Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Summary

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (MONDO:0013501) is a disease caused by VCP (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: VCP (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 600

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	frontotemporal dementia and/or amyotrophic lateral sclerosis 6
Mondo ID	MONDO:0013501
OMIM	613954
DOID	DOID:0060205
UMLS	C5436279
MedGen	1759760
GARD	0015733
Is cancer (heuristic)	no

Also known as: amyotrophic lateral sclerosis caused by mutation in VCP · VCP amyotrophic lateral sclerosis

Data availability: 600 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 › frontotemporal dementia and/or amyotrophic lateral sclerosis 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 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, 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

600 retrieved; paginated sample, class counts are floors:

316 likely benign, 185 uncertain significance, 36 conflicting classifications of pathogenicity, 20 benign, 15 benign/likely benign, 12 pathogenic, 9 likely pathogenic, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1457378	NM_007126.5(VCP):c.472A>G (p.Met158Val)	VCP	Pathogenic	criteria provided, single submitter
1457379	NM_007126.5(VCP):c.469G>A (p.Gly157Arg)	VCP	Pathogenic	criteria provided, single submitter
1457380	NM_007126.5(VCP):c.463C>A (p.Arg155Ser)	VCP	Pathogenic	criteria provided, single submitter
2051539	NM_007126.5(VCP):c.266G>A (p.Arg89Gln)	VCP	Pathogenic	criteria provided, single submitter
2136763	NM_007126.5(VCP):c.466G>A (p.Gly156Ser)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217028	NM_007126.5(VCP):c.463C>G (p.Arg155Gly)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217877	NM_007126.5(VCP):c.271A>T (p.Asn91Tyr)	VCP	Pathogenic	criteria provided, single submitter
218306	NM_007126.5(VCP):c.290G>A (p.Gly97Glu)	VCP	Pathogenic	criteria provided, single submitter
280123	NM_007126.5(VCP):c.475C>T (p.Arg159Cys)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30152	NM_007126.5(VCP):c.475C>G (p.Arg159Gly)	VCP	Pathogenic	no assertion criteria provided
30153	NM_007126.5(VCP):c.1774G>A (p.Asp592Asn)	VCP	Pathogenic	no assertion criteria provided
3768936	NM_007126.5(VCP):c.410C>T (p.Pro137Leu)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
593071	NM_007126.5(VCP):c.277C>T (p.Arg93Cys)	VCP	Pathogenic	criteria provided, multiple submitters, no conflicts
8468	NM_007126.5(VCP):c.464G>A (p.Arg155His)	VCP	Pathogenic	criteria provided, multiple submitters, no conflicts
8469	NM_007126.5(VCP):c.463C>T (p.Arg155Cys)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8471	NM_007126.5(VCP):c.283C>G (p.Arg95Gly)	VCP	Pathogenic	criteria provided, single submitter
8473	NM_007126.5(VCP):c.572G>A (p.Arg191Gln)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8474	NM_007126.5(VCP):c.476G>A (p.Arg159His)	VCP	Pathogenic	criteria provided, multiple submitters, no conflicts
873223	NM_007126.5(VCP):c.572G>C (p.Arg191Pro)	VCP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1038018	NM_007126.5(VCP):c.577-2A>G	VCP	Likely pathogenic	criteria provided, single submitter
1403085	NM_007126.5(VCP):c.273C>G (p.Asn91Lys)	VCP	Likely pathogenic	criteria provided, single submitter
1496153	NM_007126.5(VCP):c.273C>A (p.Asn91Lys)	VCP	Likely pathogenic	criteria provided, single submitter
1513178	NM_007126.5(VCP):c.284G>A (p.Arg95His)	VCP	Likely pathogenic	criteria provided, single submitter
2028838	NM_007126.5(VCP):c.382G>A (p.Gly128Ser)	VCP	Likely pathogenic	criteria provided, single submitter
218305	NM_007126.5(VCP):c.553G>A (p.Glu185Lys)	VCP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582679	NM_007126.5(VCP):c.766C>G (p.Arg256Gly)	VCP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2954479	NM_007126.5(VCP):c.283C>A (p.Arg95Ser)	VCP	Likely pathogenic	criteria provided, single submitter
836876	NM_007126.5(VCP):c.648A>G (p.Ile216Met)	VCP	Likely pathogenic	criteria provided, single submitter
1010487	NM_007126.5(VCP):c.265C>T (p.Arg89Trp)	VCP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1079222	NM_007126.5(VCP):c.446-5C>T	VCP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 10 · 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
VCP	Definitive	Autosomal dominant	inclusion body myopathy with Paget disease of bone and frontotemporal dementia	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
TOPORS	Orphanet:2754	Orofaciodigital syndrome type 6
TOPORS	Orphanet:791	Retinitis pigmentosa

