Autosomal dominant nonsyndromic hearing loss 65

Summary

Autosomal dominant nonsyndromic hearing loss 65 (MONDO:0014470) is a disease caused by TBC1D24 (GenCC Strong), with 5 cohort genes.

At a glance

• Causal gene: TBC1D24 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 748

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 65
Mondo ID	MONDO:0014470
OMIM	616044
DOID	DOID:0110586
UMLS	C3892048
MedGen	856147
GARD	0018140
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 65 · autosomal dominant nonsyndromic deafness 65 · autosomal dominant nonsyndromic deafness caused by mutation in TBC1D24 · autosomal dominant nonsyndromic deafness type 65 · deafness, autosomal dominant 65 · deafness, autosomal dominant type 65 · DFNA65 · TBC1D24 autosomal dominant nonsyndromic deafness

Data availability: 748 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 65

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

600 retrieved; paginated sample, class counts are floors:

273 uncertain significance, 193 likely benign, 54 conflicting classifications of pathogenicity, 38 pathogenic, 18 benign/likely benign, 11 pathogenic/likely pathogenic, 7 likely pathogenic, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3243524	NC_000016.9:g.(?2550259)(3154076_?)del	FLYWCH1	Pathogenic	criteria provided, single submitter
1029242	NM_001199107.2(TBC1D24):c.965+2T>C	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066340	NM_001199107.2(TBC1D24):c.115G>C (p.Ala39Pro)	TBC1D24	Pathogenic	criteria provided, single submitter
1071941	NM_001199107.2(TBC1D24):c.642_793del (p.Trp215fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
1072207	NM_001199107.2(TBC1D24):c.715del (p.Val239fs)	TBC1D24	Pathogenic	criteria provided, single submitter
133246	NM_001199107.2(TBC1D24):c.533C>T (p.Ser178Leu)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1357131	NM_001199107.2(TBC1D24):c.1397del (p.Pro466fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1369893	NM_001199107.2(TBC1D24):c.56del (p.Ile19fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1378399	NM_001199107.2(TBC1D24):c.979A>T (p.Lys327Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
1397090	NM_001199107.2(TBC1D24):c.1540C>T (p.Gln514Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
1402576	NC_000016.9:g.(?2546150)(2550959_?)del	TBC1D24	Pathogenic	criteria provided, single submitter
1451981	NM_001199107.2(TBC1D24):c.1141dup (p.Arg381fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1453407	NM_001199107.2(TBC1D24):c.636G>A (p.Trp212Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
1456664	NM_001199107.2(TBC1D24):c.752del (p.Phe251fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
1459471	NM_001199107.2(TBC1D24):c.806del (p.Ile269fs)	TBC1D24	Pathogenic	criteria provided, single submitter
1473155	NM_001199107.2(TBC1D24):c.706G>A (p.Gly236Ser)	TBC1D24	Pathogenic	criteria provided, single submitter
183152	NM_001199107.2(TBC1D24):c.119G>T (p.Arg40Leu)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1966628	NM_001199107.2(TBC1D24):c.1505dup (p.Ser503fs)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1970211	NM_001199107.2(TBC1D24):c.668_669delinsAA (p.Cys223Ter)	TBC1D24	Pathogenic	criteria provided, single submitter
2035641	NM_001199107.2(TBC1D24):c.1574del (p.Gly525fs)	TBC1D24	Pathogenic	criteria provided, single submitter
207499	NM_001199107.2(TBC1D24):c.457G>A (p.Glu153Lys)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207503	NM_001199107.2(TBC1D24):c.680G>T (p.Arg227Leu)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207505	NM_001199107.2(TBC1D24):c.845C>G (p.Pro282Arg)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207507	NM_001199107.2(TBC1D24):c.475del (p.Leu159fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
2101220	NM_001199107.2(TBC1D24):c.1402_1409dup (p.Ser472fs)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2121170	NM_001199107.2(TBC1D24):c.1488del (p.Met497fs)	TBC1D24	Pathogenic	criteria provided, single submitter
2127078	NM_001199107.2(TBC1D24):c.270_286del (p.Pro91fs)	TBC1D24	Pathogenic	criteria provided, single submitter
2163597	NM_001199107.2(TBC1D24):c.132G>A (p.Trp44Ter)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
2938575	NM_001199107.2(TBC1D24):c.1078del (p.Arg360fs)	TBC1D24	Pathogenic	criteria provided, single submitter
2942773	NM_001199107.2(TBC1D24):c.309dup (p.Tyr104fs)	TBC1D24	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 9 · 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
TBC1D24	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 65	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
CCNF	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	gencc,clinvar
CCNF	HGNC:1591	ENSG00000162063	P41002	Cyclin-F	clinvar
MLST8	HGNC:24825	ENSG00000167965	Q9BVC4	Target of rapamycin complex subunit LST8	clinvar
FLYWCH1	HGNC:25404	ENSG00000059122	Q4VC44	FLYWCH-type zinc finger-containing protein 1	clinvar
EME2	HGNC:27289	ENSG00000197774	A4GXA9	Structure-specific endonuclease subunit EME2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
CCNF	Cyclin-F	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
MLST8	Target of rapamycin complex subunit LST8	Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids.
FLYWCH1	FLYWCH-type zinc finger-containing protein 1	Transcription cofactor.
EME2	Structure-specific endonuclease subunit EME2	Non-catalytic subunit of the structure-specific, heterodimeric DNA endonuclease MUS81-EME2 which is involved in the maintenance of genome stability.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · 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
Scaffold/PPI	1	3.5×	0.608
Transcription factor	1	1.6×	0.608
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
CCNF	Other/Unknown	no		F-box_dom, Cyclin_C-dom, Cyclin_N
MLST8	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
FLYWCH1	Transcription factor	no		Znf_FLYWCH, FLYWCH_N, FWCH1/FWCH2
EME2	Other/Unknown	no		ERCC4_domain, Mms4/EME1/EME2, EME1/EME2_C

