNOG00000005082

Paralogs (8): IRF1 (ENSG00000125347), IRF3 (ENSG00000126456), IRF5 (ENSG00000128604), IRF4 (ENSG00000137265), IRF8 (ENSG00000140968), IRF2 (ENSG00000168310), IRF7 (ENSG00000185507), IRF9 (ENSG00000213928)

Protein

Protein identifiers

Interferon regulatory factor 6 — O14896 (reviewed: O14896)

All UniProt accessions (5): A0A2R8YHF3, A0A8Q3WL17, B1AJU4, O14896, G0Z349

UniProt curated annotations — full annotation on UniProt →

Function. Probable DNA-binding transcriptional activator. Key determinant of the keratinocyte proliferation-differentiation switch involved in appropriate epidermal development. Plays a role in regulating mammary epithelial cell proliferation. May regulate WDR65 transcription.

Subunit / interactions. Interacts with SERPINB5.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Expressed in normal mammary epithelial cells. Expression is reduced or absent in breast carcinomas.

Post-translational modifications. Phosphorylated. Phosphorylation status depends on the cell cycle and is a signal for ubiquitination and proteasome-mediated degradation.

Disease relevance. Van der Woude syndrome 1 (VWS1) [MIM:119300] An autosomal dominant developmental disorder characterized by lower lip pits, cleft lip and/or cleft palate. The disease is caused by variants affecting the gene represented in this entry. Popliteal pterygium syndrome (PPS) [MIM:119500] An autosomal dominant disorder characterized by oro-facial, skin and genital anomalies. Expressivity is variable. Clinical features include cleft lip/palate, lower lip cysts, syngnathia, congenital ankyloblepharon filiforme in some cases, bifid scrotum, hypoplastic scrotum, hypoplastic uterus, talipes equinovarus. The disease is caused by variants affecting the gene represented in this entry. Non-syndromic orofacial cleft 6 (OFC6) [MIM:608864] A birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the IRF family.

Isoforms (2)

UniProt ID	Names	Canonical?
O14896-1	1	yes
O14896-2	2

RefSeq proteins (2): NP_001193625, NP_006138* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001346	Interferon_reg_fact_DNA-bd_dom	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR017855	SMAD-like_dom_sf	Homologous_superfamily
IPR019471	Interferon_reg_factor-3	Domain
IPR019817	Interferon_reg_fac_CS	Conserved_site
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00605, PF10401

UniProt features (52 total): sequence variant 46, compositionally biased region 2, chain 1, DNA-binding region 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14896-F1	74.19	0.44

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-913531	Interferon Signaling

MSigDB gene sets: 439 (showing top): LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, JAEGER_METASTASIS_DN, GOBP_KERATINOCYTE_PROLIFERATION, AREB6_03, GOBP_MAMMARY_GLAND_EPITHELIUM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MAMMARY_GLAND_EPITHELIAL_CELL_DIFFERENTIATION, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_UP, RICKMAN_METASTASIS_DN, UEDA_PERIFERAL_CLOCK

GO Biological Process (20): immune system process (GO:0002376), regulation of transcription by RNA polymerase II (GO:0006357), negative regulation of cell population proliferation (GO:0008285), negative regulation of keratinocyte proliferation (GO:0010839), keratinocyte differentiation (GO:0030216), keratinocyte proliferation (GO:0043616), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), cell development (GO:0048468), roof of mouth development (GO:0060021), limb development (GO:0060173), mammary gland epithelial cell differentiation (GO:0060644), stem cell proliferation (GO:0072089), cranial skeletal system development (GO:1904888), negative regulation of stem cell proliferation (GO:2000647), regulation of DNA-templated transcription (GO:0006355), cell population proliferation (GO:0008283), epidermis development (GO:0008544), cell differentiation (GO:0030154), skin development (GO:0043588)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), protein binding (GO:0005515)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Interferon Signaling	2
Immune System	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
anatomical structure development	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
cell population proliferation	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
cellular developmental process	2
biological_process	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
epidermal cell differentiation	1
skin development	1
epithelial cell proliferation	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cell differentiation	1
appendage development	1
epithelial cell differentiation	1
mammary gland epithelium development	1
stem cell division	1
negative regulation of cell population proliferation	1
stem cell proliferation	1
regulation of stem cell proliferation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular process	1
tissue development	1
animal organ development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1

