FUS

Chr 16AD

FUS RNA binding protein

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

NCBI Gene: 2521 ENSG00000089280 UniProt: P35637 OMIM: 137070

The protein is a component of the heterogeneous nuclear ribonucleoprotein complex that regulates pre-mRNA splicing and export of processed mRNA to the cytoplasm, and belongs to the FET family of RNA-binding proteins involved in gene expression regulation and genomic integrity maintenance. Mutations cause autosomal dominant amyotrophic lateral sclerosis type 6 with or without frontotemporal dementia, and hereditary essential tremor type 4. The pathogenic mechanism involves loss of function, with the gene showing extreme intolerance to loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.242 OMIM phenotypes

Clinical Summary— FUS

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis type 6 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 284 VUS of 686 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FUS

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.10 (0.05–0.24)

0≤0.351.4

Missense OE?0.66 (0.59–0.74)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 4 / 38.6Missense obs/exp: 217 / 329.7Syn Z: -2.13

This gene — mechanism propensity

0.4686th %ile

GOF

0.3392th %ile

LOF

0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 57% of P/LP variants are LoF · LOEUF 0.24

GOF1 literature citation

Literature Evidence

GOFThe implications of this would be a progressive generalized disruption to transcription and RNA processing, and suggests a mechanism by which C-terminal FUS/TLS mutations may exert their effects by a toxic gain of function.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 20385912 ↗

ClinVar Variant Classifications

686 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31

Likely Pathogenic20

VUS284

Likely Benign215

Benign47

Conflicting39

Pathogenic

Likely Pathogenic

284

VUS

215

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	13	0	0	31
Likely Pathogenic	11	9	0	0	20
VUS	5	176	100	3	284
Likely Benign	1	11	119	84	215
Benign	0	1	42	4	47
Conflicting	—				39
Total	35	210	261	91	636

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap FUS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →