Waardenburg syndrome type 1

Summary

Waardenburg syndrome type 1 (MONDO:0008670) is a disease caused by PAX3 (GenCC Definitive), with 6 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PAX3 (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 149
• Phenotypes (HPO): 32
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000303	Mandibular prognathia	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000478	Abnormality of the eye	Very frequent (80-99%)
HP:0000504	Abnormality of vision	Very frequent (80-99%)
HP:0000506	Telecanthus	Very frequent (80-99%)
HP:0000574	Thick eyebrow	Very frequent (80-99%)
HP:0000632	Lacrimation abnormality	Very frequent (80-99%)
HP:0001053	Hypopigmented skin patches	Very frequent (80-99%)
HP:0001100	Heterochromia iridis	Very frequent (80-99%)
HP:0002211	White forelock	Very frequent (80-99%)
HP:0002226	White eyebrow	Very frequent (80-99%)
HP:0002227	White eyelashes	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0005599	Hypopigmentation of hair	Very frequent (80-99%)
HP:0008527	Congenital sensorineural hearing impairment	Very frequent (80-99%)
HP:0011364	White hair	Very frequent (80-99%)
HP:0000430	Underdeveloped nasal alae	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Frequent (30-79%)
HP:0000664	Synophrys	Frequent (30-79%)
HP:0001595	Abnormality of the hair	Frequent (30-79%)
HP:0002216	Premature graying of hair	Frequent (30-79%)
HP:0010804	Tented upper lip vermilion	Frequent (30-79%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000204	Cleft upper lip	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000912	Sprengel anomaly	Occasional (5-29%)
HP:0002251	Aganglionic megacolon	Occasional (5-29%)
HP:0002414	Spina bifida	Occasional (5-29%)
HP:0002435	Meningocele	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Waardenburg syndrome type 1
Mondo ID	MONDO:0008670
OMIM	193500
Orphanet	894
DOID	DOID:0110948
ICD-11	547536187
NCIT	C75008
UMLS	C1847800
MedGen	376211
GARD	0005519
Is cancer (heuristic)	no

Also known as: Waardenburg syndrome type 1 · Waardenburg syndrome type I · Waardenburg syndrome, type 1 · Waardenburg’s syndrome type 1 · WS1

Data availability: 149 ClinVar variants · 4 GenCC gene-disease records · 4 cell lines.

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 › Waardenburg syndrome › Waardenburg syndrome type 1

Related subtypes (4): Waardenburg syndrome type 3, Waardenburg syndrome type 2, Waardenburg-Shah syndrome, Waardenburg syndrome 2F

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

149 retrieved; paginated sample, class counts are floors:

62 pathogenic, 52 likely pathogenic, 15 uncertain significance, 11 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703585	GRCh37/hg19 2q36.1-36.2(chr2:222902251-226084516)	ACSL3	Pathogenic	no assertion criteria provided
3601587	NM_181458.4(PAX3):c.65del (p.Arg22fs)	CCDC140	Pathogenic	criteria provided, single submitter
995917	GRCh37/hg19 2q36.1(chr2:222199886-222298997)	EPHA4	Pathogenic	criteria provided, single submitter
3601598	NM_181458.4(PAX3):c.992del (p.Pro331fs)	LOC126806529	Pathogenic	criteria provided, single submitter
4688312	NM_181458.4(PAX3):c.987_988del (p.His329fs)	LOC126806529	Pathogenic	criteria provided, single submitter
800731	NM_181458.4(PAX3):c.1076_1077del (p.Thr359fs)	LOC126806529	Pathogenic	no assertion criteria provided
545015	NM_001354604.2(MITF):c.1031+1G>A	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
1048552	NM_181458.4(PAX3):c.*175C>T	PAX3	Pathogenic	criteria provided, single submitter
1048553	NM_181458.4(PAX3):c.123del (p.Gly42fs)	PAX3	Pathogenic	criteria provided, single submitter
1064868	NM_181458.4(PAX3):c.366_367del (p.Asn125fs)	PAX3	Pathogenic	criteria provided, single submitter
1185059	NM_181458.4(PAX3):c.372_373del (p.Asn125fs)	PAX3	Pathogenic	criteria provided, single submitter
1202632	NM_181458.4(PAX3):c.586+2T>A	PAX3	Pathogenic	criteria provided, single submitter
1684545	NM_181458.4(PAX3):c.713T>C (p.Phe238Ser)	PAX3	Pathogenic	no assertion criteria provided
228387	NM_181458.4(PAX3):c.668G>A (p.Arg223Gln)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
235094	NM_181458.4(PAX3):c.415A>T (p.Lys139Ter)	PAX3	Pathogenic	no assertion criteria provided
279964	NM_181458.4(PAX3):c.812G>A (p.Arg271His)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
280007	NM_181458.4(PAX3):c.784C>T (p.Arg262Ter)	PAX3	Pathogenic	criteria provided, multiple submitters, no conflicts
30595	NM_181458.4(PAX3):c.238C>G (p.His80Asp)	PAX3	Pathogenic	no assertion criteria provided
30596	NM_181458.4(PAX3):c.556del (p.His186fs)	PAX3	Pathogenic	no assertion criteria provided
3344079	NM_181458.4(PAX3):c.793-1G>C	PAX3	Pathogenic	criteria provided, single submitter
3353601	NM_181458.4(PAX3):c.232G>A (p.Val78Met)	PAX3	Pathogenic	criteria provided, single submitter
3376858	NM_181458.4(PAX3):c.1253del (p.Gly418fs)	PAX3	Pathogenic	criteria provided, single submitter
3377037	NM_181458.4(PAX3):c.86-2A>C	PAX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382706	NM_181458.4(PAX3):c.452-1G>A	PAX3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3601570	NM_181458.4(PAX3):c.169dup (p.His57fs)	PAX3	Pathogenic	criteria provided, single submitter
3601575	NM_181458.4(PAX3):c.236C>G (p.Ser79Cys)	PAX3	Pathogenic	criteria provided, single submitter
3601577	NM_181458.4(PAX3):c.341_342del (p.Val114fs)	PAX3	Pathogenic	criteria provided, single submitter
3601578	NM_181458.4(PAX3):c.348del (p.Ile118fs)	PAX3	Pathogenic	criteria provided, single submitter
3601580	NM_181458.4(PAX3):c.358G>T (p.Glu120Ter)	PAX3	Pathogenic	criteria provided, single submitter
3601581	NM_181458.4(PAX3):c.451+1G>C	PAX3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 11 · 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
PAX3	Definitive	Autosomal dominant	Waardenburg syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAX3	Orphanet:1529	Craniofacial-deafness-hand syndrome
PAX3	Orphanet:894	Waardenburg syndrome type 1
PAX3	Orphanet:896	Waardenburg syndrome type 3
PAX3	Orphanet:99756	Alveolar rhabdomyosarcoma
MITF	Orphanet:293822	MITF-related melanoma and renal cell carcinoma predisposition syndrome
MITF	Orphanet:319298	Papillary renal cell carcinoma
MITF	Orphanet:404511	Clear cell papillary renal cell carcinoma
MITF	Orphanet:42665	Tietz syndrome
MITF	Orphanet:618	Familial melanoma
MITF	Orphanet:895	Waardenburg syndrome type 2
MITF	Orphanet:897	Waardenburg-Shah syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAX3	HGNC:8617	ENSG00000135903	P23760	Paired box protein Pax-3	gencc,clinvar
CCDC140	HGNC:26514	ENSG00000163081	Q96MF4	Coiled-coil domain-containing protein 140	clinvar
EPHA4	HGNC:3388	ENSG00000116106	P54764	Ephrin type-A receptor 4	clinvar
ACSL3	HGNC:3570	ENSG00000123983	O95573	Fatty acid CoA ligase Acsl3	clinvar
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	clinvar
POLR2F	HGNC:9193	ENSG00000100142	P61218	DNA-directed RNA polymerases I, II, and III subunit RPABC2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAX3	Paired box protein Pax-3	Transcription factor that may regulate cell proliferation, migration and apoptosis.
EPHA4	Ephrin type-A receptor 4	Receptor tyrosine kinase which binds membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells.
ACSL3	Fatty acid CoA ligase Acsl3	Acyl-CoA synthetases (ACSL) activates long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation.
MITF	Microphthalmia-associated transcription factor	Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis.
POLR2F	DNA-directed RNA polymerases I, II, and III subunit RPABC2	DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	4.6×	0.396
Transcription factor	2	2.8×	0.396
Enzyme (other)	1	2.0×	0.543
Other/Unknown	2	0.6×	0.936

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAX3	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
CCDC140	Other/Unknown	no
EPHA4	Kinase	yes	2.7.10.1	Prot_kinase_dom, EPH_LBD, Ser-Thr/Tyr_kinase_cat_dom
ACSL3	Enzyme (other)	yes	6.2.1.3	AMP-dep_synth/lig_dom, AMP-binding_CS, ANL_N_sf
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N
POLR2F	Other/Unknown	no		Pol_omega/Rpo6/RPB6, Rpo6/Rpb6, DNA-dir_RNA_polK_14-18kDa_CS