Protein interactions and networks

STRING

1848 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IRF6	MSX1	P28360	815
IRF6	GRHL3	Q8TE85	809
IRF6	MAFB	Q9Y5Q3	805
IRF6	VAX1	Q5SQQ9	781
IRF6	NECTIN1	Q15223	760
IRF6	PAX9	P55771	745
IRF6	UTP25	Q68CQ4	717
IRF6	RIPK4	P57078	705
IRF6	TGFA	P01135	680
IRF6	BMP4	P12644	669
IRF6	JAG2	Q9Y219	666
IRF6	TFAP2A	P05549	654
IRF6	TBX10	O75333	646
IRF6	FOXE1	O00358	635
IRF6	ARHGAP29	Q52LW3	632

IntAct

25 interactions, top by confidence:

A	B	Type	Score
SGF29	NDC80	psi-mi:“MI:0914”(association)	0.840
IRF6	IRF8	psi-mi:“MI:0914”(association)	0.500
IRF8	IRF6	psi-mi:“MI:0914”(association)	0.500
IRF8	IRF6	psi-mi:“MI:0915”(physical association)	0.500
IRF6	E6	psi-mi:“MI:0915”(physical association)	0.370
TLX2	IRF6	psi-mi:“MI:0915”(physical association)	0.370
IRF6	RFX3	psi-mi:“MI:0915”(physical association)	0.370
IRF6	ZBTB3	psi-mi:“MI:0915”(physical association)	0.370
NUTM2F	IRF6	psi-mi:“MI:0914”(association)	0.350
PRPS2	ARHGEF37	psi-mi:“MI:0914”(association)	0.350
AKT1	IRF6	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	IRF6	psi-mi:“MI:2364”(proximity)	0.270
IRF6	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
IRF6	EGFR	psi-mi:“MI:2364”(proximity)	0.270
IRF6	BRAF	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (24): IRF6 (Affinity Capture-MS), IRF6 (Affinity Capture-MS), IRF6 (Affinity Capture-MS), VPS26A (Co-fractionation), RABGGTB (Co-fractionation), GRSF1 (Co-fractionation), ABCF1 (Co-fractionation), RABGGTA (Co-fractionation), OSGEP (Co-fractionation), IRF6 (Affinity Capture-MS), IRF6 (PCA), IRF6 (Proximity Label-MS), IRF6 (Proximity Label-MS), IRF6 (Affinity Capture-MS), IRF6 (Two-hybrid)

ESM2 similar proteins: B5DF93, D2HNW6, O14896, P52633, P56477, P70671, P97431, Q08DD6, Q13568, Q14653, Q15561, Q15562, Q1JPG0, Q3B7M3, Q3TC46, Q3ZBK7, Q4JF28, Q4KLN4, Q53GS7, Q58DJ0, Q5DTY9, Q5R8Q4, Q5RAS2, Q62717, Q68DU8, Q6A0A9, Q6DEZ2, Q6NUQ4, Q7L4E1, Q86TB9, Q86UW7, Q86UW9, Q8AVJ1, Q8BK03, Q8BYR5, Q8CDG3, Q8CF97, Q8CID0, Q8HWS3, Q8IY22

Diamond homologs: A0FIN4, O14896, P10914, P14316, P15314, P23570, P23611, P23906, P56477, P70671, P97431, Q00978, Q02556, Q08DD6, Q13568, Q14653, Q15306, Q3SZP0, Q4JF28, Q58DJ0, Q61179, Q64287, Q764M6, Q8R4E0, Q90643, Q90871, Q90876, Q98925, Q92985, F5HF68, P70434

