Frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Summary

Frontotemporal dementia and/or amyotrophic lateral sclerosis 4 (MONDO:0014641) is a disease caused by TBK1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TBK1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 459

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia and/or amyotrophic lateral sclerosis 4
Mondo ID	MONDO:0014641
OMIM	616439
DOID	DOID:0110069
UMLS	C4225325
MedGen	902979
GARD	0018398
Is cancer (heuristic)	no

Also known as: frontotemporal dementia and/or amyotrophic lateral sclerosis 4 · frontotemporal dementia and/or amyotrophic lateral sclerosis type 4 · FTDALS4

Data availability: 459 ClinVar variants · 3 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › frontotemporal dementia and/or amyotrophic lateral sclerosis 4

Related subtypes (29): amyotrophic lateral sclerosis type 1, frontotemporal dementia and/or amyotrophic lateral sclerosis 1, spinocerebellar ataxia type 2, amyotrophic lateral sclerosis type 15, frontotemporal dementia and/or amyotrophic lateral sclerosis 7, amyotrophic lateral sclerosis type 4, amyotrophic lateral sclerosis type 21, amyotrophic lateral sclerosis type 3, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis type 7, amyotrophic lateral sclerosis type 8, amyotrophic lateral sclerosis type 9, amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis type 11, amyotrophic lateral sclerosis type 12, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, amyotrophic lateral sclerosis type 18, amyotrophic lateral sclerosis type 20, amyotrophic lateral sclerosis type 19, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, amyotrophic lateral sclerosis type 22, frontotemporal dementia and/or amyotrophic lateral sclerosis 3, juvenile amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 23, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, frontotemporal dementia and/or amyotrophic lateral sclerosis 5, amyotrophic lateral sclerosis 26 with or without frontotemporal dementia, amyotrophic lateral sclerosis 27, juvenile, amyotrophic lateral sclerosis 28

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

459 retrieved; paginated sample, class counts are floors:

217 uncertain significance, 118 likely benign, 56 pathogenic, 19 benign/likely benign, 16 conflicting classifications of pathogenicity, 16 likely pathogenic, 11 benign, 5 pathogenic/likely pathogenic, 1 pathogenic; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027795	NM_013254.4(TBK1):c.1153G>T (p.Glu385Ter)	TBK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073720	NM_013254.4(TBK1):c.1740del (p.Glu580fs)	TBK1	Pathogenic	criteria provided, single submitter
1075012	NM_013254.4(TBK1):c.1934C>G (p.Ser645Ter)	TBK1	Pathogenic	criteria provided, single submitter
1339689	NM_013254.4(TBK1):c.349C>T (p.Arg117Ter)	TBK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1368046	NM_013254.4(TBK1):c.1382dup (p.Thr462fs)	TBK1	Pathogenic	criteria provided, single submitter
1383659	NM_013254.4(TBK1):c.72dup (p.Arg25fs)	TBK1	Pathogenic	criteria provided, single submitter
1395761	NM_013254.4(TBK1):c.1846_1849del (p.Ser616fs)	TBK1	Pathogenic	criteria provided, single submitter
1403814	NM_013254.4(TBK1):c.1335G>A (p.Trp445Ter)	TBK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453082	NM_013254.4(TBK1):c.1972_1973del (p.Leu658fs)	TBK1	Pathogenic	criteria provided, single submitter
1453239	NM_013254.4(TBK1):c.1070G>A (p.Arg357Gln)	TBK1	Pathogenic	criteria provided, single submitter
1455548	NM_013254.4(TBK1):c.1770_1771del (p.Tyr591fs)	TBK1	Pathogenic	criteria provided, single submitter
1458273	NM_013254.4(TBK1):c.1272del (p.Cys423_Tyr424insTer)	TBK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460399	NC_000012.11:g.(?64875602)(64879817_?)del	TBK1	Pathogenic	criteria provided, single submitter
1497076	NM_013254.4(TBK1):c.1189+1G>A	TBK1	Pathogenic	criteria provided, single submitter
1523805	NM_013254.4(TBK1):c.1189+1G>T	TBK1	Pathogenic	criteria provided, single submitter
1805458	NM_013254.4(TBK1):c.1856G>A (p.Trp619Ter)	TBK1	Pathogenic	criteria provided, single submitter
1878670	NM_013254.4(TBK1):c.738_739del (p.Ser247fs)	TBK1	Pathogenic	criteria provided, single submitter
2002131	NM_013254.4(TBK1):c.1917del (p.Asp639fs)	TBK1	Pathogenic	criteria provided, single submitter
2029525	NM_013254.4(TBK1):c.944C>A (p.Ser315Ter)	TBK1	Pathogenic	criteria provided, single submitter
203435	NM_013254.4(TBK1):c.1349_1352del (p.Ile450fs)	TBK1	Pathogenic	criteria provided, multiple submitters, no conflicts
203437	NM_013254.4(TBK1):c.2138+2T>C	TBK1	Pathogenic	criteria provided, single submitter
203438	NM_013254.4(TBK1):c.958del (p.Thr320fs)	TBK1	Pathogenic	no assertion criteria provided
203439	NM_013254.4(TBK1):c.1340+1G>A	TBK1	Pathogenic	criteria provided, single submitter
203440	NM_013254.4(TBK1):c.2086G>A (p.Glu696Lys)	TBK1	Pathogenic	no assertion criteria provided
2051653	NM_013254.4(TBK1):c.701+2T>G	TBK1	Pathogenic	criteria provided, single submitter
2059613	NM_013254.4(TBK1):c.300_309del (p.Ser102fs)	TBK1	Pathogenic	criteria provided, single submitter
2101601	NM_013254.4(TBK1):c.1234del (p.Ala412fs)	TBK1	Pathogenic	criteria provided, single submitter
2109276	NM_013254.4(TBK1):c.1305T>A (p.Tyr435Ter)	TBK1	Pathogenic	criteria provided, single submitter
2137385	NM_013254.4(TBK1):c.4C>T (p.Gln2Ter)	TBK1	Pathogenic	criteria provided, single submitter
2137386	NM_013254.4(TBK1):c.1496C>G (p.Ser499Ter)	TBK1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 5 · 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
TBK1	Definitive	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 4	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBK1	Orphanet:1930	Herpes simplex virus encephalitis
TBK1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
TBK1	Orphanet:803	Amyotrophic lateral sclerosis
KIF5A	Orphanet:100991	Autosomal dominant spastic paraplegia type 10
KIF5A	Orphanet:324611	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBK1	HGNC:11584	ENSG00000183735	Q9UHD2	Serine/threonine-protein kinase TBK1	gencc,clinvar
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBK1	Serine/threonine-protein kinase TBK1	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents.
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBK1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
lateral nuclear group of thalamus	1
cerebellar hemisphere	1
right frontal lobe	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBK1	284	ubiquitous	marker	colonic epithelium, calcaneal tendon, lateral nuclear group of thalamus
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBK1	5,476
KIF5A	3,241

