Cleft lip/palate

Summary

Cleft lip/palate (MONDO:0016044) is a disease caused by RIC1 (GenCC Strong), with 22 cohort genes and 80 clinical trials. Top therapeutic interventions include ketorolac, nalbuphine, and racepinephrine.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: RIC1 (GenCC Strong)
• Cohort genes: 22
• ClinVar variants: 16
• Phenotypes (HPO): 21
• Clinical trials: 80

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	6-9 / 10 000	80	Worldwide	Validated
Point prevalence	1-5 / 10 000		Europe	Validated
Prevalence at birth	1-5 / 10 000	56	United States	Validated
Prevalence at birth	6-9 / 10 000	98	France	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0006292	Abnormality of dental eruption	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000202	Orofacial cleft	Frequent (30-79%)
HP:0000220	Velopharyngeal insufficiency	Frequent (30-79%)
HP:0000403	Recurrent otitis media	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009088	Speech articulation difficulties	Frequent (30-79%)
HP:0100334	Unilateral cleft palate	Frequent (30-79%)
HP:0200136	Oral-pharyngeal dysphagia	Frequent (30-79%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0000689	Dental malocclusion	Occasional (5-29%)
HP:0001611	Hypernasal speech	Occasional (5-29%)
HP:0004395	Malnutrition	Occasional (5-29%)
HP:0006342	Peg-shaped maxillary lateral incisors	Occasional (5-29%)
HP:0010294	Palate fistula	Occasional (5-29%)
HP:0011044	Abnormal number of permanent teeth	Occasional (5-29%)
HP:0100337	Bilateral cleft palate	Occasional (5-29%)
HP:0200153	Agenesis of lateral incisor	Occasional (5-29%)
HP:0000327	Hypoplasia of the maxilla	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cleft lip/palate
Mondo ID	MONDO:0016044
Orphanet	199306
ICD-10-CM	Q35-Q37
SNOMED CT	66948001
UMLS	C0158646
MedGen	57640
GARD	0017092
MedDRA	10009260
Is cancer (heuristic)	no

Also known as: alveolar cleft lip and palate · cleft lip and palate · cleft lip-alveolus-palate syndrome · FLP

Data availability: 16 ClinVar variants · 7 GenCC gene-disease records · 17 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › orofacial cleft › cleft lip/palate

Related subtypes (15): cleft lip, orofacial cleft 1, cleft lip/palate-ectodermal dysplasia syndrome, orofacial cleft 2, orofacial cleft 4, orofacial cleft 9, orofacial cleft 12, orofacial cleft 13, familial median cleft of the upper and lower lips, cleft lip and alveolus, cleft palate, orofacial cleft 8, GRHL3-related orofacial clefting, orofacial cleft 7, ARHGAP29-related non-syndromic orofacial cleft

Subtypes (4): orofacial cleft 11, orofacial cleft 5, orofacial cleft 10, orofacial cleft 15