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

385 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	79
Likely pathogenic	41
Uncertain significance	146
Likely benign	26
Benign	65

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012760	NM_006147.4(IRF6):c.1128_1129del (p.Glu377fs)	Pathogenic
101515	NM_006147.4(IRF6):c.1199G>A (p.Arg400Gln)	Pathogenic
1019576	NM_006147.4(IRF6):c.1138C>T (p.Pro380Ser)	Pathogenic
1070384	NC_000001.10:g.(?209974565)(209974778_?)del	Pathogenic
1070385	NC_000001.10:g.(?209974565)(209979435_?)del	Pathogenic
1073005	NM_006147.4(IRF6):c.558C>A (p.Cys186Ter)	Pathogenic
1074446	NM_006147.4(IRF6):c.748C>T (p.Arg250Ter)	Pathogenic
1075467	NM_006147.4(IRF6):c.439del (p.Glu147fs)	Pathogenic
1197820	NM_006147.4(IRF6):c.711C>A (p.Tyr237Ter)	Pathogenic
1423078	NM_006147.4(IRF6):c.1045G>T (p.Glu349Ter)	Pathogenic
1440379	NM_006147.4(IRF6):c.263A>G (p.Asn88Ser)	Pathogenic
1445221	NM_006147.4(IRF6):c.478C>T (p.Gln160Ter)	Pathogenic
1452687	NM_006147.4(IRF6):c.321_322del (p.Val108fs)	Pathogenic
1455254	NM_006147.4(IRF6):c.1052T>C (p.Phe351Ser)	Pathogenic
1456094	NM_006147.4(IRF6):c.575G>A (p.Trp192Ter)	Pathogenic
1456673	NM_006147.4(IRF6):c.647_650dup (p.Trp217fs)	Pathogenic
1459906	NM_006147.4(IRF6):c.902del (p.Gly301fs)	Pathogenic
1708591	NM_006147.4(IRF6):c.952C>T (p.Gln318Ter)	Pathogenic
2026633	NM_006147.4(IRF6):c.2T>A (p.Met1Lys)	Pathogenic
2050435	NM_006147.4(IRF6):c.1089del (p.Ile363fs)	Pathogenic
2104432	NM_006147.4(IRF6):c.1061-1G>T	Pathogenic
2112178	NM_006147.4(IRF6):c.56_62del (p.Asp19fs)	Pathogenic
2202931	NM_006147.4(IRF6):c.274G>A (p.Glu92Lys)	Pathogenic
2202932	NM_006147.4(IRF6):c.235T>C (p.Trp79Arg)	Pathogenic
2425515	NC_000001.10:g.(?209961765)(209965792_?)del	Pathogenic
254674	NM_006147.4(IRF6):c.1316T>C (p.Leu439Pro)	Pathogenic
265196	NM_006147.4(IRF6):c.226C>T (p.Pro76Ser)	Pathogenic
265197	NM_006147.4(IRF6):c.576G>A (p.Trp192Ter)	Pathogenic
265198	NM_006147.4(IRF6):c.668-1G>A	Pathogenic
265480	NM_006147.4(IRF6):c.154G>T (p.Glu52Ter)	Pathogenic

SpliceAI

1044 predictions. Top by Δscore:

Variant	Effect	Δscore
1:209788641:TGAC:T	acceptor_gain	1.0000
1:209788642:GACC:G	acceptor_loss	1.0000
1:209788643:ACCTG:A	acceptor_loss	1.0000
1:209788645:C:CG	acceptor_loss	1.0000
1:209788646:T:G	acceptor_loss	1.0000
1:209789661:TCTCA:T	donor_loss	1.0000
1:209789662:CTCAC:C	donor_loss	1.0000
1:209789663:TCACC:T	donor_loss	1.0000
1:209789664:CA:C	donor_loss	1.0000
1:209789666:CC:C	donor_loss	1.0000
1:209789786:C:CC	acceptor_gain	1.0000
1:209789795:G:GC	acceptor_gain	1.0000
1:209790641:T:TA	donor_gain	1.0000
1:209792263:A:AC	donor_gain	1.0000
1:209792264:C:CC	donor_gain	1.0000
1:209792264:CTTA:C	donor_gain	1.0000
1:209792267:A:AC	donor_gain	1.0000
1:209792267:A:C	donor_loss	1.0000
1:209792268:C:CT	donor_gain	1.0000
1:209792268:CT:C	donor_gain	1.0000
1:209792268:CTT:C	donor_gain	1.0000
1:209792268:CTTG:C	donor_gain	1.0000
1:209792268:CTTGG:C	donor_gain	1.0000
1:209792424:GAAC:G	acceptor_gain	1.0000
1:209792425:AAC:A	acceptor_gain	1.0000
1:209792426:AC:A	acceptor_gain	1.0000
1:209792427:CC:C	acceptor_gain	1.0000
1:209792427:CCTAA:C	acceptor_loss	1.0000
1:209792428:C:CC	acceptor_gain	1.0000
1:209792428:CT:C	acceptor_loss	1.0000

AlphaMissense

3107 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:209788517:A:G	L436P	1.000
1:209788628:G:T	A399D	1.000
1:209789671:A:T	V392D	1.000
1:209789680:A:G	L389P	1.000
1:209789719:C:A	G376V	1.000
1:209789719:C:T	G376E	1.000
1:209789720:C:A	G376W	1.000
1:209789720:C:G	G376R	1.000
1:209789720:C:T	G376R	1.000
1:209789722:A:G	F375S	1.000
1:209790518:A:G	F346S	1.000
1:209790538:T:A	R339S	1.000
1:209790538:T:G	R339S	1.000
1:209790604:G:C	C317W	1.000
1:209790605:C:T	C317Y	1.000
1:209790606:A:G	C317R	1.000
1:209790608:A:G	L316P	1.000
1:209790610:C:A	R315S	1.000
1:209790610:C:G	R315S	1.000
1:209790611:C:A	R315M	1.000
1:209790611:C:G	R315T	1.000
1:209790612:T:C	R315G	1.000
1:209790617:G:T	A313D	1.000
1:209790644:A:G	L304P	1.000
1:209790650:A:G	L302P	1.000
1:209790653:C:A	G301V	1.000
1:209790653:C:T	G301E	1.000
1:209790654:C:G	G301R	1.000
1:209790654:C:T	G301R	1.000
1:209790656:C:A	R300I	1.000

dbSNP variants (sampled 300 via entrez): RS1000092935 (1:209792127 T>C,G), RS1000522771 (1:209788214 T>C), RS1000711159 (1:209789153 T>A,C), RS1000750323 (1:209797508 C>A), RS1000764540 (1:209795232 A>C,G,T), RS1001342453 (1:209792823 T>C), RS1001423064 (1:209785379 GC>G), RS1001557770 (1:209803033 T>C), RS1001608291 (1:209803488 G>A), RS1002200598 (1:209799314 G>A,T), RS1002222256 (1:209796208 G>A), RS1002373437 (1:209805896 CG>C), RS1002531085 (1:209801047 G>A), RS1002717979 (1:209792572 C>A,G), RS1002736889 (1:209807513 C>T)

Disease associations

OMIM: gene MIM:607199 | disease phenotypes: MIM:608864, MIM:119300, MIM:119500, MIM:119530, MIM:613705

GenCC curated gene-disease

Disease	Classification	Inheritance
van der Woude syndrome 1	Definitive	Autosomal dominant
IRF6-related condition	Definitive	Autosomal dominant
autosomal dominant popliteal pterygium syndrome	Definitive	Autosomal dominant
popliteal pterygium syndrome	Strong	Autosomal dominant
van der Woude syndrome	Supportive	Autosomal dominant
tooth agenesis	Supportive	Autosomal dominant
orofacial cleft 6, susceptibility to	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
IRF6-related condition	Definitive	AD

