Hereditary spastic paraplegia 8

Summary

Hereditary spastic paraplegia 8 (MONDO:0011339) is a disease caused by WASHC5 (GenCC Strong), with 7 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: WASHC5 (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 468
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0002314	Degeneration of the lateral corticospinal tracts	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007020	Progressive spastic paraplegia	Very frequent (80-99%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0000012	Urinary urgency	Frequent (30-79%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002166	Impaired vibration sensation in the lower limbs	Frequent (30-79%)
HP:0002406	Limb dysmetria	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0009049	Peroneal muscle atrophy	Frequent (30-79%)
HP:0100561	Spinal cord lesion	Frequent (30-79%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0006986	Upper limb spasticity	Occasional (5-29%)
HP:0002921	Abnormality of the cerebrospinal fluid	Excluded (0%)
HP:0003457	EMG abnormality	Excluded (0%)
HP:0012898	Abnormal lower-limb motor evoked potentials	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 8
Mondo ID	MONDO:0011339
MeSH	C580458
OMIM	603563
Orphanet	100989
DOID	DOID:0110823
UMLS	C1863704
MedGen	400359
GARD	0009591
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 8 · hereditary spastic paraplegia caused by mutation in WASHC5 · hereditary spastic paraplegia type 8 · spastic paraplegia 8 · spastic paraplegia 8, autosomal dominant · SPG8 · WASHC5 hereditary spastic paraplegia

Data availability: 468 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › paraplegia › hereditary spastic paraplegia › pure hereditary spastic paraplegia › hereditary spastic paraplegia 8

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 12, hereditary spastic paraplegia 19, hereditary spastic paraplegia 28, hereditary spastic paraplegia 37, hereditary spastic paraplegia 42, hereditary spastic paraplegia 41, hereditary spastic paraplegia 72, hereditary spastic paraplegia 62, hereditary spastic paraplegia 73, autosomal recessive spastic paraplegia type 71

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

468 retrieved; paginated sample, class counts are floors:

220 uncertain significance, 138 likely benign, 37 conflicting classifications of pathogenicity, 29 benign, 15 pathogenic, 14 benign/likely benign, 10 likely pathogenic, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1014986	NM_014846.4(WASHC5):c.1424G>A (p.Trp475Ter)	WASHC5	Pathogenic	criteria provided, single submitter
1161	NM_014846.4(WASHC5):c.1876G>T (p.Val626Phe)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162	NM_014846.4(WASHC5):c.1857G>C (p.Leu619Phe)	WASHC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1163	NM_014846.4(WASHC5):c.1411A>G (p.Asn471Asp)	WASHC5	Pathogenic	no assertion criteria provided
1510703	NM_014846.4(WASHC5):c.913G>T (p.Glu305Ter)	WASHC5	Pathogenic	criteria provided, single submitter
2926285	NM_014846.4(WASHC5):c.633T>G (p.Tyr211Ter)	WASHC5	Pathogenic	criteria provided, single submitter
2938986	NM_014846.4(WASHC5):c.1368del (p.Ser458fs)	WASHC5	Pathogenic	criteria provided, single submitter
2940559	NM_014846.4(WASHC5):c.2438_2439del (p.Pro813fs)	WASHC5	Pathogenic	criteria provided, single submitter
3763973	NM_014846.4(WASHC5):c.3163C>T (p.Gln1055Ter)	WASHC5	Pathogenic	criteria provided, single submitter
410079	NM_014846.4(WASHC5):c.2086G>A (p.Gly696Ser)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
463137	NM_014846.4(WASHC5):c.1771T>C (p.Ser591Pro)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4791041	NM_014846.4(WASHC5):c.1443_1447del (p.Lys481fs)	WASHC5	Pathogenic	criteria provided, single submitter
495056	NM_014846.4(WASHC5):c.1772C>T (p.Ser591Phe)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
573798	NM_014846.4(WASHC5):c.3024_3025del (p.Leu1009fs)	WASHC5	Pathogenic	criteria provided, single submitter
576266	NM_014846.4(WASHC5):c.511C>T (p.Arg171Ter)	WASHC5	Pathogenic	criteria provided, single submitter
578334	NM_014846.4(WASHC5):c.2087G>A (p.Gly696Asp)	WASHC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65713	NM_014846.4(WASHC5):c.2087G>C (p.Gly696Ala)	WASHC5	Pathogenic	no assertion criteria provided
989010	NM_014846.4(WASHC5):c.1474A>C (p.Thr492Pro)	WASHC5	Pathogenic	criteria provided, single submitter
989011	NM_014846.4(WASHC5):c.2645T>A (p.Phe882Tyr)	WASHC5	Pathogenic	criteria provided, single submitter
2023842	NM_014846.4(WASHC5):c.2595_2599del (p.Gln865fs)	WASHC5-AS1	Pathogenic	criteria provided, single submitter
1030376	NM_014846.4(WASHC5):c.3424-1G>T	WASHC5	Likely pathogenic	criteria provided, single submitter
1067377	NC_000008.10:g.(?126079753)(126096155_?)del	WASHC5	Likely pathogenic	criteria provided, single submitter
1430473	NM_014846.4(WASHC5):c.2505-1G>C	WASHC5	Likely pathogenic	criteria provided, single submitter
1985363	NM_014846.4(WASHC5):c.186+1G>C	WASHC5	Likely pathogenic	criteria provided, single submitter
3027461	NM_014846.4(WASHC5):c.711+1G>A	WASHC5	Likely pathogenic	criteria provided, single submitter
3780793	NM_014846.4(WASHC5):c.511del (p.Arg171fs)	WASHC5	Likely pathogenic	criteria provided, single submitter
3897060	NM_014846.4(WASHC5):c.34_35del (p.Gly12fs)	WASHC5	Likely pathogenic	criteria provided, single submitter
4537492	NM_014846.4(WASHC5):c.3058_3064del (p.Ala1020fs)	WASHC5	Likely pathogenic	criteria provided, single submitter
4790773	NM_014846.4(WASHC5):c.2771-2A>G	WASHC5	Likely pathogenic	criteria provided, single submitter
570582	NM_014846.4(WASHC5):c.1151-2A>G	WASHC5	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 15 · 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
WASHC5	Strong	Autosomal dominant	hereditary spastic paraplegia 8	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WASHC5	Orphanet:100989	Autosomal dominant spastic paraplegia type 8
WASHC5	Orphanet:7	3C syndrome
TBK1	Orphanet:1930	Herpes simplex virus encephalitis
TBK1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
TBK1	Orphanet:803	Amyotrophic lateral sclerosis
NSD1	Orphanet:1627	Deletion 5q35 syndrome
NSD1	Orphanet:228415	5q35 microduplication syndrome
NSD1	Orphanet:3447	Weaver syndrome
NSD1	Orphanet:821	Sotos syndrome
SETBP1	Orphanet:436151	Intellectual disability-expressive aphasia-facial dysmorphism syndrome
SETBP1	Orphanet:798	Schinzel-Giedion syndrome
NSMCE2	Orphanet:436182	Microcephalic primordial dwarfism-insulin resistance syndrome
NSMCE2	Orphanet:808	Seckel syndrome
DNM1L	Orphanet:330050	DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect
DNM1L	Orphanet:98673	Autosomal dominant optic atrophy, classic form