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

16 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4072404	NM_004247.4(EFTUD2):c.529-2A>G	EFTUD2	Pathogenic	criteria provided, single submitter
4074781	NM_170675.5(MEIS2):c.777_795dup (p.Asp266delinsSerPheThrTrpTyrArgTer)	MEIS2	Pathogenic	criteria provided, single submitter
40525	NM_002834.5(PTPN11):c.844A>G (p.Ile282Val)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
4492	NM_206926.2(SELENON):c.1295G>A (p.Arg432Gln)	SELENON	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
635787	NM_182961.4(SYNE1):c.26236C>T (p.Arg8746Ter)	SYNE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929484	NM_130847.3(AMOTL1):c.479C>T (p.Pro160Leu)	AMOTL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306603	NM_001371623.1(TCOF1):c.3605C>T (p.Ser1202Phe)	TCOF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
979047	NM_004360.5(CDH1):c.895G>A (p.Ala299Thr)	CDH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
979049	NM_004360.5(CDH1):c.1926C>A (p.Tyr642Ter)	CDH1	Uncertain significance	no assertion criteria provided
4075034	NM_001271.4(CHD2):c.248A>G (p.Lys83Arg)	CHD2	Uncertain significance	criteria provided, single submitter
4075004	NM_031263.4(HNRNPK):c.176G>A (p.Gly59Glu)	HNRNPK	Uncertain significance	criteria provided, single submitter
1403806	NM_024665.7(TBL1XR1):c.961A>G (p.Thr321Ala)	LOC126806878	Uncertain significance	criteria provided, multiple submitters, no conflicts
4075191	NM_002470.4(MYH3):c.2489G>C (p.Trp830Ser)	MYH3	Uncertain significance	criteria provided, single submitter
3383289	NM_001543.5(NDST1):c.530T>G (p.Leu177Arg)	NDST1	Uncertain significance	criteria provided, single submitter
4075306	NM_006662.3(SRCAP):c.8016G>C (p.Arg2672Ser)	SRCAP	Uncertain significance	criteria provided, single submitter
466291	NM_014795.4(ZEB2):c.807+8G>A	ZEB2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 39 · 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
RIC1	Strong	Autosomal dominant	cleft lip/palate	3
ARHGEF38	Moderate	Autosomal dominant	cleft lip/palate	2
PLEKHA5	Moderate	Autosomal dominant	cleft lip/palate
PLEKHA7	Moderate	Autosomal dominant	cleft lip/palate
AFDN	Limited	Autosomal dominant	cleft lip/palate
DLG1	Limited	Autosomal dominant	cleft lip/palate	2
DLGAP5	Limited	Autosomal dominant	cleft lip/palate	2
FST	Limited	Autosomal dominant	cleft lip/palate

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIC1	Orphanet:199306	Cleft lip/palate
ARHGEF38	Orphanet:199306	Cleft lip/palate
DLG1	Orphanet:199306	Cleft lip/palate
TCOF1	Orphanet:861	Treacher-Collins syndrome
ZEB2	Orphanet:261537	Mowat-Wilson syndrome due to monosomy 2q22
ZEB2	Orphanet:261552	Mowat-Wilson syndrome due to a ZEB2 point mutation
ZEB2	Orphanet:626	Large/giant congenital melanocytic nevus
SELENON	Orphanet:2020	Congenital fiber-type disproportion myopathy
SELENON	Orphanet:324604	Classic multiminicore myopathy
SELENON	Orphanet:84132	Desmin-related myopathy with Mallory body-like inclusions
SELENON	Orphanet:97244	Rigid spine syndrome
SRCAP	Orphanet:2044	Floating-Harbor syndrome
SRCAP	Orphanet:528084	Non-specific syndromic intellectual disability
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
CDH1	Orphanet:1331	Familial prostate cancer
CDH1	Orphanet:199306	Cleft lip/palate
CDH1	Orphanet:1997	Blepharo-cheilo-odontic syndrome
CDH1	Orphanet:227535	Hereditary breast cancer
CDH1	Orphanet:26106	Hereditary diffuse gastric cancer
AMOTL1	Orphanet:660021	Orofacial clefting-cardiac anomalies-facial dysmorphism syndrome
CHD2	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
CHD2	Orphanet:2382	Lennox-Gastaut syndrome
EFTUD2	Orphanet:79113	Mandibulofacial dysostosis-microcephaly syndrome
HNRNPK	Orphanet:352665	Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to 9q21.3 microdeletion
HNRNPK	Orphanet:453504	Neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-skeletal anomalies syndrome due to a point mutation
MEIS2	Orphanet:261190	Cleft palate-congenital heart defect-intellectual disability syndrome due to 15q14 microdeletion
MYH3	Orphanet:1146	Distal arthrogryposis type 1
MYH3	Orphanet:1147	Sheldon-Hall syndrome
MYH3	Orphanet:2053	Freeman-Sheldon syndrome
MYH3	Orphanet:2990	Autosomal recessive multiple pterygium syndrome
MYH3	Orphanet:3275	Spondylocarpotarsal synostosis
MYH3	Orphanet:65743	Autosomal dominant multiple pterygium syndrome
NDST1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

