Cleft lip

Summary

Cleft lip (MONDO:0004747) is a disease with 6 cohort genes and 35 clinical trials. Top therapeutic interventions include dexmedetomidine.

At a glance

• Cohort genes: 6
• ClinVar variants: 6
• Clinical trials: 35

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cleft lip
Mondo ID	MONDO:0004747
MeSH	D002971
DOID	DOID:9296
ICD-10-CM	Q36
NCIT	C87175
SNOMED CT	80281008
UMLS	C4321245
MedGen	1370297
Is cancer (heuristic)	no

Also known as: cheiloschisis · cleft lip · cleft lip (disease) · cleft lip, unilateral, complete · labium leporinum

Data availability: 6 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (15): 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 lip/palate, cleft palate, orofacial cleft 8, GRHL3-related orofacial clefting, orofacial cleft 7, ARHGAP29-related non-syndromic orofacial cleft

Subtypes (3): Rapp-Hodgkin syndrome, isolated cleft lip, Kuster syndrome

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

6 retrieved; paginated sample, class counts are floors:

3 pathogenic, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1047904	GRCh37/hg19 2q11.1-11.2(chr2:96755045-98021592)	ANKRD39	Pathogenic	criteria provided, single submitter
981664	NM_001080517.3(SETD5):c.2168dup (p.Leu723fs)	SETD5	Pathogenic	no assertion criteria provided
1047882	GRCh37/hg19 6q25.2-25.3(chr6:155308263-158394005)	TMEM242	Pathogenic	criteria provided, single submitter
1435621	NM_001384732.1(CPLANE1):c.356A>G (p.Tyr119Cys)	CPLANE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3383287	NM_004560.4(ROR2):c.2027G>A (p.Trp676Ter)	ROR2	Uncertain significance	criteria provided, single submitter
1335732	NM_021224.6(ZNF462):c.3481G>A (p.Glu1161Lys)	ZNF462	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ROR2	Orphanet:1507	Autosomal recessive Robinow syndrome
ROR2	Orphanet:572385	Brachydactyly type B1
ZNF462	Orphanet:502430	Weiss-Kruszka Syndrome
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability
CPLANE1	Orphanet:2754	Orofaciodigital syndrome type 6
CPLANE1	Orphanet:475	Isolated Joubert syndrome
CPLANE1	Orphanet:65684	Monomelic amyotrophy

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ROR2	HGNC:10257	ENSG00000169071	Q01974	Tyrosine-protein kinase transmembrane receptor ROR2	clinvar
TMEM242	HGNC:17206	ENSG00000215712	Q9NWH2	Transmembrane protein 242	clinvar
ZNF462	HGNC:21684	ENSG00000148143	Q96JM2	Zinc finger protein 462	clinvar
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	clinvar
CPLANE1	HGNC:25801	ENSG00000197603	Q9H799	Ciliogenesis and planar polarity effector 1	clinvar
ANKRD39	HGNC:28640	ENSG00000213337	Q53RE8	Ankyrin repeat domain-containing protein 39	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes.
TMEM242	Transmembrane protein 242	Scaffold protein that participates in the c-ring assembly of mitochondrial ATP synthase (F(1)F(0) ATP synthase or complex V) by facilitating the membrane insertion and oligomer formation of the subunit c/ATP5MC3.
ZNF462	Zinc finger protein 462	Zinc finger nuclear factor involved in transcription by regulating chromatin structure and organization.
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.
CPLANE1	Ciliogenesis and planar polarity effector 1	Involved in ciliogenesis.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 2 · Druggable fraction: 0.17

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	2	5.8×	0.172
Kinase	1	4.6×	0.396
Transcription factor	1	1.4×	0.719
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ROR2	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
TMEM242	Other/Unknown	no		TMEM242
ZNF462	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf
CPLANE1	Scaffold/PPI	no		CPLANE1, WD40_repeat_dom_sf
ANKRD39	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
sural nerve	2
body of uterus	1
mucosa of stomach	1
muscle layer of sigmoid colon	1
decidua	1
vena cava	1
corpus callosum	1
oviduct epithelium	1
adrenal tissue	1
colonic epithelium	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ROR2	188	ubiquitous	marker	muscle layer of sigmoid colon, mucosa of stomach, body of uterus
TMEM242	262	ubiquitous	marker	buccal mucosa cell, vena cava, decidua
ZNF462	258	ubiquitous	marker	buccal mucosa cell, oviduct epithelium, corpus callosum
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve
CPLANE1	195	ubiquitous	marker	sural nerve, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis
ANKRD39	209	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETD5	1,865
ROR2	1,813
ZNF462	1,141
ANKRD39	1,093
TMEM242	597
CPLANE1	439

Structural data

PDB: 2 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ROR2	Q01974	6
ZNF462	Q96JM2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD39	Q53RE8	84.41
TMEM242	Q9NWH2	72.63
SETD5	Q9C0A6	47.10
CPLANE1	Q9H799

