Cholesteatoma

Summary

Cholesteatoma (MONDO:0006530) is a disease with 4 cohort genes (1 GWAS associations across 3 studies) and 16 clinical trials. Top therapeutic interventions include clonidine.

At a glance

• Cohort genes: 4
• GWAS associations: 1
• ClinVar variants: 6
• Clinical trials: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cholesteatoma
Mondo ID	MONDO:0006530
EFO	EFO:1000675
MeSH	D002781
DOID	DOID:869
NCIT	C2944
SNOMED CT	363668000
UMLS	C0008373
MedGen	3043
Is cancer (heuristic)	no

Also known as: cholesteatoma · cholesteatoma (disease) · congenital cholesteatoma (type) · primary acquired cholesteatoma (type) · secondary acquired cholesteatoma (type)

Data availability: 6 ClinVar variants · 1 GWAS association (3 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › keratosis › cholesteatoma

Related subtypes (8): keratosis follicularis spinulosa decalvans, acquired keratosis, palmoplantar keratosis, porokeratosis, hereditary papulotranslucent acrokeratoderma, acrokeratosis verruciformis, seborrheic keratosis, trichostasis spinulosa

Subtypes (3): cholesteatoma of external ear, cholesteatoma of middle ear, maxillary sinus cholesteatoma

Genetics & variants

GWAS landscape

1 GWAS associations across 3 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs568600712	5e-08	TBL1XR1 - LINC00501	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90481956	Verma A	2024	1,468	449,081	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436042	Zhou W	2018	608	404,888	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90651714	Liu TY	2025	231	227,473	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs568600712	3	177277077	T>C		intergenic_variant	TBL1XR1 - LINC00501	5e-08	Tier 4: intronic/intergenic

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 likely benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322006	NM_001994.3(F13B):c.1505C>G (p.Ser502Cys)	F13B	Pathogenic	no assertion criteria provided
1322005	NM_001366446.1(RABGAP1L):c.-34+24490G>A	RABGAP1L	Likely pathogenic	no assertion criteria provided
1322001	NM_000130.5(F5):c.5599+261A>G	F5	Uncertain significance	no assertion criteria provided
1322002	NM_000130.5(F5):c.5509C>A (p.Gln1837Lys)	F5	Uncertain significance	no assertion criteria provided
1322003	NM_001122770.3(ZBTB37):c.*17408A>C	ZBTB37	Uncertain significance	no assertion criteria provided
1322004	NM_001122770.3(ZBTB37):c.*17411G>A	ZBTB37	Likely benign	no assertion criteria provided

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
F13B	Orphanet:331	Congenital factor XIII deficiency
F5	Orphanet:131	Budd-Chiari syndrome
F5	Orphanet:326	Congenital factor V deficiency
F5	Orphanet:329217	Cerebral sinovenous thrombosis
F5	Orphanet:391320	East Texas bleeding disorder
F5	Orphanet:599579	Factor V Amsterdam bleeding disorder
F5	Orphanet:600194	Factor V Atlanta bleeding disorder

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RABGAP1L	HGNC:24663	ENSG00000152061	B7ZAP0	Rab GTPase-activating protein 1-like, isoform 10	clinvar
ZBTB37	HGNC:28365	ENSG00000185278	Q5TC79	Zinc finger and BTB domain-containing protein 37	clinvar
F13B	HGNC:3534	ENSG00000143278	P05160	Coagulation factor XIII B chain	clinvar
F5	HGNC:3542	ENSG00000198734	P12259	Coagulation factor V	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZBTB37	Zinc finger and BTB domain-containing protein 37	May be involved in transcriptional regulation.
F13B	Coagulation factor XIII B chain	The B chain of factor XIII is not catalytically active, but is thought to stabilize the A subunits and regulate the rate of transglutaminase formation by thrombin.
F5	Coagulation factor V	Central regulator of hemostasis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Complement	1	67.0×	0.045
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RABGAP1L	Other/Unknown	no		Rab-GAP-TBC_dom, PTB/PI_dom, PH-like_dom_sf
ZBTB37	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
F13B	Complement	yes		Sushi_SCR_CCP_dom, Sushi/SCR/CCP_sf, ComplSys_Reg/VirEntry_Med
F5	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
liver	2
right lobe of liver	2
Brodmann (1909) area 10	1
calcaneal tendon	1
vena cava	1
adrenal tissue	1
sperm	1
choroid plexus epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RABGAP1L	291	ubiquitous	marker	calcaneal tendon, Brodmann (1909) area 10, vena cava
ZBTB37	234	ubiquitous	marker	sperm, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
F13B	36	tissue_specific	marker	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
F5	206	broad	marker	right lobe of liver, liver, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
F5	1,754
F13B	995
ZBTB37	566
RABGAP1L	197

