lissencephaly due to LIS1 mutation

Summary

lissencephaly due to LIS1 mutation (MONDO:0011830) is a disease caused by variants in PAFAH1B1 and CEP85L, with 4 cohort genes.

At a glance

• Causal genes: PAFAH1B1 (GenCC Definitive), CEP85L (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 150
• Phenotypes (HPO): 44

Clinical features

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0006891	Thick cerebral cortex	Very frequent (80-99%)
HP:0012469	Infantile spasms	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0001273	Abnormal corpus callosum morphology	Frequent (30-79%)
HP:0001302	Pachygyria	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002389	Cavum septum pellucidum	Frequent (30-79%)
HP:0002421	Poor head control	Frequent (30-79%)
HP:0002445	Tetraplegia	Frequent (30-79%)
HP:0002463	Language impairment	Frequent (30-79%)
HP:0007772	Impaired smooth pursuit	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0010850	EEG with spike-wave complexes	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012520	Dilation of Virchow-Robin spaces	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0020191	Anterior predominant thick cortex pachygyria	Frequent (30-79%)
HP:0025336	Delayed ability to sit	Frequent (30-79%)
HP:0031882	Agyria	Frequent (30-79%)
HP:0032398	Dysgyria	Frequent (30-79%)
HP:0200134	Epileptic encephalopathy	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002179	Opisthotonus	Occasional (5-29%)
HP:0002187	Intellectual disability, profound	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0003265	Neonatal hyperbilirubinemia	Occasional (5-29%)
HP:0007270	Atypical absence seizure	Occasional (5-29%)
HP:0010818	Generalized tonic seizure	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0011153	Focal motor seizure	Occasional (5-29%)
HP:0011201	EEG with changes in voltage	Occasional (5-29%)
HP:0011951	Aspiration pneumonia	Occasional (5-29%)
HP:0020189	Posterior predominant thick cortex pachygyria	Occasional (5-29%)
HP:0001320	Cerebellar vermis hypoplasia	Very rare (<1-4%)
HP:0002478	Progressive spastic quadriplegia	Very rare (<1-4%)
HP:0002650	Scoliosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly due to LIS1 mutation
Mondo ID	MONDO:0011830
OMIM	607432
Orphanet	95232
DOID	DOID:0112237
UMLS	C4749301
MedGen	1657090
GARD	0016838
Is cancer (heuristic)	no

Also known as: LIS1 · lissencephaly 1 · PAFAH1B1-related lissencephaly

Data availability: 150 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › lissencephaly spectrum disorders › classic lissencephaly › lissencephaly due to LIS1 mutation

Related subtypes (3): Miller-Dieker lissencephaly syndrome, lissencephaly type 1 due to doublecortin gene mutation, isolated lissencephaly type 1 without known genetic defects

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

150 retrieved; paginated sample, class counts are floors:

88 pathogenic, 29 likely pathogenic, 13 uncertain significance, 9 conflicting classifications of pathogenicity, 7 pathogenic/likely pathogenic, 2 benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
4083495	GRCh37/hg19 17p13.3(chr17:2568666-2598574)x1	CLUH	Pathogenic	criteria provided, single submitter
1164013	NM_000430.4(PAFAH1B1):c.1136A>G (p.His379Arg)	PAFAH1B1	Pathogenic	no assertion criteria provided
1334701	NM_000430.4(PAFAH1B1):c.1083_1084dup (p.Leu362fs)	PAFAH1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458748	NM_000430.4(PAFAH1B1):c.1009_1022del (p.His337fs)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159486	NM_000430.4(PAFAH1B1):c.1002+5G>A	PAFAH1B1	Pathogenic	criteria provided, single submitter
159489	NM_000430.4(PAFAH1B1):c.1009C>T (p.His337Tyr)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159490	NM_000430.4(PAFAH1B1):c.1024_1031del (p.Arg342fs)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159491	NM_000430.4(PAFAH1B1):c.1063del (p.Ser355fs)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159492	NM_000430.4(PAFAH1B1):c.1064G>A (p.Ser355Asn)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159493	NM_000430.4(PAFAH1B1):c.1100del (p.Tyr367fs)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159494	NM_000430.4(PAFAH1B1):c.1111C>T (p.Arg371Ter)	PAFAH1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
159495	NM_000430.4(PAFAH1B1):c.1135C>T (p.His379Tyr)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159496	NM_000430.4(PAFAH1B1):c.1159+2T>A	PAFAH1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
159497	NM_000430.4(PAFAH1B1):c.1159G>T (p.Asp387Tyr)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159498	NM_000430.4(PAFAH1B1):c.1165C>T (p.His389Tyr)	PAFAH1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159501	NM_000430.4(PAFAH1B1):c.1196G>C (p.Ser399Thr)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159502	NM_000430.4(PAFAH1B1):c.1201G>C (p.Asp401His)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159504	NM_000430.4(PAFAH1B1):c.1233A>C (p.Ter411Cys)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159505	NM_000430.4(PAFAH1B1):c.136_137del (p.Lys46fs)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159506	NM_000430.4(PAFAH1B1):c.152del (p.Leu51fs)	PAFAH1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
159509	NM_000430.4(PAFAH1B1):c.192+1G>A	PAFAH1B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
159510	NM_000430.4(PAFAH1B1):c.192+1G>T	PAFAH1B1	Pathogenic	criteria provided, single submitter
159511	NM_000430.4(PAFAH1B1):c.192G>C (p.Lys64Asn)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159512	NM_000430.4(PAFAH1B1):c.265C>T (p.Arg89Ter)	PAFAH1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
159513	NM_000430.4(PAFAH1B1):c.305dup (p.Tyr102Ter)	PAFAH1B1	Pathogenic	no assertion criteria provided
159514	NM_000430.4(PAFAH1B1):c.33-3C>T	PAFAH1B1	Pathogenic	criteria provided, single submitter
159515	NM_000430.4(PAFAH1B1):c.371T>A (p.Val124Asp)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159516	NM_000430.4(PAFAH1B1):c.37C>T (p.Arg13Ter)	PAFAH1B1	Pathogenic	criteria provided, multiple submitters, no conflicts
159517	NM_000430.4(PAFAH1B1):c.386A>T (p.Asp129Val)	PAFAH1B1	Pathogenic	criteria provided, single submitter
159519	NM_000430.4(PAFAH1B1):c.399+1G>A	PAFAH1B1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
CEP85L	Definitive	Autosomal dominant	lissencephaly 10	4
PAFAH1B1	Definitive	Autosomal dominant	lissencephaly due to LIS1 mutation	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAFAH1B1	Orphanet:217385	17p13.3 microduplication syndrome
PAFAH1B1	Orphanet:531	Miller-Dieker syndrome
PAFAH1B1	Orphanet:95232	Lissencephaly due to LIS1 mutation
PAFAH1B1	Orphanet:99796	Subcortical band heterotopia
CEP85L	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome
TUBA1A	Orphanet:171680	Lissencephaly due to TUBA1A mutation
TUBA1A	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBA1A	Orphanet:467166	Tubulinopathy-associated dysgyria
TUBA1A	Orphanet:994	Fetal akinesia deformation sequence

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
PAFAH1B1	HGNC:8574	ENSG00000007168	P43034	Platelet-activating factor acetylhydrolase IB subunit beta	gencc,clinvar
CEP85L	HGNC:21638	ENSG00000111860	Q5SZL2	Centrosomal protein of 85 kDa-like	gencc
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	clinvar
CLUH	HGNC:29094	ENSG00000132361	O75153	Clustered mitochondria protein homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAFAH1B1	Platelet-activating factor acetylhydrolase IB subunit beta	Regulatory subunit (beta subunit) of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)), an enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and participate…
CEP85L	Centrosomal protein of 85 kDa-like	Plays an essential role in neuronal cell migration.
TUBA1A	Tubulin alpha-1A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
CLUH	Clustered mitochondria protein homolog	mRNA-binding protein involved in proper cytoplasmic distribution of mitochondria.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	4.3×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAFAH1B1	Scaffold/PPI	no		WD40_rpt, LisH, WD40/YVTN_repeat-like_dom_sf
CEP85L	Other/Unknown	no		Cep85/Cep85L, CC4_CEP85
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
CLUH	Other/Unknown	no		TPR-like_helical_dom_sf, GSKIP_dom_sf, CLU_dom

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 cell	1
middle temporal gyrus	1
sperm	1
pylorus	1
thymus	1
tibialis anterior	1
cortical plate	1
endothelial cell	1
ganglionic eminence	1
apex of heart	1
gingival epithelium	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAFAH1B1	295	ubiquitous	marker	sperm, male germ cell, middle temporal gyrus
CEP85L	248	ubiquitous	marker	thymus, tibialis anterior, pylorus
TUBA1A	288	ubiquitous	marker	endothelial cell, cortical plate, ganglionic eminence
CLUH	283	ubiquitous	marker	gingival epithelium, apex of heart, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAFAH1B1	3,181
CLUH	1,875
TUBA1A	1,436
CEP85L	581

Intra-cohort edges

A	B	Sources
CEP85L	TUBA1A	intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAFAH1B1	P43034	21
TUBA1A	Q71U36	15

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLUH	O75153	83.11
CEP85L	Q5SZL2	64.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 97. 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
Centrosome maturation	2	253.8×	6e-04	PAFAH1B1, TUBA1A
COPI-independent Golgi-to-ER retrograde traffic	2	207.6×	6e-04	PAFAH1B1, TUBA1A
Loss of Nlp from mitotic centrosomes	2	158.6×	6e-04	PAFAH1B1, TUBA1A
Loss of proteins required for interphase microtubule organization from the centrosome	2	158.6×	6e-04	PAFAH1B1, TUBA1A
AURKA Activation by TPX2	2	152.3×	6e-04	PAFAH1B1, TUBA1A
Recruitment of mitotic centrosome proteins and complexes	2	135.9×	6e-04	PAFAH1B1, TUBA1A
Golgi-to-ER retrograde transport	2	132.8×	6e-04	PAFAH1B1, TUBA1A
Regulation of PLK1 Activity at G2/M Transition	2	126.9×	6e-04	PAFAH1B1, TUBA1A
Mitotic G2-G2/M phases	2	126.9×	6e-04	PAFAH1B1, TUBA1A
G2/M Transition	2	126.9×	6e-04	PAFAH1B1, TUBA1A
Recruitment of NuMA to mitotic centrosomes	2	116.5×	6e-04	PAFAH1B1, TUBA1A
Anchoring of the basal body to the plasma membrane	2	113.1×	6e-04	PAFAH1B1, TUBA1A
Cilium Assembly	2	108.8×	6e-04	PAFAH1B1, TUBA1A
Intra-Golgi and retrograde Golgi-to-ER traffic	2	104.8×	6e-04	PAFAH1B1, TUBA1A
Mitotic Metaphase and Anaphase	2	96.8×	6e-04	PAFAH1B1, TUBA1A
Mitotic Anaphase	2	96.8×	6e-04	PAFAH1B1, TUBA1A
EML4 and NUDC in mitotic spindle formation	2	92.8×	7e-04	PAFAH1B1, TUBA1A
Resolution of Sister Chromatid Cohesion	2	86.5×	7e-04	PAFAH1B1, TUBA1A
RHO GTPases Activate Formins	2	77.7×	8e-04	PAFAH1B1, TUBA1A
Mitotic Prometaphase	2	69.2×	1e-03	PAFAH1B1, TUBA1A
RHO GTPase Effectors	2	68.0×	1e-03	PAFAH1B1, TUBA1A
Organelle biogenesis and maintenance	2	66.0×	1e-03	PAFAH1B1, TUBA1A
M Phase	2	66.0×	1e-03	PAFAH1B1, TUBA1A
Separation of Sister Chromatids	2	60.7×	0.001	PAFAH1B1, TUBA1A
Cell Cycle, Mitotic	2	48.2×	0.002	PAFAH1B1, TUBA1A
Membrane Trafficking	2	37.1×	0.003	PAFAH1B1, TUBA1A
Cell Cycle	2	36.0×	0.003	PAFAH1B1, TUBA1A
Vesicle-mediated transport	2	34.8×	0.003	PAFAH1B1, TUBA1A
Signaling by Rho GTPases	2	34.2×	0.003	PAFAH1B1, TUBA1A
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	33.5×	0.003	PAFAH1B1, TUBA1A

