FUS

Chr 16AD

FUS RNA binding protein

Also known as: ALS6, ETM4, FUS1, HNRNPP2, POMP75, TLS, altFUS

NCBI Gene: 2521ENSG00000089280UniProt: P35637

This gene encodes a multifunctional protein component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex. The hnRNP complex is involved in pre-mRNA splicing and the export of fully processed mRNA to the cytoplasm. This protein belongs to the FET family of RNA-binding proteins which have been implicated in cellular processes that include regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. Alternative splicing results in multiple transcript variants. Defects in this gene result in amyotrophic lateral sclerosis type 6. [provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

Amyotrophic lateral sclerosis 6, with or without frontotemporal dementiaMIM #608030
Essential tremor, hereditary, 4MIM #614782
AD
UniProtAngiomatoid fibrous histiocytoma
549
ClinVar variants
45
Pathogenic / LP
1.00
pLI score· haploinsufficient
5
Active trials
Clinical Summary— FUS
🧬
Gene-Disease Validity (ClinGen)
amyotrophic lateral sclerosis type 6 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
45 Pathogenic / Likely Pathogenic· 251 VUS of 549 total submissions
💊
Clinical Trials
5 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.24LOEUF
pLI 0.999
Z-score 5.16
OE 0.10 (0.05–0.24)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.21Z-score
OE missense 0.66 (0.59–0.74)
217 obs / 329.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.05–0.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.66 (0.59–0.74)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.25
0≤1.21.6
LoF obs/exp: 4 / 38.6Missense obs/exp: 217 / 329.7Syn Z: -2.13

ClinVar Variant Classifications

549 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic19
VUS251
Likely Benign199
Benign20
Conflicting34
26
Pathogenic
19
Likely Pathogenic
251
VUS
199
Likely Benign
20
Benign
34
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
5
10
0
26
Likely Pathogenic
8
9
2
0
19
VUS
5
148
95
3
251
Likely Benign
1
6
110
82
199
Benign
0
0
19
1
20
Conflicting
—34
Total2516823686549

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FUS · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia

MIM #608030

Molecular basis of disorder known

Essential tremor, hereditary, 4

MIM #614782

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — FUS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frontotemporal Dementia.
Clark DG·Continuum (Minneap Minn)
2024Review
Amyotrophic lateral sclerosis caused by FUS mutations: advances with broad implications.
Moens TG et al.·Lancet Neurol
2025Review
Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis.
Korobeynikov VA et al.·Nat Med
2022
Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.
Rezai AR et al.·Proc Natl Acad Sci U S A
2020Clinical trial
FUS gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review.
Xiao X et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024Case report
Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.
Chen YP et al.·J Med Genet
2022Cohort
Ultrasound-mediated blood-brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer's disease.
Mehta RI et al.·Fluids Barriers CNS
2023Clinical trial
RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.
Rummens J et al.·Mol Neurodegener
2025Review
Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series.
Shneider NA et al.·Lancet
2025Cohort
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Kwiatkowski TJ Jr et al.·Science
2009
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Brain NeoplasmsLiquid Biopsy

BRAINFUL (BRAIN Tumor Focused Ultrasound-enabled Liquid Biopsy) Trial

ACTIVE NOT RECRUITING
NCT04940507Phase NAUniversity Health Network, TorontoStarted 2021-06-10
Magnetic Resonance Guided Focused Ultrasound Tumor Ablation and Liquid Biopsy AcquisitionMagnetic Resonance Guided Focused Ultrasound Thalamotomy
Amyotrophic Lateral Sclerosis

Development of Targeted RNA-Seq for Amyotrophic Lateral Sclerosis Diagnosis

RECRUITING
NCT06083584Centre Hospitalier Universitaire de NīmesStarted 2023-11-22
RNA sequencing
ALS

Amyotrophic Lateral Sclerosis (ALS) Families Project

RECRUITING
NCT03865420Columbia UniversityStarted 2018-09-11
Amyotrophic Lateral Sclerosis

Longitudinal Assessment of Autonomic and Sensory Nervous System in ALS

RECRUITING
NCT05747937Phase NAIstituti Clinici Scientifici Maugeri SpAStarted 2021-05-15
Skin biopsyCardiovascular Reflexes testingAdministration of clinical scales evaluating autonomic symptoms, pain small fiber neuropathy symptoms
Amyotrophic Lateral Sclerosis (ALS)

Study on the Safety and Efficacy of RAG-21 in the Treatment of Amyotrophic Lateral Sclerosis Patients With FUS Gene Mutations

NOT YET RECRUITING
NCT07080801Phase EARLY_PHASE1Beijing Tiantan HospitalStarted 2025-08
RAG-21

External Resources

Links to major genomics databases and tools