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 6 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
WNT5A-dependent internalization of FZD2, FZD5 and ROR2	1	878.5×	0.006	ROR2
PCP/CE pathway	1	300.5×	0.006	ROR2
Beta-catenin independent WNT signaling	1	292.8×	0.006	ROR2
Signaling by WNT	1	112.0×	0.011	ROR2
Signal Transduction	1	10.2×	0.098	ROR2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of transcription by RNA polymerase III	1	674.1×	0.012	SETD5
regulation of DNA-templated transcription elongation	1	561.7×	0.012	SETD5
mitochondrial proton-transporting ATP synthase complex assembly	1	421.3×	0.012	TMEM242
regulation of chromatin organization	1	306.4×	0.012	SETD5
regulation of synapse assembly	1	140.4×	0.021	SETD5
cognition	1	57.1×	0.043	SETD5
cell surface receptor protein tyrosine kinase signaling pathway	1	34.8×	0.054	ROR2
methylation	1	34.0×	0.054	SETD5
Wnt signaling pathway	1	19.9×	0.074	ROR2
chromatin organization	1	19.8×	0.074	ZNF462
cilium assembly	1	14.7×	0.090	CPLANE1
positive regulation of cell migration	1	12.3×	0.098	ROR2
regulation of DNA-templated transcription	1	6.3×	0.172	SETD5
signal transduction	1	3.2×	0.294	ROR2
positive regulation of transcription by RNA polymerase II	1	3.0×	0.294	ZNF462

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Folic Acid	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ROR2	0	0
TMEM242	0	0
ZNF462	0	0
SETD5	0	0
CPLANE1	0	0
ANKRD39	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ROR2	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ROR2	2.7.10.1	receptor protein-tyrosine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	1	ROR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	TMEM242, ZNF462, SETD5, CPLANE1, ANKRD39

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ROR2	4	—
TMEM242	0	—
ZNF462	0	—
SETD5	0	—
CPLANE1	0	—
ANKRD39	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 35.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	27
PHASE3	3
PHASE2	2
PHASE4	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03480607	PHASE4	COMPLETED	Dexmedetomidine as Adjuvant for Bupivacaine in Ultrasound Guided Infraorbital Nerve Block for Cleft Lip Repair
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT03314090	PHASE3	COMPLETED	Silicone Gel in the Treatment of Cleft Lip Scars
NCT06885801	PHASE2	NOT_YET_RECRUITING	Evaluation of a Novel Nasal Conformer in Pediatric Patients
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT02247193	PHASE1/PHASE2	COMPLETED	Botulinum Toxin to Improve Cosmesis of Primary Cleft Lip Repair
NCT06765837	PHASE1	COMPLETED	Comparison Between Low Level Laser Therapy and Active Oxygen Releasing Gel on Wound Healing Cleft Lip Patients
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)
NCT03537976	Not specified	ACTIVE_NOT_RECRUITING	Targeting Surgeons’ Decision-Making for Cleft Lip Surgery
NCT05357092	Not specified	NOT_YET_RECRUITING	Effects of AlignBabyCleft (ABaCleft)
NCT06411444	Not specified	NOT_YET_RECRUITING	Effect of Different Nasal Stent Designs With Nasoalveolar Molding Appliance
NCT00070811	Not specified	COMPLETED	Assessing the Results of Lip Surgery in Patients With Cleft Lip and Palate
NCT00097149	Not specified	COMPLETED	Systematic Pediatric Care for Oral Clefts - South America
NCT00213889	Not specified	TERMINATED	TWIST Human Gene and Cleft Lips and Palates
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)
NCT00829101	Not specified	COMPLETED	Articulation and Phonology in Children With Unilateral Cleft Lip and Palate
NCT00975208	Not specified	UNKNOWN	Osteogenesis and Dental Eruption Through Electrical Stimuli
NCT01252264	Not specified	COMPLETED	FaceBase Biorepository
NCT01380171	Not specified	COMPLETED	Primary Palatoplasty in Pediatric Patients - A Retrospective Review of Surgical Outcomes
NCT02329509	Not specified	COMPLETED	Evaluation of Facial Growth in Two Primary Protocols Used in the Surgical Treatment of Unilateral Cleft Lip and Palate Patients
NCT02415361	Not specified	COMPLETED	Follow Ups of Parents With Infants With Cleft Lip and Palate
NCT02454998	Not specified	UNKNOWN	Alveolar Bone Grafting Outcome Between Patient With and Without Orthodontic Treatment
NCT03029195	Not specified	COMPLETED	Nasoalveolar Molding for Egyptian Cleft Lip Palate Infants
NCT03572907	Not specified	WITHDRAWN	Use of Titanium Plate in Rhinoplasty in Patients With Cleft Lip and Palate : Aesthetic and Functional Impact.
NCT03839290	Not specified	UNKNOWN	Development of the Palate in Bilateral Orofacial Cleft Newborns One Year After Early Neonatal Cheiloplasty
NCT04277273	Not specified	COMPLETED	Characteristics of a Maxillofacial Prosthesis Consultation Within Assistance Publique - Hopitaux de Paris
NCT04334590	Not specified	WITHDRAWN	Fabrication of Sequential Naso-Alveolar Molding Appliances in the Treatment of Cleft Lip/Nose Deformities
NCT04627389	Not specified	UNKNOWN	Orbicularis Oris Z-plasty Modification of Modified Millard Technique and the Esthetic Outcome of Cleft Lip Repair
NCT04725370	Not specified	COMPLETED	Characterization of Cleft Lip and Palate Conditions in Guatemala
NCT05559281	Not specified	COMPLETED	Botulinum Toxin Injection in Reducing Lip Scar Following Cleft Lip Repair
NCT05748340	Not specified	COMPLETED	Unilateral Cleft Lip Repair : Modified Millard and Mishra Technique
NCT07384338	Not specified	COMPLETED	Three Dimensional Evaluation of Dento-Skeletal Effects of Leaf Self Expander in Cleft Lip and Palate Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXMEDETOMIDINE	4	1