Mondo (10): orofacial cleft 6, susceptibility to (MONDO:0012141), popliteal pterygium syndrome (MONDO:0017435), van der Woude syndrome (MONDO:0019508), van der Woude syndrome 1 (MONDO:0007333), IRF6-related condition (MONDO:1040010), autosomal dominant popliteal pterygium syndrome (MONDO:0007334), cleft palate (MONDO:0016064), orofacial cleft 1 (MONDO:0007335), orofacial cleft 10 (MONDO:0013378), tooth agenesis (MONDO:0005486)

Orphanet (4): Popliteal pterygium syndrome (Orphanet:294963), Van der Woude syndrome (Orphanet:888), Autosomal dominant popliteal pterygium syndrome (Orphanet:1300), Cleft palate (Orphanet:2014)

HPO phenotypes

101 total (30 of 101 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000013	Hypoplasia of the uterus
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000048	Bifid scrotum
HP:0000059	Hypoplastic labia majora
HP:0000062	Ambiguous genitalia
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000196	Lower lip pit
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000219	Thin upper lip vermilion
HP:0000220	Velopharyngeal insufficiency
HP:0000271	Abnormality of the face
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000389	Chronic otitis media
HP:0000403	Recurrent otitis media
HP:0000405	Conductive hearing impairment
HP:0000419	Abnormal nasal septum morphology
HP:0000453	Choanal atresia
HP:0000668	Hypodontia
HP:0000677	Oligodontia
HP:0000679	Taurodontia
HP:0000684	Delayed eruption of teeth
HP:0000685	Hypoplasia of teeth
HP:0000687	Widely spaced teeth
HP:0000689	Dental malocclusion
HP:0000690	Agenesis of maxillary lateral incisor

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000353_1	Orofacial clefts	2.000000e-06
GCST000673_2	Cleft lip	1.000000e-14
GCST001628_1	Orofacial clefts	5.000000e-10
GCST001628_21	Orofacial clefts	3.000000e-12
GCST002811_1	Nonsyndromic cleft lip with or without cleft palate	9.000000e-22
GCST002814_2	Alzheimer’s disease (APOE e4 interaction)	9.000000e-06
GCST004131_1	Inflammatory bowel disease	1.000000e-08
GCST004132_85	Crohn’s disease	7.000000e-07
GCST004166_10	Nonsyndromic cleft lip with cleft palate	9.000000e-19
GCST004866_6	Alopecia areata	2.000000e-06
GCST006270_1	Drug-induced liver injury in interferon-beta-treated multiple sclerosis	2.000000e-08
GCST006624_17	Systolic blood pressure	1.000000e-10
GCST009356_1	Nonsyndromic cleft palate	3.000000e-15
GCST009357_1	Nonsyndromic cleft lip	8.000000e-49
GCST012337_17	Nonsyndromic cleft lip with or without cleft palate	1.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003959	cleft lip
EFO:0007659	APOE carrier status
EFO:0006335	systolic blood pressure

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
C566121	Orofacial Cleft 1 (supp.)
C566605	Orofacial Cleft 10 (supp.)
C562509	Popliteal Pterygium Syndrome (supp.)
C536528	Van der Woude syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2205986	Toxicity	3	interferon beta-1a;interferon beta-1b	Drug-induced liver injury;Multiple Sclerosis

CTD chemical–gene interactions

52 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases abundance	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation, affects methylation	2
Estradiol	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	increases abundance, decreases expression	2
Particulate Matter	increases expression, affects cotreatment, increases abundance	2
pirinixic acid	affects binding, decreases expression, increases activity	1
geraniol	increases expression	1
lead acetate	decreases expression	1
arsenite	decreases expression, increases abundance	1
nickel chloride	affects cotreatment, increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	decreases expression	1
tebuconazole	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
3-nitrobenzanthrone	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Microplastics	decreases expression, increases abundance	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	increases abundance, decreases expression	1
Calcitriol	increases expression	1
Coumestrol	affects cotreatment, decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A3G5	SEES3-1V human IRF6, clone1	Embryonic stem cell	Male
CVCL_A3G6	SEES3-1V human IRF6, clone2	Embryonic stem cell	Male
CVCL_A3G7	SEES3-1V human IRF6, clone3	Embryonic stem cell	Male
CVCL_B726	RG-326	Embryonic stem cell	Male