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
VCP	HGNC:12666	ENSG00000165280	P55072	Transitional endoplasmic reticulum ATPase	gencc,clinvar
FAM219A	HGNC:19920	ENSG00000164970	Q8IW50	Protein FAM219A	clinvar
TOPORS	HGNC:21653	ENSG00000197579	Q9NS56	E3 ubiquitin-protein ligase Topors	clinvar
SPATA31G1	HGNC:31418	ENSG00000174038	Q5VYM1	Spermatogenesis-associated protein 31G1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.
TOPORS	E3 ubiquitin-protein ligase Topors	Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase.
SPATA31G1	Spermatogenesis-associated protein 31G1	Dispensable for normal development and fertility.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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	3.0×	0.605
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VCP	Enzyme (other)	yes	3.6.4.6	CDC4_N-term_subdom, AAA+_ATPase, ATPase_AAA_core
FAM219A	Other/Unknown	no		FAM219
TOPORS	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
SPATA31G1	Other/Unknown	no		Spata31g1-like

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
islet of Langerhans	1
stromal cell of endometrium	1
medulla oblongata	1
superior vestibular nucleus	1
ventricular zone	1
calcaneal tendon	1
secondary oocyte	1
sperm	1
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VCP	294	ubiquitous	marker	stromal cell of endometrium, adrenal tissue, islet of Langerhans
FAM219A	245	ubiquitous	yes	ventricular zone, superior vestibular nucleus, medulla oblongata
TOPORS	285	ubiquitous	marker	secondary oocyte, calcaneal tendon, sperm
SPATA31G1	153	tissue_specific	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015
TOPORS	1,552
SPATA31G1	811
FAM219A	411

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VCP	P55072	144

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FAM219A	Q8IW50	63.93
TOPORS	Q9NS56	49.39
SPATA31G1	Q5VYM1	39.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 58. 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
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×	0.017	VCP
Early SARS-CoV-2 Infection Events	1	519.1×	0.017	VCP
SUMOylation of immune response proteins	1	475.8×	0.017	TOPORS
Josephin domain DUBs	1	475.8×	0.017	VCP
Protein ubiquitination	1	407.9×	0.018	VCP
Protein methylation	1	335.9×	0.018	VCP
Translesion Synthesis by POLH	1	300.5×	0.018	VCP
Attachment and Entry	1	300.5×	0.018	VCP
ABC transporter disorders	1	219.6×	0.020	VCP
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	211.5×	0.020	VCP
Cellular response to heat stress	1	196.9×	0.020	VCP
HSF1 activation	1	190.3×	0.020	VCP
SUMOylation of SUMOylation proteins	1	163.1×	0.021	TOPORS
Dengue Virus Genome Translation and Replication	1	158.6×	0.021	VCP
RHOH GTPase cycle	1	154.3×	0.021	VCP
Ovarian tumor domain proteases	1	139.3×	0.021	VCP
Selective autophagy	1	139.3×	0.021	VCP
Aggrephagy	1	124.1×	0.021	VCP
SUMOylation of transcription cofactors	1	121.5×	0.021	TOPORS
Hh mutants are degraded by ERAD	1	121.5×	0.021	VCP
Defective CFTR causes cystic fibrosis	1	109.8×	0.022	VCP
Hedgehog ligand biogenesis	1	105.7×	0.022	VCP
E3 ubiquitin ligases ubiquitinate target proteins	1	96.8×	0.022	VCP
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	96.8×	0.022	VCP
Signaling by Hedgehog	1	92.1×	0.022	VCP
Autophagy	1	74.2×	0.026	VCP
SARS-CoV-1 Infection	1	71.4×	0.026	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
ubiquitin-dependent protein catabolic process	2	74.2×	0.002	VCP, TOPORS
DNA damage response	2	53.5×	0.002	VCP, TOPORS
proteasome-mediated ubiquitin-dependent protein catabolic process	2	52.2×	0.002	VCP, TOPORS
endosome to lysosome transport via multivesicular body sorting pathway	1	1404.3×	0.003	VCP
aggresome assembly	1	1404.3×	0.003	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×	0.004	VCP
cellular response to misfolded protein	1	702.2×	0.004	VCP
positive regulation of ATP biosynthetic process	1	601.9×	0.005	VCP
viral genome replication	1	561.7×	0.005	VCP
maintenance of protein location in nucleus	1	561.7×	0.005	TOPORS
photoreceptor cell outer segment organization	1	526.6×	0.005	TOPORS
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×	0.006	VCP
retina layer formation	1	324.1×	0.006	TOPORS
regulation of synapse organization	1	324.1×	0.006	VCP

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
FAM219A	0	0
TOPORS	0	0
SPATA31G1	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

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: 4; 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	3	FAM219A, TOPORS, SPATA31G1

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)
FAM219A	0	—
TOPORS	0	—
SPATA31G1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.