22 cohort genes, 22 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	22

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLGAP5	HGNC:16864	ENSG00000126787	Q15398	Disks large-associated protein 5	gencc
RIC1	HGNC:17686	ENSG00000107036	Q4ADV7	Guanine nucleotide exchange factor subunit RIC1	gencc
ARHGEF38	HGNC:25968	ENSG00000236699	Q9NXL2	Rho guanine nucleotide exchange factor 38	gencc
PLEKHA7	HGNC:27049	ENSG00000166689	Q6IQ23	Pleckstrin homology domain-containing family A member 7	gencc
DLG1	HGNC:2900	ENSG00000075711	Q12959	Disks large homolog 1	gencc
PLEKHA5	HGNC:30036	ENSG00000052126	Q9HAU0	Pleckstrin homology domain-containing family A member 5	gencc
FST	HGNC:3971	ENSG00000134363	P19883	Follistatin	gencc
AFDN	HGNC:7137	ENSG00000130396	P55196	Afadin	gencc
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	clinvar
ZEB2	HGNC:14881	ENSG00000169554	O60315	Zinc finger E-box-binding homeobox 2	clinvar
SELENON	HGNC:15999	ENSG00000162430	Q9NZV5	Selenoprotein N	clinvar
SRCAP	HGNC:16974	ENSG00000080603	Q6ZRS2	Chromatin remodeling protein SRCAP	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	clinvar
AMOTL1	HGNC:17811	ENSG00000166025	Q8IY63	Angiomotin-like protein 1	clinvar
CHD2	HGNC:1917	ENSG00000173575	O14647	ATP-dependent chromatin remodeler CHD2	clinvar
EFTUD2	HGNC:30858	ENSG00000108883	Q15029	116 kDa U5 small nuclear ribonucleoprotein component	clinvar
HNRNPK	HGNC:5044	ENSG00000165119	P61978	Heterogeneous nuclear ribonucleoprotein K	clinvar
MEIS2	HGNC:7001	ENSG00000134138	O14770	Homeobox protein Meis2	clinvar
MYH3	HGNC:7573	ENSG00000109063	P11055	Myosin-3	clinvar
NDST1	HGNC:7680	ENSG00000070614	P52848	Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLGAP5	Disks large-associated protein 5	Potential cell cycle regulator that may play a role in carcinogenesis of cancer cells.
RIC1	Guanine nucleotide exchange factor subunit RIC1	The RIC1-RGP1 complex acts as a guanine nucleotide exchange factor (GEF), which activates RAB6A by exchanging bound GDP for free GTP, and may thereby be required for efficient fusion of endosome-derived vesicles with the Golgi compartment.
ARHGEF38	Rho guanine nucleotide exchange factor 38	May act as a guanine-nucleotide releasing factor.
PLEKHA7	Pleckstrin homology domain-containing family A member 7	Required for zonula adherens biogenesis and maintenance.
DLG1	Disks large homolog 1	Essential multidomain scaffolding protein required for normal development.
FST	Follistatin	Multifunctional regulatory protein whose primary function is to antagonize members of the transforming growth factor beta (TGF-beta) superfamily including activin, myostatin, GDF11 or bone morphogenetic proteins (BMPs).
AFDN	Afadin	Belongs to an adhesion system, probably together with the E-cadherin-catenin system, which plays a role in the organization of homotypic, interneuronal and heterotypic cell-cell adherens junctions (AJs).
TCOF1	Treacle protein	Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification.
ZEB2	Zinc finger E-box-binding homeobox 2	Transcriptional inhibitor that binds to DNA sequence 5’-CACCT-3’ in different promoters.
SELENON	Selenoprotein N	Plays an important role in cell protection against oxidative stress and in the regulation of redox-related calcium homeostasis.
SRCAP	Chromatin remodeling protein SRCAP	Acts both as a chromatin remodeler and transcription coregulator.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
AMOTL1	Angiomotin-like protein 1	Inhibits the Wnt/beta-catenin signaling pathway, probably by recruiting CTNNB1 to recycling endosomes and hence preventing its translocation to the nucleus.
CHD2	ATP-dependent chromatin remodeler CHD2	ATP-dependent chromatin-remodeling factor that specifically binds to the promoter of target genes, leading to chromatin remodeling, possibly by promoting deposition of histone H3.3.
EFTUD2	116 kDa U5 small nuclear ribonucleoprotein component	Required for pre-mRNA splicing as component of the spliceosome, including pre-catalytic, catalytic and post-catalytic spliceosomal complexes.
HNRNPK	Heterogeneous nuclear ribonucleoprotein K	One of the major pre-mRNA-binding proteins.
MEIS2	Homeobox protein Meis2	Involved in transcriptional regulation.
MYH3	Myosin-3	Muscle contraction.
NDST1	Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1	Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 3 · Difficult: 8 · Unknown: 11 · Druggable fraction: 0.14

