Gingival overgrowth

Summary

Gingival overgrowth (MONDO:0002507) is a disease with 2 cohort genes and 24 clinical trials. Top therapeutic interventions include folic acid.

At a glance

• Cohort genes: 2
• ClinVar variants: 4
• Clinical trials: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	gingival overgrowth
Mondo ID	MONDO:0002507
MeSH	D019214
DOID	DOID:3086
ICD-10-CM	K06.1
SNOMED CT	54711002
UMLS	C0376480
MedGen	87712
Is cancer (heuristic)	no

Also known as: gingival enlargement

Data availability: 4 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › periodontal disorder › gingival disorder › gingival overgrowth

Related subtypes (5): gingival recession, gingivitis, pericoronitis, gingival neoplasm, leukoplakia of gingiva

Subtypes (3): epulis, gingival hypertrophy, hereditary gingival fibromatosis

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:

3 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
560221	NM_033310.3(KCNK4):c.515C>A (p.Ala172Glu)	KCNK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
560222	NM_033310.3(KCNK4):c.730G>C (p.Ala244Pro)	KCNK4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13919	NM_020975.6(RET):c.2753T>C (p.Met918Thr)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267799	46;XY;t(3;17)(p14.3;q24.3)dn		Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNK4	Orphanet:598603	Facial dysmorphism-hypertrichosis-epilepsy-intellectual disability/developmental delay-gingival overgrowth syndrome
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad 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
KCNK4	HGNC:6279	ENSG00000182450	Q9NYG8	Potassium channel subfamily K member 4	clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNK4	Potassium channel subfamily K member 4	K(+) channel that conducts voltage-dependent outward rectifying currents upon membrane depolarization.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	55.8×	0.036
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNK4	Ion channel	yes		2pore_dom_K_chnl, 2pore_dom_K_chnl_TRAAK, K_chnl_dom
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amygdala	1
nucleus accumbens	1
temporal lobe	1
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNK4	66	tissue_specific	yes	nucleus accumbens, temporal lobe, amygdala
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RET	4,203
KCNK4	1,057

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RET	P07949	34
KCNK4	Q9NYG8	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
TWIK related potassium channel (TREK)	1	1903.3×	0.006	KCNK4
Tandem pore domain potassium channels	1	475.8×	0.008	KCNK4
Formation of the nephric duct	1	317.2×	0.008	RET
Phase 4 - resting membrane potential	1	300.5×	0.008	KCNK4
NPAS4 regulates expression of target genes	1	248.3×	0.008	RET
Formation of the ureteric bud	1	248.3×	0.008	RET
RET signaling	1	129.8×	0.013	RET
Potassium Channels	1	67.2×	0.022	KCNK4
Cardiac conduction	1	54.4×	0.024	KCNK4
Muscle contraction	1	38.6×	0.031	KCNK4
RAF/MAP kinase cascade	1	30.5×	0.035	RET
Neuronal System	1	22.1×	0.045	KCNK4

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
embryonic epithelial tube formation	1	4213.0×	0.002	RET
posterior midgut development	1	4213.0×	0.002	RET
cellular response to alkaline pH	1	4213.0×	0.002	KCNK4
response to ultrasound	1	4213.0×	0.002	KCNK4
sensory perception of temperature stimulus	1	2808.7×	0.002	KCNK4
cellular response to temperature stimulus	1	2808.7×	0.002	KCNK4
positive regulation of metanephric glomerulus development	1	2808.7×	0.002	RET
cellular response to arachidonate	1	2808.7×	0.002	KCNK4
ureter maturation	1	2106.5×	0.002	RET
detection of mechanical stimulus involved in sensory perception of touch	1	2106.5×	0.002	KCNK4
Peyer’s patch morphogenesis	1	2106.5×	0.002	RET
GDF15-GFRAL signaling pathway	1	2106.5×	0.002	RET
lymphocyte migration into lymphoid organs	1	936.2×	0.004	RET
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	766.0×	0.004	RET
positive regulation of cell size	1	648.1×	0.005	RET
glial cell-derived neurotrophic factor receptor signaling pathway	1	601.9×	0.005	RET
membrane protein proteolysis	1	526.6×	0.005	RET
positive regulation of cell adhesion mediated by integrin	1	526.6×	0.005	RET
neuron cell-cell adhesion	1	495.6×	0.005	RET
enteric nervous system development	1	495.6×	0.005	RET
response to pain	1	443.5×	0.005	RET
regulation of axonogenesis	1	443.5×	0.005	RET
neuron maturation	1	401.2×	0.005	RET
cellular response to acidic pH	1	366.4×	0.005	KCNK4
cellular response to fatty acid	1	351.1×	0.005	KCNK4
neuronal action potential	1	240.7×	0.007	KCNK4
ureteric bud development	1	227.7×	0.007	RET
sensory perception of pain	1	187.2×	0.009	KCNK4
neural crest cell migration	1	168.5×	0.009	RET
regulation of cell adhesion	1	153.2×	0.010	RET