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
F5	P12259	18
F13B	P05160	2
RABGAP1L	B7ZAP0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZBTB37	Q5TC79	56.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 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
Defective cleavage of FV variant at a.a.534	1	1903.3×	0.003	F5
Defective cleavage of FV variant at R334	1	1903.3×	0.003	F5
Fibrin formation	1	439.2×	0.008	F13B
Amplification and propagation of coagulation cascade	1	317.2×	0.009	F5
Initiation of coagulation cascade	1	237.9×	0.009	F5
Cargo concentration in the ER	1	167.9×	0.011	F5
Regulation of clotting cascade	1	116.5×	0.013	F5
COPII-mediated vesicle transport	1	81.6×	0.017	F5
Post-translational protein phosphorylation	1	50.1×	0.023	F5
Platelet degranulation	1	43.9×	0.023	F5
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.023	F5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
blood coagulation	2	86.9×	0.002	F13B, F5
response to vitamin K	1	1404.3×	0.004	F5
blood coagulation, fibrin clot formation	1	421.3×	0.008	F13B
blood circulation	1	127.7×	0.017	F5
regulation of immune system process	1	117.0×	0.017	ZBTB37
regulation of cytokine production	1	62.0×	0.027	ZBTB37
regulation of protein localization	1	51.4×	0.028	RABGAP1L
endocytosis	1	23.8×	0.052	RABGAP1L
protein transport	1	11.0×	0.098	RABGAP1L
negative regulation of transcription by RNA polymerase II	1	4.4×	0.207	ZBTB37

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
F5	EDOXABAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
F5	2	4
RABGAP1L	0	0
ZBTB37	0	0
F13B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EDOXABAN	4	F5
RAZAXABAN	2	F5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
F5	10	Binding:10
F13B	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
EDOXABAN	4	F5
RAZAXABAN	2	F5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	F5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	F13B
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RABGAP1L, ZBTB37

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RABGAP1L	0	—
ZBTB37	0	—
F13B	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 16.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	15
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01638052	PHASE2	COMPLETED	Great Auricular Nerve Block for Children Undergoing Tympanomastoid Surgery
NCT05921643	Not specified	RECRUITING	Short- and Medium-term Evaluation of Mastoid Filling Using Bioactive Glass
NCT06268938	Not specified	ACTIVE_NOT_RECRUITING	Outcomes of Mastoid Obliteration Canal Wall Down Tympanomastoidectomy in Cholesteatoma Surgery
NCT06424704	Not specified	NOT_YET_RECRUITING	Chronic Suppurative Otitis Media Microbiology
NCT06738927	Not specified	NOT_YET_RECRUITING	Otological Study of Facial Cleft Patients Over 10 Years of Age (Excluding Isolated Cleft Lip) (EFEOF)
NCT00270660	Not specified	UNKNOWN	A Study of the Clinicopathologic Behaviour of the Different Types of Unsafe Chronic Otitis Media
NCT00682409	Not specified	COMPLETED	Magnetic Resonance (MR) Imaging in the Post Operative Follow-up of Cholesteatoma in Children
NCT01855425	Not specified	COMPLETED	Cone Beam CT for Diagnosis of Select Otorhinolaryngology (ENT) Indications at Lower Dose
NCT02019888	Not specified	COMPLETED	Wide Frequency Band Test of Hearing in Veterans
NCT02903550	Not specified	UNKNOWN	Usefulness of Non EPI-DWI-MRI / CT 3D Static Co-registration Prior to Surgery of Cholesteatomas
NCT03294421	Not specified	UNKNOWN	Combined Access Closed Tympanomastoidectomy: Microsurgery Allied to Endoscopy
NCT03305796	Not specified	UNKNOWN	Detection of Cholesteatoma Using Diffusion Magnetic Resonance Imaging
NCT03915392	Not specified	UNKNOWN	Diffusion Weighted MRI Accuracy in Cholesteatoma Localization
NCT03954288	Not specified	UNKNOWN	The Serum Sclerostin Levels in Cholesteatoma Patients
NCT04959539	Not specified	COMPLETED	Endoscopic Transcanal Tympanoplasty With Attico-antrostomy Versus Endoscopic-assisted Canal Wall up Mastoidectomy in Management of Localized Cholesteatoma: A Randomized Clinical Trial
NCT06016335	Not specified	COMPLETED	MRI-based Synthetic CT Images of the Head and Neck

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLONIDINE	4	1