Clinical trials (associated diseases)

86 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	PHASE2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	PHASE2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty
NCT02350803	PHASE2	COMPLETED	Does Use of Rigid Fixation After Removing Distraction Osteogenesis Device Reduce the Relapse?
NCT03412474	PHASE2	COMPLETED	Suprazygomatic Block in Cleft Palate Surgery in Children
NCT03392701	Not specified	COMPLETED	Possible Links Between Inflammation and Lipid Metabolism
NCT05850221	Not specified	COMPLETED	Anaerobic Exercise and Mental Acuity
NCT06437405	Not specified	COMPLETED	Resistance Exercise Plus Vinegar Ingestion on Biomarkers in Healthy Adults
NCT01470235	Not specified	UNKNOWN	Hypodontia and Ovarian Cancer
NCT03445026	Not specified	UNKNOWN	Frequency of Hypodontia After Chemotherapy in Childhood Cancer Survivors Study
NCT05771246	Not specified	COMPLETED	Craniofacial Morphology And Sella Turcica Bridging Associated With Third Molar Agenesis.
NCT01616953	PHASE1/PHASE2	COMPLETED	Cell Therapy for Craniofacial Bone Defects
NCT02247193	PHASE1/PHASE2	COMPLETED	Botulinum Toxin to Improve Cosmesis of Primary Cleft Lip Repair
NCT00097149	Not specified	COMPLETED	Systematic Pediatric Care for Oral Clefts - South America
NCT00285714	Not specified	UNKNOWN	3D Imaging of Hard and Soft Tissue in Orthognathic Surgery
NCT00340977	Not specified	COMPLETED	Svangerskap, Arv, Og Miljo (Pregnancy, Heredity and Environment)
NCT00423072	Not specified	COMPLETED	Middle Ear Pressure Disregulation in Cleft Palate Patients
NCT00584272	Not specified	COMPLETED	Retrospective Study on the Outcome of Cleft Palate Repair: Comparing US Surgical and Ethicon Suture Materials
NCT00773994	Not specified	COMPLETED	Pilot Study Evaluating Characteristic Closure Patterns of the Normal Velopharyngeal Portal
NCT00779961	Not specified	UNKNOWN	An Investigation for the Optimal Timing of a Cleft Palate Repair
NCT00829101	Not specified	COMPLETED	Articulation and Phonology in Children With Unilateral Cleft Lip and Palate
NCT00993551	Not specified	COMPLETED	Timing of Primary Surgery for Cleft Palate
NCT00993993	Not specified	COMPLETED	Relational Development in Children With Cleft Lips and Palates: Influence of the Waiting Period Prior to the First Surgical Intervention and the Parents’ Psychological Perception of the Abnormality
NCT01046591	Not specified	COMPLETED	Sleep and Behavior in Children With Cleft Palate
NCT01252264	Not specified	COMPLETED	FaceBase Biorepository
NCT01380171	Not specified	COMPLETED	Primary Palatoplasty in Pediatric Patients - A Retrospective Review of Surgical Outcomes
NCT01500109	Not specified	COMPLETED	Efficacy of Oral Versus Intravenous Acetaminophen for Primary Pediatric Cleft Palate Repair
NCT01535131	Not specified	COMPLETED	Furlow Palatoplasty With Tensor Tenopexy
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT01867632	Not specified	COMPLETED	Acellular Dermal Matrix in Primary Palatoplasty
NCT02329509	Not specified	COMPLETED	Evaluation of Facial Growth in Two Primary Protocols Used in the Surgical Treatment of Unilateral Cleft Lip and Palate Patients