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	2
male germ line stem cell (sensu Vertebrata) in testis	1
nasal cavity mucosa	1
olfactory segment of nasal mucosa	1
epithelium of nasopharynx	1
mucosa of paranasal sinus	1
superficial temporal artery	1
frontal pole	1
middle temporal gyrus	1
endothelial cell	1
lateral nuclear group of thalamus	1
pigmented layer of retina	1
retina	1
skeletal muscle tissue of biceps brachii	1
C1 segment of cervical spinal cord	1
spinal cord	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAX3	116	broad	marker	olfactory segment of nasal mucosa, male germ line stem cell (sensu Vertebrata) in testis, nasal cavity mucosa
CCDC140	42		yes	superficial temporal artery, epithelium of nasopharynx, mucosa of paranasal sinus
EPHA4	271	ubiquitous	marker	Brodmann (1909) area 23, frontal pole, middle temporal gyrus
ACSL3	293	ubiquitous	marker	endothelial cell, lateral nuclear group of thalamus, Brodmann (1909) area 23
MITF	293	ubiquitous	marker	pigmented layer of retina, retina, skeletal muscle tissue of biceps brachii
POLR2F	293	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPHA4	3,214
ACSL3	3,134
PAX3	2,960
MITF	2,908
POLR2F	369
CCDC140	324

Intra-cohort edges

A	B	Sources
CCDC140	PAX3	string_interaction
MITF	PAX3	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR2F	P61218	60
EPHA4	P54764	17
MITF	O75030	12
PAX3	P23760	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSL3	O95573	88.79
CCDC140	Q96MF4	58.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 127. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcriptional and post-translational regulation of MITF-M expression and activity	2	71.4×	0.039	PAX3, MITF
Free fatty acids regulate insulin secretion	1	761.3×	0.041	ACSL3
Intracellular metabolism of fatty acids regulates insulin secretion	1	761.3×	0.041	ACSL3
Regulation of MITF-M dependent genes involved in metabolism	1	761.3×	0.041	MITF
Regulation of MITF-M dependent genes involved in invasion	1	571.0×	0.041	MITF
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	326.3×	0.041	MITF
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	175.7×	0.041	MITF
FGFR2 mutant receptor activation	1	152.3×	0.041	POLR2F
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	134.3×	0.041	MITF
RNA Polymerase III Chain Elongation	1	126.9×	0.041	POLR2F
Regulation of MITF-M-dependent genes involved in apoptosis	1	126.9×	0.041	MITF
Specification of the neural plate border	1	126.9×	0.041	PAX3
Signaling by FGFR2 IIIa TM	1	120.2×	0.041	POLR2F
SUMOylation of transcription factors	1	114.2×	0.041	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	114.2×	0.041	MITF
Abortive elongation of HIV-1 transcript in the absence of Tat	1	99.3×	0.041	POLR2F
RNA Polymerase III Transcription Termination	1	99.3×	0.041	POLR2F
MicroRNA (miRNA) biogenesis	1	91.4×	0.041	POLR2F
Synthesis of very long-chain fatty acyl-CoAs	1	91.4×	0.041	ACSL3
Activation of HOX genes during differentiation	1	87.8×	0.041	POLR2F
Fatty acyl-CoA biosynthesis	1	87.8×	0.041	ACSL3
Signaling by FGFR in disease	1	84.6×	0.041	POLR2F
FGFR2 alternative splicing	1	84.6×	0.041	POLR2F
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	84.6×	0.041	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	81.6×	0.041	POLR2F
Signaling by FGFR2	1	81.6×	0.041	POLR2F
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	81.6×	0.041	POLR2F
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	81.6×	0.041	POLR2F
RNA Pol II CTD phosphorylation and interaction with CE	1	81.6×	0.041	POLR2F
PIWI-interacting RNA (piRNA) biogenesis	1	78.8×	0.041	POLR2F