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	6	4.7×	0.007
Phosphatase	1	3.8×	0.696
Kinase	1	1.3×	0.853
Other/Unknown	11	0.9×	0.853
Transcription factor	2	0.8×	0.853
Enzyme (other)	1	0.6×	0.853

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLGAP5	Other/Unknown	no		SAPAP
RIC1	Scaffold/PPI	no		RIC1_C, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
ARHGEF38	Scaffold/PPI	no		DH_dom, SH3_domain, BAR_dom
PLEKHA7	Scaffold/PPI	no		WW_dom, PH_domain, PH-like_dom_sf
DLG1	Kinase	yes	2.7.4.8	SH3_domain, PDZ, L27_dom
PLEKHA5	Scaffold/PPI	no		WW_dom, PH_domain, PH-like_dom_sf
FST	Other/Unknown	no		Kazal_dom, Fol_N, Follistatin/Osteonectin_EGF
AFDN	Scaffold/PPI	no		RA_dom, FHA_dom, PDZ
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
ZEB2	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
SELENON	Other/Unknown	no		EF_hand_dom
SRCAP	Other/Unknown	no		SNF2_N, Helicase_C-like, Helicase_ATP-bd
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
AMOTL1	Other/Unknown	no		Angiomotin, Angiomotin_C, Angiomotin-like
CHD2	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
EFTUD2	Other/Unknown	no		EFG_V-like, T_Tr_GTP-bd_dom, EFTu-like_2
HNRNPK	Other/Unknown	no		KH_dom, KH_dom_type_1, ROK_N
MEIS2	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
MYH3	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
NDST1	Enzyme (other)	yes	2.8.2.8	Sulfotransferase_dom, Heparan_SO4_deacetylase_dom, P-loop_NTPase
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