Cohort genes → proteins

7 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WASHC5	HGNC:28984	ENSG00000164961	Q12768	WASH complex subunit 5	gencc,clinvar
TBK1	HGNC:11584	ENSG00000183735	Q9UHD2	Serine/threonine-protein kinase TBK1	clinvar
NSD1	HGNC:14234	ENSG00000165671	Q96L73	Histone-lysine N-methyltransferase, H3 lysine-36 specific	clinvar
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	clinvar
NSMCE2	HGNC:26513	ENSG00000156831	Q96MF7	E3 SUMO-protein ligase NSE2	clinvar
DNM1L	HGNC:2973	ENSG00000087470	O00429	Dynamin-1-like protein	clinvar
WASHC5-AS1	HGNC:43440	ENSG00000253167		WASHC5 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WASHC5	WASH complex subunit 5	Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fi…
TBK1	Serine/threonine-protein kinase TBK1	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents.
NSD1	Histone-lysine N-methyltransferase, H3 lysine-36 specific	Histone methyltransferase that dimethylates Lys-36 of histone H3 (H3K36me2).
NSMCE2	E3 SUMO-protein ligase NSE2	E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination.
DNM1L	Dynamin-1-like protein	Functions in mitochondrial and peroxisomal division.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.29

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	4.0×	0.454
Transcription factor	2	2.4×	0.454
Enzyme (other)	1	1.7×	0.609
Other/Unknown	3	0.8×	0.858