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBK1	Q9UHD2	25
KIF5A	Q12840	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 64. Enrichment computed across 2 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
STAT6-mediated induction of chemokines	1	1903.3×	0.014	TBK1
IRF3 mediated activation of type 1 IFN	1	951.7×	0.014	TBK1
ZBP1(DAI) mediated induction of type I IFNs	1	519.1×	0.014	TBK1
STING mediated induction of host immune responses	1	519.1×	0.014	TBK1
Mitophagy	1	519.1×	0.014	TBK1
RHO GTPases activate KTN1	1	519.1×	0.014	KIF5A
Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation	1	475.8×	0.014	TBK1
IRF3-mediated induction of type I IFN	1	407.9×	0.014	TBK1
TICAM1-dependent activation of IRF3/IRF7	1	407.9×	0.014	TBK1
Regulation of innate immune responses to cytosolic DNA	1	380.7×	0.014	TBK1
TRAF3-dependent IRF activation pathway	1	380.7×	0.014	TBK1
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	1	380.7×	0.014	TBK1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	300.5×	0.016	TBK1
Interleukin-37 signaling	1	259.6×	0.018	TBK1
Insulin processing	1	228.4×	0.018	KIF5A
TNFR1-induced proapoptotic signaling	1	219.6×	0.018	TBK1
TNF signaling	1	211.5×	0.018	TBK1
TRAF6 mediated IRF7 activation	1	190.3×	0.018	TBK1
PINK1-PRKN Mediated Mitophagy	1	178.4×	0.018	TBK1
Negative regulators of DDX58/IFIH1 signaling	1	163.1×	0.018	TBK1
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.018	TBK1
Selective autophagy	1	139.3×	0.018	TBK1
Peptide hormone metabolism	1	135.9×	0.018	KIF5A
Interleukin-1 family signaling	1	135.9×	0.018	TBK1
SARS-CoV-1 activates/modulates innate immune responses	1	135.9×	0.018	TBK1
Immune System	2	13.0×	0.018	TBK1, KIF5A
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	126.9×	0.019	TBK1
Regulation of TNFR1 signaling	1	112.0×	0.020	TBK1
Signal Transduction	2	10.2×	0.021	TBK1, KIF5A
Toll Like Receptor 3 (TLR3) Cascade	1	96.8×	0.021	TBK1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dendritic cell proliferation	1	2808.7×	0.005	TBK1
cGAS/STING signaling pathway	1	1685.2×	0.005	TBK1
retrograde neuronal dense core vesicle transport	1	1685.2×	0.005	KIF5A
anterograde dendritic transport of neurotransmitter receptor complex	1	1203.7×	0.005	KIF5A
anterograde axonal protein transport	1	1053.2×	0.005	KIF5A
positive regulation of xenophagy	1	1053.2×	0.005	TBK1
positive regulation of TORC2 signaling	1	1053.2×	0.005	TBK1
regulation of type I interferon production	1	842.6×	0.006	TBK1
T follicular helper cell differentiation	1	702.2×	0.006	TBK1
cytoplasmic pattern recognition receptor signaling pathway	1	443.5×	0.007	TBK1
peptidyl-threonine phosphorylation	1	443.5×	0.007	TBK1
synaptic vesicle transport	1	421.3×	0.007	KIF5A
positive regulation of type I interferon-mediated signaling pathway	1	421.3×	0.007	TBK1
positive regulation of interferon-alpha production	1	324.1×	0.009	TBK1
positive regulation of macroautophagy	1	263.3×	0.009	TBK1
toll-like receptor 4 signaling pathway	1	263.3×	0.009	TBK1
peptidyl-serine phosphorylation	1	247.8×	0.009	TBK1
activation of innate immune response	1	240.7×	0.009	TBK1
positive regulation of type I interferon production	1	210.7×	0.010	TBK1
positive regulation of interferon-beta production	1	195.9×	0.010	TBK1
canonical NF-kappaB signal transduction	1	183.2×	0.010	TBK1
type I interferon-mediated signaling pathway	1	172.0×	0.011	TBK1
negative regulation of TORC1 signaling	1	162.0×	0.011	TBK1
microtubule-based movement	1	147.8×	0.011	KIF5A
positive regulation of TORC1 signaling	1	147.8×	0.011	TBK1
macroautophagy	1	120.4×	0.013	TBK1
antiviral innate immune response	1	113.9×	0.013	TBK1
positive regulation of autophagy	1	104.0×	0.014	TBK1
response to virus	1	72.0×	0.019	TBK1
defense response to Gram-positive bacterium	1	63.8×	0.021	TBK1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBK1	38	4
KIF5A	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
ORANTINIB	3	TBK1
ALVOCIDIB	3	TBK1
DOVITINIB	3	TBK1
LESTAURTINIB	3	TBK1
RUBOXISTAURIN	3	TBK1
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
MILCICLIB	2	TBK1
TOZASERTIB	2	TBK1
UCN-01	2	TBK1
PF-00562271	1	TBK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TBK1	475	Binding:473, Functional:2
KIF5A	8	Binding:8

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: 2; 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
ORANTINIB	3	TBK1
ALVOCIDIB	3	TBK1
DOVITINIB	3	TBK1
LESTAURTINIB	3	TBK1
RUBOXISTAURIN	3	TBK1
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
MILCICLIB	2	TBK1
TOZASERTIB	2	TBK1
UCN-01	2	TBK1
PF-00562271	1	TBK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TBK1
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	1	KIF5A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KIF5A	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.