20 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)	22
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	6
ventricular zone	5
stromal cell of endometrium	4
tibialis anterior	3
ganglionic eminence	3
calcaneal tendon	3
oocyte	2
bone marrow cell	2
monocyte	2
colonic epithelium	2
lower esophagus mucosa	2
pancreatic ductal cell	2
esophagus squamous epithelium	2
buccal mucosa cell	2
dorsal motor nucleus of vagus nerve	2
secondary oocyte	1
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
corpus callosum	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLGAP5	186	ubiquitous	marker	secondary oocyte, ventricular zone, oocyte
RIC1	257	ubiquitous	marker	tibialis anterior, bone marrow cell, monocyte
ARHGEF38	165	tissue_specific	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium
PLEKHA7	214	broad	marker	sural nerve, pancreatic ductal cell, lower esophagus mucosa
DLG1	294	ubiquitous	marker	endothelial cell, esophagus squamous epithelium, corpus callosum
PLEKHA5	282	ubiquitous	marker	mucosa of paranasal sinus, buccal mucosa cell, bronchial epithelial cell
FST	222	ubiquitous	marker	stromal cell of endometrium, buccal mucosa cell, right lobe of liver
AFDN	269	ubiquitous	marker	right uterine tube, sural nerve, lower esophagus mucosa
TCOF1	265	ubiquitous	marker	sural nerve, oocyte, dorsal motor nucleus of vagus nerve
ZEB2	290	ubiquitous	marker	cortical plate, sural nerve, monocyte
SELENON	244	ubiquitous	marker	stromal cell of endometrium, ventricular zone, ganglionic eminence
SRCAP	167	ubiquitous	yes	sural nerve, stromal cell of endometrium, granulocyte
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
AMOTL1	251	ubiquitous	marker	tibialis anterior, deltoid, cardiac muscle of right atrium
CHD2	268	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
EFTUD2	253	ubiquitous	marker	bone marrow cell, tibialis anterior, ventricular zone
HNRNPK	167	ubiquitous	marker	ventricular zone, calcaneal tendon, ganglionic eminence
MEIS2	281	ubiquitous	marker	ventricular zone, ganglionic eminence, pancreatic ductal cell
MYH3	203	tissue_specific	yes	left testis, right testis, testis
NDST1	290	ubiquitous	marker	stromal cell of endometrium, C1 segment of cervical spinal cord, spinal cord
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH1	8,738
EFTUD2	8,471
PTPN11	6,009
HNRNPK	5,582
DLG1	4,800
ZEB2	3,193
SRCAP	2,987
SYNE1	2,886
TCOF1	2,769
AFDN	2,641

Intra-cohort edges

A	B	Sources
AFDN	PLEKHA7	string_interaction
CDH1	PLEKHA7	intact, string_interaction
CDH1	ZEB2	string_interaction
NDST1	TCOF1	string_interaction

