van der Woude syndrome 2

Summary

van der Woude syndrome 2 (MONDO:0011712) is a disease caused by GRHL3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: GRHL3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 92

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	van der Woude syndrome 2
Mondo ID	MONDO:0011712
MeSH	C536529
OMIM	606713
UMLS	C1847604
MedGen	338272
GARD	0007846
Is cancer (heuristic)	no

Also known as: GRHL3 van der Woude syndrome · van der Woude syndrome 2 · van der Woude syndrome caused by mutation in GRHL3 · Van Der Woude syndrome type 2 · VWS2

Data availability: 92 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 2

Related subtypes (1): van der Woude syndrome 1

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

92 retrieved; paginated sample, class counts are floors:

27 benign, 25 uncertain significance, 20 likely benign, 8 conflicting classifications of pathogenicity, 6 pathogenic, 3 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
101516	NM_198173.3(GRHL3):c.970_971insGT (p.Phe324fs)	GRHL3	Pathogenic	no assertion criteria provided
101517	NM_198173.3(GRHL3):c.1563_1566del (p.Glu522fs)	GRHL3	Pathogenic	no assertion criteria provided
101518	NM_198173.3(GRHL3):c.893G>A (p.Arg298His)	GRHL3	Pathogenic	no assertion criteria provided
101519	NM_198173.3(GRHL3):c.1419+1G>T	GRHL3	Pathogenic	no assertion criteria provided
101520	NM_198173.3(GRHL3):c.1171C>T (p.Arg391Cys)	GRHL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068818	NM_198173.3(GRHL3):c.1419+1G>A	GRHL3	Pathogenic	criteria provided, single submitter
465251	NM_198173.3(GRHL3):c.899G>A (p.Trp300Ter)	GRHL3	Pathogenic	criteria provided, single submitter
2006242	NM_198173.3(GRHL3):c.204+2T>C	GRHL3	Likely pathogenic	criteria provided, single submitter
3062261	NM_198173.3(GRHL3):c.1115del (p.Leu372fs)	GRHL3	Likely pathogenic	criteria provided, single submitter
3235927	NM_198173.3(GRHL3):c.318dup (p.Thr107fs)	GRHL3	Likely pathogenic	criteria provided, single submitter
1166315	NM_198173.3(GRHL3):c.1469G>A (p.Arg490His)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219243	NM_198173.3(GRHL3):c.738C>T (p.Gly246=)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2987893	NM_198173.3(GRHL3):c.472G>A (p.Gly158Ser)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3025145	NM_198174.3(GRHL3):c.1767G>A (p.Val589=)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3282677	NM_198173.3(GRHL3):c.1288G>A (p.Val430Ile)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3667955	NM_198173.3(GRHL3):c.1030G>A (p.Val344Met)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
790225	NM_198173.3(GRHL3):c.1159C>T (p.Arg387Cys)	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
932032	NM_198173.3(GRHL3):c.205-3C>A	GRHL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31150	NM_001378189.1(CFAP57):c.1567G>T (p.Asp523Tyr)	CFAP57	Uncertain significance	no assertion criteria provided
1062655	NM_198173.3(GRHL3):c.550C>G (p.His184Asp)	GRHL3	Uncertain significance	criteria provided, single submitter
1251960	NM_198174.3(GRHL3):c.1806G>A (p.Trp602Ter)	GRHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2057464	NM_198173.3(GRHL3):c.790C>T (p.Arg264Trp)	GRHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2150740	NC_000001.11:g.24364216C>T	GRHL3	Uncertain significance	criteria provided, single submitter
2151352	NM_198173.3(GRHL3):c.1223T>C (p.Met408Thr)	GRHL3	Uncertain significance	criteria provided, single submitter
2432271	NM_198173.3(GRHL3):c.720C>T (p.Ala240=)	GRHL3	Uncertain significance	criteria provided, single submitter
2455364	NM_198173.3(GRHL3):c.1468C>T (p.Arg490Cys)	GRHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2759274	NM_198173.3(GRHL3):c.797C>T (p.Pro266Leu)	GRHL3	Uncertain significance	criteria provided, single submitter
3233335	NM_198173.3(GRHL3):c.1250G>A (p.Arg417Gln)	GRHL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3352906	NM_198174.3(GRHL3):c.1735C>T (p.Pro579Ser)	GRHL3	Uncertain significance	criteria provided, single submitter
3656352	NC_000001.11:g.24364250A>C	GRHL3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · 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
GRHL3	Definitive	Autosomal dominant	van der Woude syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GRHL3	HGNC:25839	ENSG00000158055	Q8TE85	Grainyhead-like protein 3 homolog	gencc,clinvar
CFAP57	HGNC:26485	ENSG00000243710	Q96MR6	Cilia- and flagella-associated protein 57	clinvar
STPG1	HGNC:28070	ENSG00000001460	Q5TH74	O(6)-methylguanine-induced apoptosis 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CFAP57	Cilia- and flagella-associated protein 57	Associates with components of the nexin-dynein regulatory complex (N-DRC), a key regulator of ciliary/flagellar motility, and might act as an inner dynein arm (IDA) hub or linkage.
STPG1	O(6)-methylguanine-induced apoptosis 2	May positively contribute to the induction of apoptosis triggered by O(6)-methylguanine.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRHL3	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C
CFAP57	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
STPG1	Other/Unknown	no		SHIPPO-rpt

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
esophagus mucosa	1
gingival epithelium	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lobe of liver	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRHL3	164	broad	marker	lower esophagus mucosa, esophagus mucosa, gingival epithelium
CFAP57	157	broad	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver
STPG1	196	ubiquitous	marker	right testis, left testis, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRHL3	1,270
CFAP57	747
STPG1	240

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFAP57	Q96MR6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STPG1	Q5TH74	63.83
GRHL3	Q8TE85	61.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of mitochondrial membrane permeability involved in apoptotic process	1	1404.3×	0.011	STPG1
ectoderm development	1	401.2×	0.011	GRHL3
establishment of planar polarity	1	351.1×	0.011	GRHL3
eyelid development in camera-type eye	1	351.1×	0.011	GRHL3
axonemal dynein complex assembly	1	351.1×	0.011	CFAP57
sperm flagellum assembly	1	224.7×	0.015	CFAP57
cochlea morphogenesis	1	193.7×	0.015	GRHL3
pattern specification process	1	156.0×	0.015	GRHL3
establishment of skin barrier	1	151.8×	0.015	GRHL3
wound healing	1	75.9×	0.025	GRHL3
epidermis development	1	70.2×	0.025	GRHL3
neural tube closure	1	62.4×	0.025	GRHL3
single fertilization	1	61.1×	0.025	CFAP57
regulation of actin cytoskeleton organization	1	52.5×	0.027	GRHL3
central nervous system development	1	38.5×	0.034	GRHL3
transcription by RNA polymerase II	1	23.5×	0.052	GRHL3
positive regulation of apoptotic process	1	18.9×	0.061	STPG1
positive regulation of gene expression	1	12.9×	0.084	GRHL3
positive regulation of transcription by RNA polymerase II	1	5.0×	0.198	GRHL3
regulation of transcription by RNA polymerase II	1	3.9×	0.236	GRHL3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRHL3	0	0
CFAP57	0	0
STPG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	GRHL3, CFAP57, STPG1

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)
GRHL3	0	—
CFAP57	0	—
STPG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.