# NM_004960.4(FUS):c.1554_1557del (p.Gln519fs)

https://sugi.bio/variant/fus-p-gln519fs

## Summary

**FUS p.Gln519fs (c.1554_1557del)** is classified **Pathogenic** in FUS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-23). No gnomAD frequency available for this variant; Associated with amyotrophic lateral sclerosis type 6.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2144142389 · 3 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FUS gene that is considered disease-causing, submitted by 3 submitters, and is linked to amyotrophic lateral sclerosis type 6.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | FUS is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Frontotemporal dementia with motor neuron disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormal lower motor neuron morphology — Very frequent (99-80%)
- Abnormal upper motor neuron morphology — Very frequent (99-80%)
- Frontotemporal dementia — Very frequent (99-80%)
- Atypical behavior — Frequent (79-30%)
- Depression — Frequent (79-30%)
- Hallucinations — Frequent (79-30%)
- Apathy — Frequent (79-30%)
- Dysarthria — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009874/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FUS](https://sugi.bio/atlas/gene/FUS/) |
| Protein change (HGVS p.) | p.Gln519fs |
| Coding change (HGVS c.) | c.1554_1557del |
| MANE Select transcript | [NM_004960](https://www.ncbi.nlm.nih.gov/nuccore/NM_004960) |
| dbSNP | [rs2144142389](https://www.ncbi.nlm.nih.gov/snp/rs2144142389/) |
| Variant type | Microsatellite |
| Location | chr16:31191407-31191410 (GRCh38) |
| ClinVar | [VCV1073222](https://www.ncbi.nlm.nih.gov/clinvar/variation/1073222/) |

**All HGVS expressions:** `LRG_655:g.16276ACAG[1]`, `NC_000016.10:g.31191407ACAG[1]`, `NC_000016.9:g.31202728ACAG[1]`, `NG_012889.2:g.16276ACAG[1]`, `NM_001170634.1:c.1551_1554del`, `NM_001170937.1:c.1542_1545del`, `NM_004960.4:c.1554_1557del`, `NM_004960.4:c.1554_1557delACAG`, `NR_028388.2:n.1620ACAG[1]`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.717, GERP 2.02, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.104, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (15 of 15)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FUS** population constraint: LOEUF 0.104, pLI 1, missense-Z 2.8346. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **amyotrophic lateral sclerosis type 6** — Definitive (AD)

## Protein context {#protein}

Residue **519** lies in an α-helix; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 54.96, 9% of residues very-high.

**23 experimental structure(s)** (PDB): [2LA6](https://www.rcsb.org/structure/2LA6), [2LCW](https://www.rcsb.org/structure/2LCW), [4FDD](https://www.rcsb.org/structure/4FDD), [4FQ3](https://www.rcsb.org/structure/4FQ3), [5W3N](https://www.rcsb.org/structure/5W3N), [5XRR](https://www.rcsb.org/structure/5XRR).

## What this gene does {#gene-function}

*Describes the biological roles of FUS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FUS's established molecular role includes chromatin binding. p.Gln519fs falls in the disordered region. In Reactome, FUS is annotated in disease pathway(s) including **Dengue Virus-Host Interactions**.

**Disease mechanism (Reactome):** FUS loss or alteration is curated in [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481).

### Pathways affected {#pathways}

FUS participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus-Host Interactions](https://reactome.org/content/detail/R-HSA-9918481) | curated |
| [Processing of Capped Intron-Containing Pre-mRNA](https://reactome.org/content/detail/R-HSA-72203) | curated |
| [mRNA Polyadenylation](https://reactome.org/content/detail/R-HSA-9770562) | curated |
| [mRNA Splicing - Major Pathway](https://reactome.org/content/detail/R-HSA-72163) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** chromatin binding, transcription coactivator activity, RNA binding, identical protein binding, molecular condensate scaffold activity.

**Biological process:** regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, RNA splicing, regulation of RNA splicing, mRNA stabilization, protein homooligomerization.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-23.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-05 |
| Genetics and Molecular Pathology, SA Pathology | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-23 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-01 |

## Associated conditions {#conditions}

[amyotrophic lateral sclerosis type 6](https://sugi.bio/atlas/disease/amyotrophic-lateral-sclerosis-type-6/), [tremor, hereditary essential, 4](https://sugi.bio/atlas/disease/tremor-hereditary-essential-4/).

**Reported phenotype names (ClinVar):** Amyotrophic lateral sclerosis type 6, Tremor, hereditary essential, 4, not provided, none provided, Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, FUS-Related Amyotrophic Laterial Sclerosis, AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA.

## Same-residue context {#hotspot}

Residue **519** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [FUS p.Gln519Arg](/variant/fus-p-gln519arg), [FUS p.Gln519Ter](/variant/fus-p-gln519ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FUS variant pages (same residue, condition, or type): [FUS p.Gln519Ter](/variant/fus-p-gln519ter), [FUS p.Gln519Glu](/variant/fus-p-gln519glu), [FUS p.Gly504fs](/variant/fus-p-gly504fs), [FUS p.Gly228_Gly231del](/variant/fus-p-gly228-gly231del), [FUS p.Ser165del](/variant/fus-p-ser165del), [FUS c.518_523del](/variant/fus-c-518-523del), [FUS c.521_523+3dupGAGGTG](/variant/fus-c-521-523-plus-3dupgaggtg), [FUS p.Gly231del](/variant/fus-p-gly231del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1073222). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*