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
neuron migration	3	100.3×	1e-04	PAFAH1B1, TUBA1A, CEP85L
microtubule-based process	2	495.6×	2e-04	PAFAH1B1, TUBA1A
adult locomotory behavior	2	150.5×	0.002	PAFAH1B1, TUBA1A
cerebral cortex development	2	102.8×	0.003	PAFAH1B1, TUBA1A
platelet activating factor metabolic process	1	1404.3×	0.006	PAFAH1B1
microtubule sliding	1	1404.3×	0.006	PAFAH1B1
nuclear membrane disassembly	1	1404.3×	0.006	PAFAH1B1
microtubule cytoskeleton organization involved in establishment of planar polarity	1	1404.3×	0.006	PAFAH1B1
ameboidal-type cell migration	1	1053.2×	0.006	PAFAH1B1
establishment of planar polarity of embryonic epithelium	1	1053.2×	0.006	PAFAH1B1
myeloid leukocyte migration	1	1053.2×	0.006	PAFAH1B1
radial glia-guided pyramidal neuron migration	1	1053.2×	0.006	PAFAH1B1
microtubule cytoskeleton organization	2	60.6×	0.006	PAFAH1B1, TUBA1A
pyramidal neuron differentiation	1	842.6×	0.007	TUBA1A
cerebellar cortex morphogenesis	1	702.2×	0.007	TUBA1A
maintenance of centrosome location	1	702.2×	0.007	PAFAH1B1
corpus callosum morphogenesis	1	601.9×	0.008	PAFAH1B1
intracellular distribution of mitochondria	1	601.9×	0.008	CLUH
osteoclast development	1	526.6×	0.008	PAFAH1B1
stem cell division	1	468.1×	0.008	PAFAH1B1
cortical microtubule organization	1	468.1×	0.008	PAFAH1B1
auditory receptor cell development	1	468.1×	0.008	PAFAH1B1
neuron projection arborization	1	468.1×	0.008	TUBA1A
positive regulation of cytokine-mediated signaling pathway	1	421.3×	0.008	PAFAH1B1
establishment of centrosome localization	1	421.3×	0.008	PAFAH1B1
response to L-glutamate	1	421.3×	0.008	TUBA1A
retrograde axonal transport	1	383.0×	0.008	PAFAH1B1
interneuron migration	1	383.0×	0.008	PAFAH1B1
microtubule organizing center organization	1	351.1×	0.008	PAFAH1B1
forebrain morphogenesis	1	351.1×	0.008	TUBA1A

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
TUBA1A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBA1A	22	4
PAFAH1B1	0	0
CEP85L	0	0
CLUH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBA1A
VINBLASTINE	4	TUBA1A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A
DOCETAXEL	4	TUBA1A
NOSCAPINE	4	TUBA1A
VINBLASTINE SULFATE	4	TUBA1A
PACLITAXEL	4	TUBA1A
LEVOFLOXACIN	4	TUBA1A
VINORELBINE	4	TUBA1A
TIRBANIBULIN	4	TUBA1A
PODOFILOX	4	TUBA1A
VINCRISTINE	4	TUBA1A
DOCETAXEL ANHYDROUS	4	TUBA1A
PATUPILONE	3	TUBA1A
ABT-751	2	TUBA1A
MAYTANSINE	2	TUBA1A
DOLASTATIN-10	2	TUBA1A
INDIBULIN	2	TUBA1A
PARBENDAZOLE	2	TUBA1A
NOCODAZOLE	2	TUBA1A
MOLIBRESIB	2	TUBA1A
COMBRETASTATIN	1	TUBA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6
CLUH	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TUBA1A	1,696

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

22 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)
COLCHICINE	4	TUBA1A
VINBLASTINE	4	TUBA1A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A
DOCETAXEL	4	TUBA1A
NOSCAPINE	4	TUBA1A
VINBLASTINE SULFATE	4	TUBA1A
PACLITAXEL	4	TUBA1A
LEVOFLOXACIN	4	TUBA1A
VINORELBINE	4	TUBA1A
TIRBANIBULIN	4	TUBA1A
PODOFILOX	4	TUBA1A
VINCRISTINE	4	TUBA1A
DOCETAXEL ANHYDROUS	4	TUBA1A
PATUPILONE	3	TUBA1A
ABT-751	2	TUBA1A
MAYTANSINE	2	TUBA1A
DOLASTATIN-10	2	TUBA1A
INDIBULIN	2	TUBA1A
PARBENDAZOLE	2	TUBA1A
NOCODAZOLE	2	TUBA1A
MOLIBRESIB	2	TUBA1A
COMBRETASTATIN	1	TUBA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBA1A
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	3	PAFAH1B1, CEP85L, CLUH

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)
PAFAH1B1	0	—
CEP85L	0	—
CLUH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.