Tremor, hereditary essential, 4

Summary

Tremor, hereditary essential, 4 (MONDO:0013888) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 336

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tremor, hereditary essential, 4
Mondo ID	MONDO:0013888
OMIM	614782
DOID	DOID:0111431
UMLS	C3539195
MedGen	761337
Is cancer (heuristic)	no

Also known as: essential tremor caused by mutation in FUS · essential tremor, hereditary, 4 · ETM4 · FUS essential tremor · tremor, hereditary essential, 4 · tremor, hereditary essential, type 4

Data availability: 336 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › essential tremor › tremor, hereditary essential, 4

Related subtypes (5): tremor, hereditary essential, 1, tremor, hereditary essential, 2, tremor, hereditary essential, 3, tremor, hereditary essential, 5, tremor, hereditary essential, 6

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

336 retrieved; paginated sample, class counts are floors:

124 likely benign, 117 uncertain significance, 35 conflicting classifications of pathogenicity, 24 benign/likely benign, 22 pathogenic, 9 benign, 4 pathogenic/likely pathogenic, 1 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
3571508	NM_004960.4(FUS):c.1408del (p.Asp470fs)	FUS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37070	NM_004960.4(FUS):c.868C>T (p.Gln290Ter)	FUS	Pathogenic	no assertion criteria provided
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
873232	NM_004960.4(FUS):c.1562G>T (p.Arg521Leu)	FUS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
540279	NM_004960.4(FUS):c.1564A>G (p.Arg522Gly)	FUS	Likely pathogenic	criteria provided, single submitter
1054806	NM_004960.4(FUS):c.1317T>C (p.Ser439=)	FUS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1077589	NM_004960.4(FUS):c.684_692del (p.Gly229_Gly231del)	FUS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213403	NM_004960.4(FUS):c.167CTT[1] (p.Ser57del)	FUS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
FUS	Limited	Autosomal dominant	tremor, hereditary essential, 4	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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	gencc,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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	1
right testis	1
ventricular zone	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FUS	5,250

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FUS	P35637	23

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mRNA Polyadenylation	1	87.8×	0.022	FUS
Processing of Capped Intron-Containing Pre-mRNA	1	82.2×	0.022	FUS
mRNA Splicing - Major Pathway	1	54.6×	0.022	FUS
Dengue Virus-Host Interactions	1	45.7×	0.022	FUS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
membraneless organelle assembly	1	1123.5×	0.006	FUS
amyloid fibril formation	1	601.9×	0.006	FUS
positive regulation of double-strand break repair via homologous recombination	1	383.0×	0.006	FUS
mRNA stabilization	1	366.4×	0.006	FUS
regulation of RNA splicing	1	218.9×	0.008	FUS
protein homooligomerization	1	122.1×	0.012	FUS
RNA splicing	1	88.2×	0.015	FUS
regulation of DNA-templated transcription	1	31.6×	0.036	FUS
regulation of transcription by RNA polymerase II	1	11.7×	0.086	FUS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FUS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
FUS	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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.