# NM_004960.4(FUS):c.1483dup (p.Arg495fs)

https://sugi.bio/variant/fus-p-arg495fs

## Summary

**FUS p.Arg495fs (c.1483dup)** is classified **Likely pathogenic** in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Associated with nanophthalmos 4.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the FUS gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to nanophthalmos 4.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018629/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.Arg495fs |
| Coding change (HGVS c.) | c.1483dup |
| MANE Select transcript | [NM_004960](https://www.ncbi.nlm.nih.gov/nuccore/NM_004960) |
| Variant type | Duplication |
| Location | chr16:31191050-31191051 (GRCh38) |
| ClinVar | [VCV4533182](https://www.ncbi.nlm.nih.gov/clinvar/variation/4533182/) |

**All HGVS expressions:** `LRG_655:g.15921dup`, `LRG_655t1:c.1483dup`, `NC_000016.10:g.31191052dup`, `NC_000016.9:g.31202373dup`, `NG_012889.2:g.15921dup`, `NM_001170634.1:c.1480dup`, `NM_001170937.1:c.1471dup`, `NM_004960.4:c.1483dup`, `NR_028388.2:n.1553dup`

## 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 6.18, GERP 2.17, 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 exon 14 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **495** lies in a modified residue (asymmetric dimethylarginine); 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.Arg495fs 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Intergen Genetics and Rare Diseases Diagnosis Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-01 |

## Associated conditions {#conditions}

[nanophthalmos 4](https://sugi.bio/atlas/disease/nanophthalmos-4/).

**Reported phenotype names (ClinVar):** Nanophthalmos 4, NANOPHTHALMIA 4.

## Same-residue context {#hotspot}

Residue **495** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FUS p.Arg495Ter](/variant/fus-p-arg495ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FUS variant pages (same residue, condition, or type): [FUS p.Arg495Ter](/variant/fus-p-arg495ter), [FUS p.Arg495Gln](/variant/fus-p-arg495gln), [FUS p.Arg495=](/variant/fus-p-arg495), [FUS p.Gly247_Arg248insGly](/variant/fus-p-gly247-arg248insgly), [FUS p.Gly458_Pro459insGly](/variant/fus-p-gly458-pro459insgly), [FUS c.524-13dup](/variant/fus-c-524-minus-13dup), [FUS p.Arg498fs](/variant/fus-p-arg498fs), [FUS p.Gly465fs](/variant/fus-p-gly465fs).

### 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 4533182). 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.*