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WASHC5	Other/Unknown	no		WASH_strumpellin
TBK1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
NSD1	Transcription factor	no	2.1.1.357	PWWP_dom, SET_dom, Znf_PHD
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
NSMCE2	Transcription factor	no		Znf_MIZ, Znf_RING/FYVE/PHD, Nse2(Mms21)
DNM1L	Enzyme (other)	yes	3.6.5.5	Dynamin_stalk, Dynamin_GTPase, GED
WASHC5-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
colonic epithelium	3
corpus callosum	2
lateral nuclear group of thalamus	2
stromal cell of endometrium	1
sural nerve	1
buccal mucosa cell	1
caput epididymis	1
ventricular zone	1
bone marrow cell	1
tibialis anterior	1
sperm	1
substantia nigra pars compacta	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WASHC5	283	ubiquitous	marker	corpus callosum, calcaneal tendon, stromal cell of endometrium
TBK1	284	ubiquitous	marker	colonic epithelium, calcaneal tendon, lateral nuclear group of thalamus
NSD1	235	ubiquitous	marker	sural nerve, colonic epithelium, calcaneal tendon
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
NSMCE2	259	ubiquitous	marker	colonic epithelium, bone marrow cell, tibialis anterior
DNM1L	295	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, sperm
WASHC5-AS1	127		yes	male germ line stem cell (sensu Vertebrata) in testis, ganglionic eminence, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBK1	5,476
DNM1L	4,801
NSD1	2,979
SETBP1	2,077
NSMCE2	1,550
WASHC5	1,115
WASHC5-AS1	0

Intra-cohort edges

A	B	Sources
NSD1	SETBP1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBK1	Q9UHD2	25
DNM1L	O00429	11
NSD1	Q96L73	4
NSMCE2	Q96MF7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WASHC5	Q12768	90.27
SETBP1	Q9Y6X0	43.30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 50. Enrichment computed across 7 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
STAT6-mediated induction of chemokines	1	951.7×	0.024	TBK1
IRF3 mediated activation of type 1 IFN	1	475.8×	0.024	TBK1
ZBP1(DAI) mediated induction of type I IFNs	1	259.6×	0.024	TBK1
STING mediated induction of host immune responses	1	259.6×	0.024	TBK1
Mitophagy	1	259.6×	0.024	TBK1
Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation	1	237.9×	0.024	TBK1
IRF3-mediated induction of type I IFN	1	203.9×	0.024	TBK1
TICAM1-dependent activation of IRF3/IRF7	1	203.9×	0.024	TBK1
Regulation of innate immune responses to cytosolic DNA	1	190.3×	0.024	TBK1
TRAF3-dependent IRF activation pathway	1	190.3×	0.024	TBK1
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	1	190.3×	0.024	TBK1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	150.3×	0.028	TBK1
Interleukin-37 signaling	1	129.8×	0.029	TBK1
Apoptotic execution phase	1	119.0×	0.029	DNM1L
TNFR1-induced proapoptotic signaling	1	109.8×	0.029	TBK1
TNF signaling	1	105.7×	0.029	TBK1
TRAF6 mediated IRF7 activation	1	95.2×	0.031	TBK1
PINK1-PRKN Mediated Mitophagy	1	89.2×	0.031	TBK1
Negative regulators of DDX58/IFIH1 signaling	1	81.6×	0.032	TBK1
Cytosolic sensors of pathogen-associated DNA	1	71.4×	0.032	TBK1
Selective autophagy	1	69.6×	0.032	TBK1
Interleukin-1 family signaling	1	68.0×	0.032	TBK1
SARS-CoV-1 activates/modulates innate immune responses	1	68.0×	0.032	TBK1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	63.4×	0.033	TBK1
Regulation of TNFR1 signaling	1	56.0×	0.035	TBK1
Toll Like Receptor 3 (TLR3) Cascade	1	48.4×	0.038	TBK1
TRIF (TICAM1)-mediated TLR4 signaling	1	47.6×	0.038	TBK1
MyD88-independent TLR4 cascade	1	46.0×	0.038	TBK1
SARS-CoV-1-host interactions	1	43.9×	0.039	TBK1
PKMTs methylate histone lysines	1	40.2×	0.041	NSD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of peptidyl-serine phosphorylation	1	2808.7×	0.010	NSD1
regulation of RNA polymerase II regulatory region sequence-specific DNA binding	1	2808.7×	0.010	NSD1
regulation of actin nucleation	1	1404.3×	0.010	WASHC5
mitochondrial membrane fission	1	1404.3×	0.010	DNM1L
regulation of ATP metabolic process	1	1404.3×	0.010	DNM1L
dendritic cell proliferation	1	936.2×	0.010	TBK1
meiotic spindle assembly	1	936.2×	0.010	WASHC5
endosome fission	1	936.2×	0.010	WASHC5
regulation of peroxisome organization	1	936.2×	0.010	DNM1L
positive regulation of maintenance of mitotic sister chromatid cohesion	1	561.7×	0.012	NSMCE2
polar body extrusion after meiotic divisions	1	561.7×	0.012	WASHC5
cGAS/STING signaling pathway	1	561.7×	0.012	TBK1
mitocytosis	1	468.1×	0.013	DNM1L
intracellular distribution of mitochondria	1	401.2×	0.013	DNM1L
regulation of vesicle size	1	401.2×	0.013	WASHC5
positive regulation of xenophagy	1	351.1×	0.014	TBK1
positive regulation of TORC2 signaling	1	351.1×	0.014	TBK1
regulation of type I interferon production	1	280.9×	0.015	TBK1
telomere maintenance via recombination	1	255.3×	0.015	NSMCE2
peroxisome fission	1	255.3×	0.015	DNM1L
mitochondrial fragmentation involved in apoptotic process	1	234.1×	0.015	DNM1L
T follicular helper cell differentiation	1	234.1×	0.015	TBK1
protein localization to mitochondrion	1	216.1×	0.015	DNM1L
positive regulation of mitotic metaphase/anaphase transition	1	200.6×	0.015	NSMCE2
chromatin looping	1	200.6×	0.015	NSMCE2
regulation of mitophagy	1	200.6×	0.015	DNM1L
mitochondrial fission	1	175.5×	0.016	DNM1L
regulation of Arp2/3 complex-mediated actin nucleation	1	175.5×	0.016	WASHC5
protein-containing complex localization	1	165.2×	0.017	WASHC5
cytoplasmic pattern recognition receptor signaling pathway	1	147.8×	0.017	TBK1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 5 of 7 evidence-associated genes (71%) 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
TBK1	MOMELOTINIB
NSD1	VENETOCLAX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBK1	38	4
NSD1	7	4
WASHC5	0	0
SETBP1	0	0
NSMCE2	0	0
DNM1L	0	0
WASHC5-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TBK1
AMLEXANOX	4	TBK1
FEDRATINIB	4	TBK1
RUXOLITINIB	4	TBK1
ENTRECTINIB	4	TBK1
PACRITINIB	4	TBK1
BOSUTINIB	4	TBK1
FILGOTINIB	4	TBK1
NINTEDANIB	4	TBK1
SUNITINIB	4	TBK1
ERLOTINIB	4	TBK1
CRIZOTINIB	4	TBK1
MIDOSTAURIN	4	TBK1
VENETOCLAX	4	NSD1
PRIMAQUINE	4	NSD1
CHLOROQUINE PHOSPHATE	4	NSD1
ORANTINIB	3	TBK1
ALVOCIDIB	3	TBK1
DOVITINIB	3	TBK1
LESTAURTINIB	3	TBK1
RUBOXISTAURIN	3	TBK1
SURAMIN	3	NSD1
SILMITASERTIB	2	TBK1
FORETINIB	2	TBK1
SU-014813	2	TBK1
CENISERTIB	2	TBK1
ADAVOSERTIB	2	TBK1
CERDULATINIB	2	TBK1
R-406	2	TBK1
AT-9283	2	TBK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
TBK1	475	Binding:473, Functional:2
NSD1	90	Binding:90
DNM1L	4	Binding:4
WASHC5	1	Binding:1
NSMCE2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NSD1	2.1.1.357, 2.1.1.362	[histone H3]-lysine36 N-dimethyltransferase, [histone H4]-N-methyl-L-lysine20 N-methyltransferase
DNM1L	3.6.5.5	dynamin GTPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TBK1	475