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	3
right hemisphere of cerebellum	3
cerebellar cortex	2
Brodmann (1909) area 23	1
middle temporal gyrus	1
parotid gland	1
hair follicle	1
olfactory bulb	1
type B pancreatic cell	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
CCNF	213	ubiquitous	marker	type B pancreatic cell, olfactory bulb, hair follicle
MLST8	263	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
FLYWCH1	249	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
EME2	231	ubiquitous	marker	oviduct epithelium, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CCNF	6,626
MLST8	2,702
EME2	1,255
TBC1D24	1,016
FLYWCH1	826

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MLST8	Q9BVC4	45
CCNF	P41002	1
FLYWCH1	Q4VC44	1
EME2	A4GXA9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D24	Q9ULP9	84.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dengue virus modulates apoptosis	1	178.4×	0.038	MLST8
Regulation of TP53 Expression and Degradation	1	129.8×	0.038	MLST8
mTORC1-mediated signalling	1	119.0×	0.038	MLST8
Regulation of T cell activation by CD28 family	1	105.7×	0.038	MLST8
Constitutive Signaling by AKT1 E17K in Cancer	1	105.7×	0.038	MLST8
VEGFR2 mediated vascular permeability	1	102.0×	0.038	MLST8
Cellular response to heat stress	1	98.5×	0.038	MLST8
Energy dependent regulation of mTOR by LKB1-AMPK	1	98.5×	0.038	MLST8
CD28 dependent PI3K/Akt signaling	1	98.5×	0.038	MLST8
Co-stimulation by CD28	1	95.2×	0.038	MLST8
PI3K/AKT Signaling in Cancer	1	92.1×	0.038	MLST8
Rab regulation of trafficking	1	92.1×	0.038	TBC1D24
HSF1-dependent transactivation	1	79.3×	0.038	MLST8
Resolution of D-loop Structures through Holliday Junction Intermediates	1	75.1×	0.038	EME2
Response of endothelial cells to shear stress	1	75.1×	0.038	MLST8
Regulation of TP53 Degradation	1	73.2×	0.038	MLST8
Fanconi Anemia Pathway	1	69.6×	0.038	EME2
MTOR signalling	1	66.4×	0.038	MLST8
TBC/RABGAPs	1	64.9×	0.038	TBC1D24
Cellular responses to mechanical stimuli	1	64.9×	0.038	MLST8
Adaptive Immune System	2	14.9×	0.038	CCNF, MLST8
PTEN Regulation	1	57.1×	0.041	MLST8
Signaling by VEGF	1	54.9×	0.041	MLST8
Amino acids regulate mTORC1	1	50.1×	0.043	MLST8
Regulation of PTEN gene transcription	1	44.6×	0.046	MLST8
Cellular response to starvation	1	41.4×	0.047	MLST8
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	40.2×	0.047	MLST8
Autophagy	1	37.1×	0.050	MLST8
VEGFA-VEGFR2 Pathway	1	34.8×	0.051	MLST8
Regulation of TP53 Activity	1	33.2×	0.051	MLST8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
re-entry into mitotic cell cycle	1	1123.5×	0.015	CCNF
negative regulation of cellular response to oxidative stress	1	842.6×	0.015	TBC1D24
positive regulation of pentose-phosphate shunt	1	842.6×	0.015	MLST8