Structural data

PDB: 15 · AlphaFold-only: 7 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
EFTUD2	Q15029	68
CDH1	P12830	22
DLG1	Q12959	13
SRCAP	Q6ZRS2	10
HNRNPK	P61978	9
AFDN	P55196	6
NDST1	P52848	5
DLGAP5	Q15398	4
FST	P19883	4
MEIS2	O14770	4
PLEKHA7	Q6IQ23	3
SYNE1	Q8NF91	3
PLEKHA5	Q9HAU0	1
ZEB2	O60315	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARHGEF38	Q9NXL2	75.04
MYH3	P11055	74.35
RIC1	Q4ADV7	73.43
AMOTL1	Q8IY63	61.14
CHD2	O14647	60.81
TCOF1	Q13428	41.78
SELENON	Q9NZV5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 142. Enrichment computed across 22 evidence-associated genes (17 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 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Positive Regulation of CDH1 Gene Transcription	2	112.0×	0.019	ZEB2, CDH1
Antagonism of Activin by Follistatin	1	167.9×	0.079	FST
MET activates PTPN11	1	134.3×	0.079	PTPN11
Co-inhibition by BTLA	1	134.3×	0.079	PTPN11
NrCAM interactions	1	96.0×	0.079	DLG1
STAT5 Activation	1	96.0×	0.079	PTPN11
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	84.0×	0.079	CDH1
Netrin mediated repulsion signals	1	74.6×	0.079	PTPN11
InlA-mediated entry of Listeria monocytogenes into host cells	1	74.6×	0.079	CDH1
MAPK1 (ERK2) activation	1	67.2×	0.079	PTPN11
Activation of Ca-permeable Kainate Receptor	1	67.2×	0.079	DLG1
STAT5 activation downstream of FLT3 ITD mutants	1	67.2×	0.079	PTPN11
Formation of the posterior neural plate	1	67.2×	0.079	ZEB2
MAPK3 (ERK1) activation	1	61.1×	0.079	PTPN11
Signaling by Leptin	1	61.1×	0.079	PTPN11
Apoptotic cleavage of cell adhesion proteins	1	61.1×	0.079	CDH1
Listeria monocytogenes entry into host cells	1	61.1×	0.079	CDH1
Regulation of CDH11 gene transcription	1	61.1×	0.079	ZEB2
Regulation of CDH1 mRNA translation by microRNAs	1	61.1×	0.079	CDH1
Formation of the anterior neural plate	1	61.1×	0.079	ZEB2
Interleukin-6 signaling	1	56.0×	0.079	PTPN11
Activated NTRK2 signals through FRS2 and FRS3	1	56.0×	0.079	PTPN11
Regulation of CDH1 Function	1	56.0×	0.079	CDH1
PECAM1 interactions	1	51.7×	0.079	PTPN11
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	51.7×	0.079	CDH1
Regulation of IFNG signaling	1	48.0×	0.079	PTPN11
Prolactin receptor signaling	1	44.8×	0.079	PTPN11
Signaling by FLT3 ITD and TKD mutants	1	44.8×	0.079	PTPN11
Developmental Lineage of Mammary Stem Cells	1	44.8×	0.079	CDH1
Spry regulation of FGF signaling	1	42.0×	0.079	PTPN11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 21 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cell-cell adhesion mediated by cadherin	3	58.7×	0.005	CDH1, PLEKHA7, AFDN
pore complex assembly	2	178.3×	0.008	PLEKHA7, AFDN
regulation of extracellular matrix constituent secretion	1	802.5×	0.027	RIC1
negative regulation of cortisol secretion	1	802.5×	0.027	PTPN11
negative regulation of growth hormone secretion	1	802.5×	0.027	PTPN11
mammillary axonal complex development	1	802.5×	0.027	ZEB2
regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	802.5×	0.027	HNRNPK
regulation of potassium ion import	1	802.5×	0.027	DLG1
positive regulation of myofibroblast contraction	1	802.5×	0.027	ZEB2
regulation of blood-brain barrier permeability	1	802.5×	0.027	ZEB2
endothelial cell proliferation	2	51.8×	0.027	ZEB2, DLG1
face morphogenesis	2	47.2×	0.027	MYH3, PTPN11
positive regulation of mitotic cell cycle	2	44.6×	0.027	MEIS2, PTPN11
ATP metabolic process	2	44.6×	0.027	SELENON, MYH3
positive regulation of skeletal muscle cell proliferation	1	401.2×	0.030	SELENON
microvillus organization	1	401.2×	0.030	PTPN11
intestinal epithelial cell migration	1	401.2×	0.030	PTPN11
regulation of protein localization to synapse	1	401.2×	0.030	DLG1
positive regulation of lens fiber cell differentiation	1	401.2×	0.030	ZEB2
positive regulation of response to oxidative stress	1	401.2×	0.030	SELENON
regulation of melanosome organization	1	401.2×	0.030	ZEB2
regulation of myofibroblast cell apoptotic process	1	401.2×	0.030	ZEB2
negative regulation of T cell proliferation	2	31.5×	0.030	DLG1, PTPN11
bicellular tight junction assembly	2	31.5×	0.030	DLG1, AFDN
fibroblast growth factor receptor signaling pathway	2	27.2×	0.030	NDST1, PTPN11
establishment of cell polarity involved in ameboidal cell migration	1	267.5×	0.032	AMOTL1
L-ascorbic acid transmembrane transport	1	267.5×	0.032	SELENON
cerebellar cortex formation	1	267.5×	0.032	PTPN11
zonula adherens maintenance	1	267.5×	0.032	PLEKHA7
regulation of ryanodine-sensitive calcium-release channel activity	1	267.5×	0.032	SELENON