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): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 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
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
KCNK4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
KCNK4	18	Binding:18

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RET	1,586

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

30 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)
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RET
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	KCNK4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
KCNK4	18	—

Clinical trials & evidence

Clinical trials

Clinical trials: 24.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	20
PHASE3	1
PHASE2	1
PHASE1	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00781196	PHASE3	COMPLETED	Folic Acid Supplementation in Phenytoin Induced Gingival Overgrowth
NCT06806319	PHASE2	COMPLETED	Assessment of Growth Factors Levels Associated with Wound Healing After Soft Tissue Crown Lengthening
NCT04030767	PHASE1	UNKNOWN	Evaluating Lip Repositioning for the Treatment of Excess Gingival Display With and Without Pretreatment With Botox
NCT07169357	EARLY_PHASE1	ENROLLING_BY_INVITATION	Testing the Efficacy of Photobiomodulation Therapy and Hyaluronic Acid Gel on Post-surgical Healing After Gingivectomy
NCT06753305	Not specified	RECRUITING	The Effect of Ozone Therapy on Gingivoplasty
NCT00104026	Not specified	COMPLETED	Genes Associated With Hereditary and Drug-Induced Gingival Overgrowth
NCT01286298	Not specified	UNKNOWN	Diode Laser in Gingival Enlargement Related to Orthodontics
NCT01821157	Not specified	COMPLETED	Flapless Esthetic Crown Lengthening for the Treatment of Excessive Gingival Display
NCT03435068	Not specified	COMPLETED	Soft Tissue Wound Healing Following Different Gingivectomy Techniques
NCT03436537	Not specified	COMPLETED	Development and Validation of the Periodontal Aesthetic Perception Scale in Patients With Periodontal Problems
NCT03514316	Not specified	COMPLETED	Scalpel Versus Laser Gingivectomy in Orthodontic Patients in the Management of Periodontal Health
NCT03569683	Not specified	COMPLETED	Comparison Between Laser, Synthetic Gel and Herbal Gel as Topical Agents After Gum Surgery
NCT04016064	Not specified	COMPLETED	Temperature and Healing in Treatment of Gingival Enlargement
NCT04304391	Not specified	COMPLETED	Evaluation of Healing Process After Laser Asissted Gingivectomy Techniques
NCT04805463	Not specified	COMPLETED	Different Platelet Concentrates After Gingivectomy and Gingivoplasty Evaluation of Its Effect on Early Wound Healing.
NCT05787912	Not specified	COMPLETED	Efficacy of Hyaluronic Acid Gel and Photobiomodulation on Wound Healing After Surgical Gingivectomy
NCT06865092	Not specified	COMPLETED	Comparison of I-PRF, T-PRF, and 0.8% Hyaluronic Acid Applications in Wound Healing After Gingivectomy.
NCT07034625	Not specified	COMPLETED	Comparative Evaluation of Hyaluronic Acid Spray and Low-Level Laser Therapy on Wound Healing Following Gingivectomy: A Randomized, Noninferiority Trial
NCT07124143	Not specified	COMPLETED	The Effect of Platelet-Rich Plasma on Wound Healing After Gingivectomy
NCT07234994	Not specified	COMPLETED	Comparison of the Effect of Ozonized Gel to That of Photobiomodulation Therapy on Wound Healing Following Surgical Gingivectomy
NCT07263763	Not specified	COMPLETED	Gingival Hyperplasia Treatment With Surgical Scalpel vs Diode Laser in Orthodontic Patients.
NCT07517328	Not specified	COMPLETED	Wound Healing After Gingivectomy
NCT07551310	Not specified	COMPLETED	Lymphocyte Subpopulations in Peripheral Giant Cell Granuloma
NCT07575087	Not specified	COMPLETED	Comparison of Dual Digitally Guided vs Conventional Crown Lengthening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FOLIC ACID	4	1