Amyotrophic lateral sclerosis type 6

Summary

Amyotrophic lateral sclerosis type 6 (MONDO:0011951) is a disease caused by FUS (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FUS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 459

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 6
Mondo ID	MONDO:0011951
MeSH	C567699
OMIM	608030
DOID	DOID:0060198
UMLS	C2931786
MedGen	419901
GARD	0009874
Is cancer (heuristic)	no

Also known as: ALS6 · amyotrophic lateral sclerosis 6 with or without frontotemporal dementia · amyotrophic lateral sclerosis caused by mutation in FUS · FUS amyotrophic lateral sclerosis

Data availability: 459 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 › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 6

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 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, frontotemporal dementia and/or amyotrophic lateral sclerosis 4, 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:

194 uncertain significance, 135 likely benign, 36 conflicting classifications of pathogenicity, 31 benign, 26 benign/likely benign, 25 pathogenic, 8 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073222	NM_004960.4(FUS):c.1554_1557del (p.Gln519fs)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
1423819	NM_004960.4(FUS):c.1500dup (p.Gly501fs)	FUS	Pathogenic	criteria provided, single submitter
1458206	NM_004960.4(FUS):c.1509_1510del (p.Gly504fs)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
1485282	NM_004960.4(FUS):c.1391_1392dup (p.Gly465fs)	FUS	Pathogenic	criteria provided, single submitter
16222	NM_004960.4(FUS):c.1561C>G (p.Arg521Gly)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
16223	NM_004960.4(FUS):c.1553G>A (p.Arg518Lys)	FUS	Pathogenic	criteria provided, single submitter
16224	NM_004960.4(FUS):c.1561C>T (p.Arg521Cys)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
16225	NM_004960.4(FUS):c.1562G>A (p.Arg521His)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
1918103	NM_004960.4(FUS):c.253C>T (p.Gln85Ter)	FUS	Pathogenic	criteria provided, single submitter
2046744	NM_004960.4(FUS):c.1573C>A (p.Pro525Thr)	FUS	Pathogenic	criteria provided, single submitter
2419096	NM_004960.4(FUS):c.1449_1488del (p.Tyr484fs)	FUS	Pathogenic	criteria provided, single submitter
280110	NM_004960.4(FUS):c.1574C>T (p.Pro525Leu)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
2925591	NM_004960.4(FUS):c.1528A>G (p.Lys510Glu)	FUS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925592	NM_004960.4(FUS):c.1540A>G (p.Arg514Gly)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
2945054	NM_004960.4(FUS):c.1531dup (p.Met511fs)	FUS	Pathogenic	criteria provided, single submitter
29707	NM_004960.4(FUS):c.1483C>T (p.Arg495Ter)	FUS	Pathogenic	criteria provided, multiple submitters, no conflicts
29708	NM_004960.4(FUS):c.616G>A (p.Gly206Ser)	FUS	Pathogenic	no assertion criteria provided
3571508	NM_004960.4(FUS):c.1408del (p.Asp470fs)	FUS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3759352	NM_004960.4(FUS):c.1542G>T (p.Arg514Ser)	FUS	Pathogenic	criteria provided, single submitter
3760171	NM_004960.4(FUS):c.1496del (p.Gly499fs)	FUS	Pathogenic	criteria provided, single submitter
447355	NM_004960.4(FUS):c.1394-2del	FUS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4783811	NM_004960.4(FUS):c.1561C>A (p.Arg521Ser)	FUS	Pathogenic	criteria provided, single submitter
4792377	NM_004960.4(FUS):c.1441C>T (p.Arg481Ter)	FUS	Pathogenic	criteria provided, single submitter
665141	NM_004960.4(FUS):c.1509_1510dup (p.Gly504fs)	FUS	Pathogenic	criteria provided, single submitter
847302	NM_004960.4(FUS):c.1541+1G>A	FUS	Pathogenic	criteria provided, single submitter
873230	NM_004960.4(FUS):c.1394-1G>T	FUS	Pathogenic	criteria provided, single submitter
873231	NM_004960.4(FUS):c.1555C>T (p.Gln519Ter)	FUS	Pathogenic	criteria provided, single submitter
873232	NM_004960.4(FUS):c.1562G>T (p.Arg521Leu)	FUS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
933229	NM_004960.4(FUS):c.1509dup (p.Gly504fs)	FUS	Pathogenic	criteria provided, single submitter
1333381	NM_004960.4(FUS):c.1542-1G>C	FUS	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 13 · 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
FUS	Definitive	Autosomal dominant	amyotrophic lateral sclerosis	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FUS	Orphanet:275872	Frontotemporal dementia with motor neuron disease
FUS	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
FUS	Orphanet:79105	Myxofibrosarcoma
FUS	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:99967	Myxoid/round cell liposarcoma
VCP	Orphanet:100070	Progressive non-fluent aphasia
VCP	Orphanet:275864	Behavioral variant of frontotemporal dementia
VCP	Orphanet:275872	Frontotemporal dementia with motor neuron disease
VCP	Orphanet:329475	Spastic paraplegia-Paget disease of bone syndrome
VCP	Orphanet:329478	Adult-onset distal myopathy due to VCP mutation
VCP	Orphanet:435387	Autosomal dominant Charcot-Marie-Tooth disease type 2Y
VCP	Orphanet:52430	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
VCP	Orphanet:803	Amyotrophic lateral sclerosis