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 3 · Undrugged: 19

Druggability breadth: 6 of 22 evidence-associated genes (27%) 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
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTPN11	8	4
TCOF1	1	2
EFTUD2	1	2
DLGAP5	0	0
RIC1	0	0
ARHGEF38	0	0
PLEKHA7	0	0
DLG1	0	0
PLEKHA5	0	0
FST	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRAMUSTINE PHOSPHATE	4	PTPN11
MOLIBRESIB	2	EFTUD2, TCOF1
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PTPN11	588	Binding:585, Functional:2, ADMET:1
CDH1	18	Binding:18
TCOF1	8	Binding:8
EFTUD2	8	Binding:8
HNRNPK	7	Binding:7
PLEKHA7	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DLG1	2.7.4.8	guanylate kinase
NDST1	2.8.2.8	[heparan sulfate]-glucosamine N-sulfotransferase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 22; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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)
ESTRAMUSTINE PHOSPHATE	4	PTPN11
MOLIBRESIB	2	EFTUD2, TCOF1
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PTPN11
B	Phased (≥1) drug, not yet approved	2	TCOF1, EFTUD2
C	Druggable family + PDB, no drug	2	DLG1, NDST1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	17	DLGAP5, RIC1, ARHGEF38, PLEKHA7, PLEKHA5, FST, AFDN, ZEB2, SELENON, SRCAP (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DLGAP5	0	—
RIC1	0	—
ARHGEF38	0	—
PLEKHA7	1	—
DLG1	0	—
PLEKHA5	0	—
FST	0	—
AFDN	0	—
ZEB2	0	—
SELENON	0	—
SRCAP	0	—
SYNE1	0	—
CDH1	18	—
AMOTL1	0	—
CHD2	0	—
HNRNPK	7	—
MEIS2	0	—
MYH3	0	—
NDST1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 80.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	74
PHASE4	2
PHASE3	2
PHASE2	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04234971	PHASE4	RECRUITING	Cost Effectiveness in Alveolar Bone Grafting in Patients With Cleft Lip and Palate
NCT04771156	PHASE4	RECRUITING	Ketorolac in Palatoplasty
NCT06284434	PHASE3	RECRUITING	Liposomal Bupivacaine Use in Alveolar Bone Graft Patients
NCT03766217	PHASE3	COMPLETED	Bone Tissue Engineering With Dental Pulp Stem Cells for Alveolar Cleft Repair
NCT06408337	PHASE1/PHASE2	RECRUITING	Phase I-IIa, to Evaluate the Safety, Feasibility, and Efficacy of the Use of BIOCLEFT in the Treatment of Cleft Palate.
NCT00930124	PHASE2	COMPLETED	Cleft Orthognathic Surgery Versus Distraction Osteogenesis - Which is Better?
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT02702869	Not specified	ENROLLING_BY_INVITATION	Allied Cleft & Craniofacial Quality-Improvement and Research Network (ACCQUIREnet)
NCT03065686	Not specified	RECRUITING	Identification of Genetic Factors Implicated in Orofacial Cleft Using Whole Exome Sequencing
NCT04422847	Not specified	RECRUITING	Use of Computer Aided Design and 3D Printing for Anesthesiology Management in a Pediatric Patient With Cleft Facial Defect
NCT05081258	Not specified	RECRUITING	Influence of Presurgical Orthodontic Molding on the Growth of Newborns With Unilateral Cleft Lip Palate
NCT05467527	Not specified	RECRUITING	PACT Programme for Parents of Children With SHCN
NCT05775679	Not specified	RECRUITING	Test-Retest Reliability, Responsiveness and Interpretability of CLEFT-Q
NCT05876169	Not specified	ENROLLING_BY_INVITATION	How Does Orthognathic Surgery Affect Jaw and Neck Motor Function?
NCT06105099	Not specified	RECRUITING	Effect of Performance-specific Cleft Speech Intervention and Long-term Learning in Children With a Cleft Palate
NCT06122805	Not specified	RECRUITING	Effectiveness of Dual Light Electric Toothbrush vs. Manual Toothbrush in Orthodontic Patients Undergoing Oral Surgery