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)
MOMELOTINIB	4	TBK1
AMLEXANOX	4	TBK1
FEDRATINIB	4	TBK1
RUXOLITINIB	4	TBK1
ENTRECTINIB	4	TBK1
PACRITINIB	4	TBK1
BOSUTINIB	4	TBK1
FILGOTINIB	4	TBK1
NINTEDANIB	4	TBK1
SUNITINIB	4	TBK1
ERLOTINIB	4	TBK1
CRIZOTINIB	4	TBK1
MIDOSTAURIN	4	TBK1
VENETOCLAX	4	NSD1
PRIMAQUINE	4	NSD1
CHLOROQUINE PHOSPHATE	4	NSD1
ORANTINIB	3	TBK1
ALVOCIDIB	3	TBK1
DOVITINIB	3	TBK1
LESTAURTINIB	3	TBK1
RUBOXISTAURIN	3	TBK1
SURAMIN	3	NSD1
SILMITASERTIB	2	TBK1
FORETINIB	2	TBK1
SU-014813	2	TBK1
CENISERTIB	2	TBK1
ADAVOSERTIB	2	TBK1
CERDULATINIB	2	TBK1
R-406	2	TBK1
AT-9283	2	TBK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TBK1, NSD1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DNM1L
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	WASHC5, SETBP1, NSMCE2, WASHC5-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WASHC5	1	—
SETBP1	0	—
NSMCE2	1	—
DNM1L	4	—
WASHC5-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.