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
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	gencc,clinvar
VCP	HGNC:12666	ENSG00000165280	P55072	Transitional endoplasmic reticulum ATPase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
VCP	Enzyme (other)	yes	3.6.4.6	CDC4_N-term_subdom, AAA+_ATPase, ATPase_AAA_core

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
right hemisphere of cerebellum	1
right testis	1
ventricular zone	1
adrenal tissue	1
islet of Langerhans	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FUS	304	ubiquitous	marker	right testis, ventricular zone, right hemisphere of cerebellum
VCP	294	ubiquitous	marker	stromal cell of endometrium, adrenal tissue, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015
FUS	5,250

Intra-cohort edges

A	B	Sources
FUS	VCP	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VCP	P55072	144
FUS	P35637	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. 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
Attachment and Entry	1	1427.5×	0.017	VCP
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1	1142.0×	0.017	VCP
DNA Damage Bypass	1	1142.0×	0.017	VCP
Hh mutants abrogate ligand secretion	1	713.8×	0.020	VCP
Early SARS-CoV-2 Infection Events	1	519.1×	0.020	VCP
Josephin domain DUBs	1	475.8×	0.020	VCP
Protein ubiquitination	1	407.9×	0.020	VCP
Protein methylation	1	335.9×	0.020	VCP
Translesion Synthesis by POLH	1	300.5×	0.020	VCP
Attachment and Entry	1	300.5×	0.020	VCP
ABC transporter disorders	1	219.6×	0.022	VCP
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	211.5×	0.022	VCP
Cellular response to heat stress	1	196.9×	0.022	VCP
HSF1 activation	1	190.3×	0.022	VCP
Dengue Virus Genome Translation and Replication	1	158.6×	0.023	VCP
RHOH GTPase cycle	1	154.3×	0.023	VCP
Ovarian tumor domain proteases	1	139.3×	0.023	VCP
Selective autophagy	1	139.3×	0.023	VCP
Aggrephagy	1	124.1×	0.024	VCP
Hh mutants are degraded by ERAD	1	121.5×	0.024	VCP
Defective CFTR causes cystic fibrosis	1	109.8×	0.025	VCP
Hedgehog ligand biogenesis	1	105.7×	0.025	VCP
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.025	VCP
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	96.8×	0.025	VCP
Signaling by Hedgehog	1	92.1×	0.026	VCP
Autophagy	1	74.2×	0.029	VCP
SARS-CoV-1 Infection	1	71.4×	0.029	VCP
Cellular response to chemical stress	1	71.4×	0.029	VCP
Disorders of transmembrane transporters	1	69.6×	0.029	VCP
Deubiquitination	1	62.1×	0.031	VCP

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
flavin adenine dinucleotide catabolic process	1	8426.0×	0.002	VCP
endoplasmic reticulum stress-induced pre-emptive quality control	1	4213.0×	0.002	VCP
positive regulation of protein K63-linked deubiquitination	1	4213.0×	0.002	VCP
mitotic spindle disassembly	1	2808.7×	0.002	VCP
cytoplasm protein quality control	1	2808.7×	0.002	VCP
cellular response to arsenite ion	1	2808.7×	0.002	VCP
positive regulation of oxidative phosphorylation	1	2808.7×	0.002	VCP
regulation of protein localization to chromatin	1	2808.7×	0.002	VCP
endosome to lysosome transport via multivesicular body sorting pathway	1	1404.3×	0.004	VCP
aggresome assembly	1	1404.3×	0.004	VCP
stress granule disassembly	1	1203.7×	0.004	VCP
positive regulation of mitochondrial membrane potential	1	1053.2×	0.004	VCP
regulation of aerobic respiration	1	1053.2×	0.004	VCP
NAD+ metabolic process	1	936.2×	0.004	VCP
protein-DNA covalent cross-linking repair	1	842.6×	0.004	VCP
negative regulation of protein localization to chromatin	1	766.0×	0.005	VCP
cellular response to misfolded protein	1	702.2×	0.005	VCP
positive regulation of ATP biosynthetic process	1	601.9×	0.005	VCP
viral genome replication	1	561.7×	0.005	VCP
membraneless organelle assembly	1	561.7×	0.005	FUS
retrograde protein transport, ER to cytosol	1	495.6×	0.005	VCP
translesion synthesis	1	468.1×	0.005	VCP
proteasomal protein catabolic process	1	383.0×	0.006	VCP
negative regulation of hippo signaling	1	351.1×	0.007	VCP
regulation of synapse organization	1	324.1×	0.007	VCP
amyloid fibril formation	1	300.9×	0.007	FUS
ATP metabolic process	1	234.1×	0.009	VCP
negative regulation of smoothened signaling pathway	1	227.7×	0.009	VCP
interstrand cross-link repair	1	216.1×	0.009	VCP
establishment of protein localization	1	216.1×	0.009	VCP

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
VCP	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VCP	4	4
FUS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
CB-5083	1	VCP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
VCP	120	Binding:120
FUS	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
VCP	3.6.4.6	vesicle-fusing ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
VCP	120

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

4 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)
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
CB-5083	1	VCP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	VCP
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	FUS

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)
FUS	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.