van der Woude syndrome 1

Summary

van der Woude syndrome 1 (MONDO:0007333) is a disease caused by IRF6 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: IRF6 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 126

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	van der Woude syndrome 1
Mondo ID	MONDO:0007333
OMIM	119300
UMLS	C4551864
MedGen	1640616
GARD	0024552
Is cancer (heuristic)	no

Also known as: IRF6 van der Woude syndrome · van der Woude syndrome 1 · van der Woude syndrome caused by mutation in IRF6 · Van Der Woude syndrome type 1 · VWS1

Data availability: 126 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › van der Woude syndrome › van der Woude syndrome 1

Related subtypes (1): van der Woude syndrome 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

126 retrieved; paginated sample, class counts are floors:

45 uncertain significance, 32 benign, 21 pathogenic, 10 likely pathogenic, 6 not provided, 5 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3420	nsv1067914	C1orf74	Pathogenic	no assertion criteria provided
521483	NM_001205293.3(CACNA1E):c.2104G>A (p.Ala702Thr)	CACNA1E	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
101515	NM_006147.4(IRF6):c.1199G>A (p.Arg400Gln)	IRF6	Pathogenic	no assertion criteria provided
217873	NM_006147.4(IRF6):c.1210G>A (p.Glu404Lys)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265199	NM_006147.4(IRF6):c.859C>T (p.Gln287Ter)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687776	NM_006147.4(IRF6):c.298A>G (p.Thr100Ala)	IRF6	Pathogenic	criteria provided, single submitter
30652	NM_006147.4(IRF6):c.65T>C (p.Leu22Pro)	IRF6	Pathogenic	no assertion criteria provided
3382711	NM_006147.4(IRF6):c.1072del (p.His358fs)	IRF6	Pathogenic	criteria provided, single submitter
3411	NM_006147.4(IRF6):c.274G>T (p.Glu92Ter)	IRF6	Pathogenic	criteria provided, single submitter
3415	NM_006147.4(IRF6):c.251G>A (p.Arg84His)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
3416	NM_006147.4(IRF6):c.5C>T (p.Ala2Val)	IRF6	Pathogenic	no assertion criteria provided
3417	NM_006147.4(IRF6):c.16C>T (p.Arg6Cys)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3418	NM_006147.4(IRF6):c.1137G>A (p.Trp379Ter)	IRF6	Pathogenic	no assertion criteria provided
3419	NM_006147.4(IRF6):c.1198C>T (p.Arg400Trp)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
3422	NM_006147.4(IRF6):c.1186C>T (p.Pro396Ser)	IRF6	Pathogenic	no assertion criteria provided
3423	NM_006147.4(IRF6):c.1016G>T (p.Arg339Ile)	IRF6	Pathogenic	no assertion criteria provided
3861266	NM_006147.4(IRF6):c.16dup (p.Arg6fs)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
397639	NM_006147.4(IRF6):c.113T>C (p.Ile38Thr)	IRF6	Pathogenic	criteria provided, single submitter
40077	NM_006147.4(IRF6):c.145C>T (p.Gln49Ter)	IRF6	Pathogenic	criteria provided, single submitter
449039	NM_006147.4(IRF6):c.25C>T (p.Arg9Trp)	IRF6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4529474	NM_006147.4(IRF6):c.797T>C (p.Phe266Ser)	IRF6	Pathogenic	criteria provided, single submitter
458680	NM_006147.4(IRF6):c.1195del (p.Ala399fs)	IRF6	Pathogenic	criteria provided, single submitter
458682	NM_006147.4(IRF6):c.1234C>T (p.Arg412Ter)	IRF6	Pathogenic	criteria provided, multiple submitters, no conflicts
617619	NM_006147.4(IRF6):c.720del (p.Thr240_Met241insTer)	IRF6	Pathogenic	no assertion criteria provided
872903	NM_006147.4(IRF6):c.137_174+12del	IRF6	Pathogenic	criteria provided, single submitter
996215	NM_006147.4(IRF6):c.373_374dup (p.Asn125fs)	IRF6	Pathogenic	no assertion criteria provided
1698899	NM_006147.4(IRF6):c.696C>A (p.Tyr232Ter)	IRF6	Likely pathogenic	criteria provided, single submitter
3383146	NM_006147.4(IRF6):c.827T>C (p.Phe276Ser)	IRF6	Likely pathogenic	criteria provided, single submitter
3412	NM_006147.4(IRF6):c.870_888delinsA (p.Phe290_Asp296delinsLeu)	IRF6	Likely pathogenic	criteria provided, single submitter
3894586	NM_006147.4(IRF6):c.761G>C (p.Gly254Ala)	IRF6	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
IRF6	Definitive	Autosomal dominant	van der Woude syndrome 1	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IRF6	Orphanet:1300	Autosomal dominant popliteal pterygium syndrome
IRF6	Orphanet:141291	Cleft lip and alveolus
IRF6	Orphanet:199302	Isolated cleft lip
IRF6	Orphanet:199306	Cleft lip/palate
IRF6	Orphanet:708014	Ectodermal dysplasia-natal teeth-skin abscesses-plantar hyperkeratosis-hearing impairment
IRF6	Orphanet:888	Van der Woude syndrome
IRF6	Orphanet:99798	Oligodontia
CACNA1E	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
GRHL3	Orphanet:101023	Cleft hard palate
GRHL3	Orphanet:155878	Submucosal cleft palate
GRHL3	Orphanet:888	Van der Woude syndrome
GRHL3	Orphanet:99771	Bifid uvula
GRHL3	Orphanet:99772	Cleft velum