NCT06338319	Not specified	ENROLLING_BY_INVITATION	Book Sharing for Toddlers With Clefts
NCT06381713	Not specified	RECRUITING	Effect and Cost-utility of of High Intensity vs. Low Intensity Speech Intervention in Children With Cleft Palate
NCT06411444	Not specified	NOT_YET_RECRUITING	Effect of Different Nasal Stent Designs With Nasoalveolar Molding Appliance
NCT06451276	Not specified	NOT_YET_RECRUITING	The Effectiveness of Adhesive Versus Conventional Nasoalveolar Molding on Children With Unilateral Cleft Lip and Palate
NCT06510881	Not specified	RECRUITING	Single Stage Versus Multiple Staged Repair of Nasal & Alveolar Deformities in Patients With Cleft Lip and Palate
NCT06895395	Not specified	RECRUITING	High and Low Intensity Speech Intervention in Children With a Cleft Palate: Perceptions of Children, Their Caregivers and Speech-language Pathologists
NCT06994754	Not specified	RECRUITING	Evaluation of Maxillary Expansion Using Clear Aligners’ Therapy in Patients With Cleft Lip and Palate at the Mixed Dentition Stage
NCT07340008	Not specified	RECRUITING	Analgosedation With Ketamine, Nalbuphine, or Dexmedetomidine for Suture Removal in Children After Cleft Surgery
NCT00070811	Not specified	COMPLETED	Assessing the Results of Lip Surgery in Patients With Cleft Lip and Palate
NCT00156442	Not specified	COMPLETED	A Study to Examine the Relationship Between Sleep Apnea and Cleft Lip/Palate
NCT01871623	Not specified	UNKNOWN	One-Piece Le Fort I Osteotomy Versus Segmental Le Fort I Osteotomy
NCT01932164	Not specified	COMPLETED	Use of Mesenchymal Stem Cells for Alveolar Bone Tissue Engineering for Cleft Lip and Palate Patients
NCT02789787	Not specified	COMPLETED	Clinical Effectiveness of Late Maxillary Protraction for Cleft Lip and Palate
NCT02845193	Not specified	COMPLETED	Effect of Novel Nasoalveolar Molding Techniques on Parents’ Satisfaction and Short Term Treatment Outcomes in Unilateral Cleft Lip and Palate Infants: A Randomized Controlled Trial
NCT02881606	Not specified	COMPLETED	Evaluation of the Clinical Effectiveness of Naso-alveolar Molding (NAM) Versus Computer Aided Design NAM (CAD/NAM) in Infants With Bilateral Cleft Lip and Palate: A Randomized Clinical Trial
NCT03011489	Not specified	UNKNOWN	Parent’s Satisfaction and Evaluation of Postsurgical Outcomes in Unilateral Cleft Lip / Palate Newly Born Infants With / Without Vacuum Formed Nasoalveolar Molding Aligners : A Controlled Clinical Trial
NCT03165331	Not specified	UNKNOWN	Online Psychosocial Support for Young People With a Visible Difference: A Randomised Control Study
NCT03217890	Not specified	UNKNOWN	the Relationship Between Cleft Lip and / or Palate (Different Types) and ABO Blood Groups.
NCT03308266	Not specified	COMPLETED	Electromyographic Analysis of the Masticatory Muscles in Cleft Lip and Palate Children With Temporomandibular Disorders
NCT03395015	Not specified	COMPLETED	Efficacy of Maxillo-facial Treatment on Cleft Lip and Palate Patients Faces: Aesthetic Considerations
NCT03514563	Not specified	TERMINATED	Three Dimensional Facial Growth Analysis
NCT03563495	Not specified	COMPLETED	Tissue Engineered Constructs for Alveolar Cleft Repair
NCT03582111	Not specified	COMPLETED	Ultrasound Diagnosis of Cleft Lip and Palate
NCT03686761	Not specified	COMPLETED	Periodontal Changes Following Mid Maxillary Distraction

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
KETOROLAC	4	3
NALBUPHINE	4	1
RACEPINEPHRINE	2	1
CHEMBL207591	0	1