Isolated cleft lip

Summary

Isolated cleft lip (MONDO:0016043) is a disease with 1 cohort gene.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000389	Chronic otitis media	Frequent (30-79%)
HP:0100335	Non-midline cleft of the upper lip	Frequent (30-79%)
HP:0000220	Velopharyngeal insufficiency	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0001572	Macrodontia	Occasional (5-29%)
HP:0006332	Supernumerary maxillary incisor	Occasional (5-29%)
HP:0009088	Speech articulation difficulties	Occasional (5-29%)
HP:0011438	Maternal teratogenic exposure	Occasional (5-29%)
HP:0031469	Low self esteem	Occasional (5-29%)
HP:0040115	Abnormality of the Eustachian tube	Occasional (5-29%)
HP:0100336	Bilateral cleft lip	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Very rare (<1-4%)
HP:0000668	Hypodontia	Very rare (<1-4%)
HP:0001328	Specific learning disability	Very rare (<1-4%)
HP:0001537	Umbilical hernia	Very rare (<1-4%)
HP:0001561	Polyhydramnios	Very rare (<1-4%)
HP:0001696	Situs inversus totalis	Very rare (<1-4%)
HP:0001762	Talipes equinovarus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated cleft lip
Mondo ID	MONDO:0016043
Orphanet	199302
ICD-11	172183323
UMLS	C0008924
MedGen	40327
GARD	0017091
MedDRA	10009259
Is cancer (heuristic)	no

Also known as: isolated cleft lip (disease) · nonsyndromic cleft lip (disease)

Data availability: 3 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (2): Rapp-Hodgkin syndrome, Kuster syndrome

Subtypes (2): orofacial cleft 3, orofacial cleft 5

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

3 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
267887	46;XY;t(1;2)(p34.2;q35)dn		Pathogenic	criteria provided, single submitter
374189	NM_000165.5(GJA1):c.486G>C (p.Lys162Asn)	GJA1	Likely pathogenic	criteria provided, single submitter
267810	46;XX;t(4;15)(q31.3;q15)		Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome
GJA1	Orphanet:2710	Oculodentodigital dysplasia
GJA1	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJA1	Orphanet:93404	Syndactyly type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
hair follicle	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA1	4,942

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJA1	P17302	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 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
Oligomerization of connexins into connexons	1	3806.7×	1e-03	GJA1
Transport of connexins along the secretory pathway	1	3806.7×	1e-03	GJA1
Regulation of gap junction activity	1	3806.7×	1e-03	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	2284.0×	0.001	GJA1
Formation of annular gap junctions	1	1038.2×	0.002	GJA1
Gap junction degradation	1	951.7×	0.002	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	671.8×	0.002	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.003	GJA1
Gap junction assembly	1	292.8×	0.004	GJA1
RHOJ GTPase cycle	1	200.3×	0.005	GJA1
RHOQ GTPase cycle	1	181.3×	0.006	GJA1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microtubule-based transport	1	16852.0×	9e-04	GJA1
positive regulation of mesodermal cell differentiation	1	16852.0×	9e-04	GJA1
negative regulation of gonadotropin secretion	1	8426.0×	0.001	GJA1
positive regulation of morphogenesis of an epithelium	1	5617.3×	0.001	GJA1
cell communication by electrical coupling	1	4213.0×	0.001	GJA1
negative regulation of trophoblast cell migration	1	2407.4×	0.002	GJA1
gap junction assembly	1	2106.5×	0.002	GJA1
glutamate secretion	1	1685.2×	0.002	GJA1
atrial cardiac muscle cell action potential	1	1685.2×	0.002	GJA1
export across plasma membrane	1	1685.2×	0.002	GJA1
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.002	GJA1
cardiac conduction system development	1	1053.2×	0.002	GJA1
bone remodeling	1	936.2×	0.002	GJA1
xenobiotic transport	1	842.6×	0.003	GJA1
positive regulation of stem cell proliferation	1	526.6×	0.004	GJA1
establishment of mitotic spindle orientation	1	481.5×	0.004	GJA1
maintenance of blood-brain barrier	1	481.5×	0.004	GJA1
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	GJA1
cellular response to amyloid-beta	1	391.9×	0.004	GJA1
bone development	1	276.3×	0.005	GJA1
monoatomic ion transmembrane transport	1	208.1×	0.007	GJA1
positive regulation of cold-induced thermogenesis	1	163.6×	0.008	GJA1
negative regulation of cell growth	1	144.0×	0.009	GJA1
intracellular protein localization	1	104.7×	0.012	GJA1
heart development	1	78.8×	0.015	GJA1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	GJA1
cell-cell signaling	1	69.6×	0.016	GJA1
positive regulation of gene expression	1	38.7×	0.028	GJA1
spermatogenesis	1	35.2×	0.029	GJA1
signal transduction	1	16.1×	0.062	GJA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GJA1	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
KANAMYCIN	4	GJA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJA1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.