Cleft soft palate

Summary

Cleft soft palate (MONDO:0007338) is a disease with 2 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Cohort genes: 2
• ClinVar variants: 4
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000185	Cleft soft palate	Frequent (30-79%)
HP:0000220	Velopharyngeal insufficiency	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0010863	Receptive language delay	Frequent (30-79%)
HP:0011469	Nasal regurgitation	Frequent (30-79%)
HP:0200136	Oral-pharyngeal dysphagia	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Occasional (5-29%)
HP:0000403	Recurrent otitis media	Occasional (5-29%)
HP:0000405	Conductive hearing impairment	Occasional (5-29%)
HP:0001611	Hypernasal speech	Occasional (5-29%)
HP:0009088	Speech articulation difficulties	Occasional (5-29%)
HP:0011219	Short face	Occasional (5-29%)
HP:0011951	Aspiration pneumonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cleft soft palate
Mondo ID	MONDO:0007338
MeSH	C562950
OMIM	119570
Orphanet	99772
DOID	DOID:0110214
ICD-10-CM	Q35.3
ICD-11	797497023
SNOMED CT	253997002
UMLS	C0432098
MedGen	98471
GARD	0016907
Is cancer (heuristic)	no

Also known as: cleft soft palate · cleft velum · cleft velum palatinum

Data availability: 4 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 palate › cleft soft palate

Related subtypes (8): isolated cleft palate, Rapp-Hodgkin syndrome, bifid uvula, cleft palate with or without ankyloglossia, X-linked, cleft hard palate, submucosal cleft palate, Kuster syndrome, soft and hard cleft palate

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

4 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
374012	NM_182943.3(PLOD2):c.2038C>T (p.Arg680Ter)	PLOD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374011	NM_182943.3(PLOD2):c.1361G>T (p.Gly454Val)	PLOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267836	46;XY;t(1;6)(q23;q13)dn		Uncertain significance	criteria provided, single submitter
268030	46;XY;t(10;17)(p13;q23)dn		Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 6 · 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
CDH1	Moderate	Autosomal dominant	cleft soft palate	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
PLOD2	Orphanet:2771	Bruck syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	gencc
PLOD2	HGNC:9082	ENSG00000152952	O00469	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
PLOD2	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2	Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
PLOD2	Enzyme (other)	yes	1.14.11.4	Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	2
esophagus squamous epithelium	1
gingival epithelium	1
calcaneal tendon	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
PLOD2	288	ubiquitous	marker	tibia, calcaneal tendon, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDH1	8,738
PLOD2	1,703

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDH1	P12830	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLOD2	O00469	92.63

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	713.8×	0.013	CDH1
InlA-mediated entry of Listeria monocytogenes into host cells	1	634.4×	0.013	CDH1
Apoptotic cleavage of cell adhesion proteins	1	519.1×	0.013	CDH1
Listeria monocytogenes entry into host cells	1	519.1×	0.013	CDH1
Regulation of CDH1 mRNA translation by microRNAs	1	519.1×	0.013	CDH1
Regulation of CDH1 Function	1	475.8×	0.013	CDH1
Positive Regulation of CDH1 Gene Transcription	1	475.8×	0.013	CDH1
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	439.2×	0.013	CDH1
Developmental Lineage of Mammary Stem Cells	1	380.7×	0.013	CDH1
Formation of definitive endoderm	1	356.9×	0.013	CDH1
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	271.9×	0.013	CDH1
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	248.3×	0.013	CDH1
Apoptotic cleavage of cellular proteins	1	237.9×	0.013	CDH1
Apoptotic execution phase	1	237.9×	0.013	CDH1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	228.4×	0.013	CDH1
RHO GTPases activate IQGAPs	1	173.0×	0.015	CDH1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	167.9×	0.015	CDH1
Bacterial Infection Pathways	1	167.9×	0.015	CDH1
Gastrulation	1	129.8×	0.017	CDH1
Adherens junctions interactions	1	124.1×	0.017	CDH1
Cell-cell junction organization	1	124.1×	0.017	CDH1
Degradation of CDH1	1	98.5×	0.020	CDH1
Cell junction organization	1	93.6×	0.020	CDH1
MITF-M-dependent gene expression	1	90.6×	0.020	CDH1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.020	CDH1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.020	PLOD2
Apoptosis	1	84.0×	0.020	CDH1
Activation of STAT3 by cadherin engagement	1	81.6×	0.020	CDH1
Programmed Cell Death	1	73.2×	0.021	CDH1
Cell-Cell communication	1	68.8×	0.022	CDH1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete hydroxylysine biosynthetic process	1	2808.7×	0.004	PLOD2
response to heparin	1	2808.7×	0.004	CDH1
regulation of protein catabolic process at postsynapse, modulating synaptic transmission	1	2106.5×	0.004	CDH1
cellular response to indole-3-methanol	1	1685.2×	0.004	CDH1
response to Gram-positive bacterium	1	1404.3×	0.004	CDH1
desmosome assembly	1	1203.7×	0.004	CDH1
positive regulation of protein localization	1	702.2×	0.006	CDH1
cellular response to lithium ion	1	561.7×	0.006	CDH1
collagen biosynthetic process	1	526.6×	0.006	PLOD2
negative regulation of cell-cell adhesion	1	495.6×	0.006	CDH1
negative regulation of axon extension	1	366.4×	0.008	CDH1
pituitary gland development	1	324.1×	0.008	CDH1
adherens junction organization	1	255.3×	0.009	CDH1
calcium-dependent cell-cell adhesion	1	240.7×	0.009	CDH1
cell-cell junction assembly	1	221.7×	0.009	CDH1
positive regulation of protein import into nucleus	1	210.7×	0.009	CDH1
cell-cell adhesion mediated by cadherin	1	205.5×	0.009	CDH1
synapse assembly	1	115.4×	0.014	CDH1
collagen fibril organization	1	112.3×	0.014	PLOD2
response to toxic substance	1	105.3×	0.015	CDH1
cell morphogenesis	1	78.8×	0.019	CDH1
homophilic cell-cell adhesion	1	70.2×	0.020	CDH1
neuron projection development	1	61.1×	0.022	CDH1
negative regulation of cell migration	1	55.8×	0.023	CDH1
protein localization to plasma membrane	1	54.4×	0.023	CDH1
cell-cell adhesion	1	50.8×	0.023	CDH1
response to hypoxia	1	47.9×	0.024	PLOD2
regulation of gene expression	1	41.7×	0.026	CDH1
response to xenobiotic stimulus	1	34.5×	0.031	CDH1
cell migration	1	30.8×	0.033	CDH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDH1	0	0
PLOD2	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
CDH1	18	Binding:18
PLOD2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLOD2	1.14.11.4, 2.4.1.50	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	PLOD2
E	Difficult family or no structure, no drug	1	CDH1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDH1	18	—
PLOD2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.