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IRF6	HGNC:6121	ENSG00000117595	O14896	Interferon regulatory factor 6	gencc,clinvar
CACNA1E	HGNC:1392	ENSG00000198216	Q15878	Voltage-dependent R-type calcium channel subunit alpha-1E	clinvar
GRHL3	HGNC:25839	ENSG00000158055	Q8TE85	Grainyhead-like protein 3 homolog	clinvar
C1orf74	HGNC:26319	ENSG00000162757	Q96LT6	UPF0739 protein C1orf74	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRF6	Interferon regulatory factor 6	Probable DNA-binding transcriptional activator.
CACNA1E	Voltage-dependent R-type calcium channel subunit alpha-1E	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells.
GRHL3	Grainyhead-like protein 3 homolog	Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	27.9×	0.106
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IRF6	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
CACNA1E	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_R_a1su
GRHL3	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C
C1orf74	Other/Unknown	no		DUF4504

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus squamous epithelium	1
secondary oocyte	1
upper leg skin	1
Brodmann (1909) area 23	1
cortical plate	1
middle temporal gyrus	1
esophagus mucosa	1
gingival epithelium	1
lower esophagus mucosa	1
endothelial cell	1
epithelial cell of pancreas	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRF6	228	broad	marker	secondary oocyte, upper leg skin, esophagus squamous epithelium
CACNA1E	144	broad	marker	middle temporal gyrus, cortical plate, Brodmann (1909) area 23
GRHL3	164	broad	marker	lower esophagus mucosa, esophagus mucosa, gingival epithelium
C1orf74	181	ubiquitous	yes	epithelial cell of pancreas, granulocyte, endothelial cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1E	2,008
IRF6	1,897
GRHL3	1,270
C1orf74	239

Intra-cohort edges

A	B	Sources
GRHL3	IRF6	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1E	Q15878	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C1orf74	Q96LT6	90.75
IRF6	O14896	74.19
GRHL3	Q8TE85	61.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Presynaptic depolarization and calcium channel opening	1	475.8×	0.023	CACNA1E
Regulation of insulin secretion	1	109.8×	0.030	CACNA1E
Integration of energy metabolism	1	87.8×	0.030	CACNA1E
Interferon alpha/beta signaling	1	76.1×	0.030	IRF6
Interferon gamma signaling	1	62.8×	0.030	IRF6
Interferon Signaling	1	60.1×	0.030	IRF6
Transmission across Chemical Synapses	1	38.1×	0.041	CACNA1E
Neuronal System	1	22.1×	0.059	CACNA1E
Cytokine Signaling in Immune system	1	20.4×	0.059	IRF6
Immune System	1	6.5×	0.163	IRF6
Metabolism	1	5.8×	0.165	CACNA1E

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ectoderm development	1	401.2×	0.015	GRHL3
mammary gland epithelial cell differentiation	1	401.2×	0.015	IRF6
establishment of planar polarity	1	351.1×	0.015	GRHL3
eyelid development in camera-type eye	1	351.1×	0.015	GRHL3
cranial skeletal system development	1	312.1×	0.015	IRF6
cell development	1	295.6×	0.015	IRF6
negative regulation of stem cell proliferation	1	280.9×	0.015	IRF6
negative regulation of keratinocyte proliferation	1	234.1×	0.015	IRF6
keratinocyte proliferation	1	193.7×	0.015	IRF6
cochlea morphogenesis	1	193.7×	0.015	GRHL3
calcium ion import across plasma membrane	1	181.2×	0.015	CACNA1E
pattern specification process	1	156.0×	0.015	GRHL3
establishment of skin barrier	1	151.8×	0.015	GRHL3
limb development	1	137.0×	0.015	IRF6
immune system process	1	130.6×	0.015	IRF6
stem cell proliferation	1	104.0×	0.018	IRF6
keratinocyte differentiation	1	82.6×	0.020	IRF6
roof of mouth development	1	82.6×	0.020	IRF6
wound healing	1	75.9×	0.020	GRHL3
positive regulation of transcription by RNA polymerase II	2	9.9×	0.020	IRF6, GRHL3
epidermis development	1	70.2×	0.020	GRHL3
neural tube closure	1	62.4×	0.022	GRHL3
regulation of actin cytoskeleton organization	1	52.5×	0.025	GRHL3
regulation of transcription by RNA polymerase II	2	7.8×	0.026	IRF6, GRHL3
central nervous system development	1	38.5×	0.031	GRHL3
chemical synaptic transmission	1	25.8×	0.044	CACNA1E
transcription by RNA polymerase II	1	23.5×	0.047	GRHL3
negative regulation of cell population proliferation	1	14.0×	0.075	IRF6
positive regulation of gene expression	1	12.9×	0.078	GRHL3
positive regulation of DNA-templated transcription	1	9.3×	0.104	IRF6

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CACNA1E	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1E	2	4
IRF6	0	0
GRHL3	0	0
C1orf74	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1E
TACRINE	4	CACNA1E

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CACNA1E	14	Binding:14

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
NIMODIPINE	4	CACNA1E
TACRINE	4	CACNA1E

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1E
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	IRF6, GRHL3, C1orf74

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
IRF6	0	—
GRHL3	0	—
C1orf74	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.