negative regulation of centrosome duplication	1	674.1×	0.015	CCNF
TORC2 signaling	1	306.4×	0.019	MLST8
cellular response to osmotic stress	1	240.7×	0.019	MLST8
positive regulation of neuron migration	1	198.3×	0.019	TBC1D24
resolution of meiotic recombination intermediates	1	187.2×	0.019	EME2
mitotic intra-S DNA damage checkpoint signaling	1	187.2×	0.019	EME2
positive regulation of lipid biosynthetic process	1	177.4×	0.019	MLST8
positive regulation of dendrite morphogenesis	1	177.4×	0.019	TBC1D24
TORC1 signaling	1	160.5×	0.019	MLST8
TOR signaling	1	153.2×	0.019	MLST8
DNA damage response	2	21.4×	0.019	MLST8, FLYWCH1
positive regulation of glycolytic process	1	134.8×	0.020	MLST8
positive regulation of excitatory postsynaptic potential	1	105.3×	0.021	TBC1D24
positive regulation of TOR signaling	1	99.1×	0.021	MLST8
cellular response to nutrient levels	1	93.6×	0.021	MLST8
axon development	1	91.1×	0.021	TBC1D24
placenta development	1	88.7×	0.021	CCNF
synaptic vesicle endocytosis	1	86.4×	0.021	TBC1D24
replication fork processing	1	84.3×	0.021	EME2
dendrite development	1	78.4×	0.022	TBC1D24
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	74.9×	0.022	CCNF
positive regulation of actin filament polymerization	1	66.1×	0.024	MLST8
telomere maintenance	1	53.5×	0.028	EME2
negative regulation of autophagy	1	51.9×	0.028	MLST8
double-strand break repair	1	40.6×	0.034	EME2
G1/S transition of mitotic cell cycle	1	40.1×	0.034	CCNF
positive regulation of cell growth	1	36.6×	0.036	MLST8

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) 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
MLST8	EVEROLIMUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLST8	13	4
TBC1D24	0	0
CCNF	0	0
FLYWCH1	0	0
EME2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EVEROLIMUS	4	MLST8
SIROLIMUS	4	MLST8
DACTOLISIB	3	MLST8
OMIPALISIB	2	MLST8
VISTUSERTIB	2	MLST8
OSI-027	2	MLST8
SAPANISERTIB	2	MLST8
ONATASERTIB	2	MLST8
CC-115	2	MLST8
PAXALISIB	2	MLST8
BIMIRALISIB	2	MLST8
AZD-8055	1	MLST8
RMC-5552	1	MLST8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MLST8	275	Binding:275

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MLST8	275

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

13 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)
EVEROLIMUS	4	MLST8
SIROLIMUS	4	MLST8
DACTOLISIB	3	MLST8
OMIPALISIB	2	MLST8
VISTUSERTIB	2	MLST8
OSI-027	2	MLST8
SAPANISERTIB	2	MLST8
ONATASERTIB	2	MLST8
CC-115	2	MLST8
PAXALISIB	2	MLST8
BIMIRALISIB	2	MLST8
AZD-8055	1	MLST8
RMC-5552	1	MLST8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MLST8
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	4	TBC1D24, CCNF, FLYWCH1, EME2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBC1D24	0	—
CCNF	0	—
FLYWCH1	0	—
EME2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.