Orofacial cleft 5

Summary

Orofacial cleft 5 (MONDO:0012142) is a disease caused by MSX1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: MSX1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	orofacial cleft 5
Mondo ID	MONDO:0012142
MeSH	C563843
OMIM	608874
DOID	DOID:0080399
UMLS	C1837210
MedGen	373280
GARD	0018305
Is cancer (heuristic)	no

Also known as: MSX1 orofacial cleft · OFC5 · orofacial cleft 5 · orofacial cleft caused by mutation in MSX1 · orofacial cleft type 5

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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

6 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1319948	NM_002448.3(MSX1):c.519_525dup (p.Arg176Ter)	MSX1	Pathogenic	no assertion criteria provided
14884	NM_002448.3(MSX1):c.365G>A (p.Gly122Glu)	MSX1	Pathogenic	no assertion criteria provided
225414	NM_002448.3(MSX1):c.471G>T (p.Arg157Ser)	MSX1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14883	NM_002448.3(MSX1):c.251A>T (p.Glu84Val)	LOC129992137	Uncertain significance	criteria provided, single submitter
703022	NM_002448.3(MSX1):c.218C>T (p.Pro73Leu)	LOC129992137	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
14885	NM_002448.3(MSX1):c.458C>A (p.Pro153Gln)	MSX1	Likely benign	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
MSX1	Definitive	Autosomal dominant	orofacial cleft 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSX1	Orphanet:141291	Cleft lip and alveolus
MSX1	Orphanet:199302	Isolated cleft lip
MSX1	Orphanet:199306	Cleft lip/palate
MSX1	Orphanet:2228	Hypodontia-dysplasia of nails syndrome
MSX1	Orphanet:99798	Oligodontia

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
MSX1	HGNC:7391	ENSG00000163132	P28360	Homeobox protein MSX-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSX1	Homeobox protein MSX-1	Acts as a transcriptional repressor.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MSX1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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
buccal mucosa cell	1
choroid plexus epithelium	1
endocervix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSX1	222	ubiquitous	marker	buccal mucosa cell, choroid plexus epithelium, endocervix

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MSX1	2,261

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MSX1	P28360	66.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Specification of the neural plate border	1	634.4×	0.005	MSX1
Gastrulation	1	259.6×	0.006	MSX1
Developmental Biology	1	14.5×	0.069	MSX1

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
negative regulation of odontoblast differentiation	1	16852.0×	0.002	MSX1
cell surface receptor signaling pathway involved in heart development	1	8426.0×	0.002	MSX1
positive regulation of mesenchymal cell apoptotic process	1	5617.3×	0.002	MSX1
negative regulation of striated muscle cell differentiation	1	4213.0×	0.002	MSX1
activation of meiosis	1	4213.0×	0.002	MSX1
embryonic nail plate morphogenesis	1	3370.4×	0.002	MSX1
regulation of odontogenesis	1	3370.4×	0.002	MSX1
positive regulation of odontogenesis	1	3370.4×	0.002	MSX1
cartilage morphogenesis	1	3370.4×	0.002	MSX1
positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2808.7×	0.002	MSX1
nose development	1	2407.4×	0.002	MSX1
cellular response to nicotine	1	2106.5×	0.002	MSX1
mammary gland epithelium development	1	1872.4×	0.002	MSX1
embryonic morphogenesis	1	1532.0×	0.002	MSX1
mesenchymal cell apoptotic process	1	1532.0×	0.002	MSX1
epithelial to mesenchymal transition involved in endocardial cushion formation	1	1404.3×	0.002	MSX1
mesenchymal cell proliferation	1	1123.5×	0.002	MSX1
cardiac conduction system development	1	1053.2×	0.002	MSX1
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	991.3×	0.002	MSX1
signal transduction involved in regulation of gene expression	1	702.2×	0.003	MSX1
middle ear morphogenesis	1	702.2×	0.003	MSX1
pituitary gland development	1	648.1×	0.003	MSX1
midbrain development	1	601.9×	0.003	MSX1
bone morphogenesis	1	601.9×	0.003	MSX1
embryonic hindlimb morphogenesis	1	581.1×	0.003	MSX1
embryonic forelimb morphogenesis	1	495.6×	0.003	MSX1
face morphogenesis	1	495.6×	0.003	MSX1
positive regulation of BMP signaling pathway	1	455.5×	0.004	MSX1
positive regulation of cell cycle	1	443.5×	0.004	MSX1
inner ear development	1	374.5×	0.004	MSX1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
MSX1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	1	MSX1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MSX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.