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
neuron projection fasciculation	1	3370.4×	0.007	EPHA4
fasciculation of motor neuron axon	1	1685.2×	0.007	EPHA4
melanocyte apoptotic process	1	1685.2×	0.007	MITF
regulation of RNA biosynthetic process	1	1685.2×	0.007	MITF
regulation of astrocyte differentiation	1	1123.5×	0.007	EPHA4
fasciculation of sensory neuron axon	1	1123.5×	0.007	EPHA4
regulation of modification of synaptic structure	1	1123.5×	0.007	EPHA4
positive regulation of phosphatidylcholine biosynthetic process	1	1123.5×	0.007	ACSL3
positive regulation of secretion	1	842.6×	0.007	ACSL3
neuron projection guidance	1	842.6×	0.007	EPHA4
negative regulation of cellular response to hypoxia	1	842.6×	0.007	EPHA4
obsolete negative regulation of proteolysis involved in protein catabolic process	1	842.6×	0.007	EPHA4
positive regulation of leukocyte adhesion to arterial endothelial cell	1	842.6×	0.007	EPHA4
negative regulation of cell migration	2	44.6×	0.007	EPHA4, MITF
nephric duct morphogenesis	1	674.1×	0.008	EPHA4
positive regulation of Golgi to plasma membrane protein transport	1	561.7×	0.009	ACSL3
corticospinal tract morphogenesis	1	481.5×	0.009	EPHA4
long-chain fatty-acyl-CoA metabolic process	1	481.5×	0.009	ACSL3
synapse pruning	1	481.5×	0.009	EPHA4
regulation of synapse pruning	1	421.3×	0.010	EPHA4
positive regulation of DNA-templated transcription initiation	1	374.5×	0.010	MITF
long-chain fatty acid import into cell	1	337.0×	0.010	ACSL3
positive regulation of amyloid precursor protein catabolic process	1	337.0×	0.010	EPHA4
tRNA transcription by RNA polymerase III	1	306.4×	0.010	POLR2F
regulation of osteoclast differentiation	1	306.4×	0.010	MITF
negative regulation of axon regeneration	1	306.4×	0.010	EPHA4
transcription by RNA polymerase I	1	280.9×	0.010	POLR2F
glial cell migration	1	280.9×	0.010	EPHA4
negative regulation of long-term synaptic potentiation	1	259.3×	0.011	EPHA4
very-low-density lipoprotein particle assembly	1	240.7×	0.011	ACSL3

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
EPHA4	PONATINIB
MITF	PERHEXILINE MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EPHA4	34	4
MITF	3	4
PAX3	0	0
CCDC140	0	0
ACSL3	0	0
POLR2F	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	EPHA4
FEDRATINIB	4	EPHA4
TIVOZANIB	4	EPHA4
SORAFENIB	4	EPHA4
DASATINIB ANHYDROUS	4	EPHA4
VANDETANIB	4	EPHA4
NILOTINIB	4	EPHA4
BOSUTINIB	4	EPHA4
DASATINIB	4	EPHA4
CRIZOTINIB	4	EPHA4
PERHEXILINE MALEATE	4	MITF
SARACATINIB	3	EPHA4
CANERTINIB	3	EPHA4
TESEVATINIB	3	EPHA4
POZIOTINIB	3	EPHA4
ALISERTIB	3	EPHA4
LESTAURTINIB	3	EPHA4
NIFUROXAZIDE	3	MITF
DORAMAPIMOD	2	EPHA4
NEFLAMAPIMOD	2	EPHA4
FORETINIB	2	EPHA4
BAFETINIB	2	EPHA4
SAPITINIB	2	EPHA4
GOLVATINIB	2	EPHA4
DANUSERTIB	2	EPHA4
TG100-801	2	EPHA4
R-406	2	EPHA4
AT-9283	2	EPHA4
RAF-265	2	EPHA4
MILCICLIB	2	EPHA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
EPHA4	286	Binding:286
PAX3	17	Binding:17
MITF	10	Functional:10
ACSL3	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPHA4	2.7.10.1	receptor protein-tyrosine kinase
ACSL3	6.2.1.3	long-chain-fatty-acid-CoA ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EPHA4	286

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	EPHA4
FEDRATINIB	4	EPHA4
TIVOZANIB	4	EPHA4
SORAFENIB	4	EPHA4
DASATINIB ANHYDROUS	4	EPHA4
VANDETANIB	4	EPHA4
NILOTINIB	4	EPHA4
BOSUTINIB	4	EPHA4
DASATINIB	4	EPHA4
CRIZOTINIB	4	EPHA4
PERHEXILINE MALEATE	4	MITF
SARACATINIB	3	EPHA4
CANERTINIB	3	EPHA4
TESEVATINIB	3	EPHA4
POZIOTINIB	3	EPHA4
ALISERTIB	3	EPHA4
LESTAURTINIB	3	EPHA4
NIFUROXAZIDE	3	MITF
DORAMAPIMOD	2	EPHA4
NEFLAMAPIMOD	2	EPHA4
FORETINIB	2	EPHA4
BAFETINIB	2	EPHA4
SAPITINIB	2	EPHA4
GOLVATINIB	2	EPHA4
DANUSERTIB	2	EPHA4
TG100-801	2	EPHA4
R-406	2	EPHA4
AT-9283	2	EPHA4
RAF-265	2	EPHA4
MILCICLIB	2	EPHA4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	EPHA4, MITF
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ACSL3
E	Difficult family or no structure, no drug	3	PAX3, CCDC140, POLR2F

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)
PAX3	17	—
CCDC140	0	—
ACSL3	2	—
POLR2F	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns