# NM_004960.4(FUS):c.1483C>T (p.Arg495Ter)

https://sugi.bio/variant/fus-p-arg495ter

## Summary

**FUS p.Arg495Ter (c.1483C>T)** is classified **Pathogenic** in FUS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-06-14). Absent from gnomAD v4.1; Associated with FUS-related disorder.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs387906627 · 5 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the FUS gene that is considered disease-causing, submitted by 5 submitters, and is linked to FUS-related disorder.

*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:** [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.Arg495Ter |
| Coding change (HGVS c.) | c.1483C>T |
| MANE Select transcript | [NM_004960](https://www.ncbi.nlm.nih.gov/nuccore/NM_004960) |
| dbSNP | [rs387906627](https://www.ncbi.nlm.nih.gov/snp/rs387906627/) |
| Variant type | single nucleotide variant |
| Location | chr16:31191052-31191052 (GRCh38) |
| ClinVar | [VCV29707](https://www.ncbi.nlm.nih.gov/clinvar/variation/29707/) |

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

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.486, GERP -2.14, phastCons 0.997 — weakly conserved position
- Molecular consequence: **nonsense (stop-gain)** — 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.
- CADD: **PHRED 38.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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.Arg495Ter 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 2023-06-14.

**Submitter consensus:** unanimous (5/5 Pathogenic).

**Submission history:** 5 submissions (2010–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2010-08-31 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2021-04-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-14 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-24 |
| Illumina Laboratory Services, Illumina | Pathogenic | criteria provided, single submitter | clinical testing | 2019-10-31 |

## Associated conditions {#conditions}

[FUS-related disorder](https://sugi.bio/atlas/disease/fus-related-disorder/), [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):** FUS-related disorder, Amyotrophic lateral sclerosis type 6, not provided, Tremor, hereditary essential, 4, FUS-related condition, FUS-Related Amyotrophic Laterial Sclerosis, Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA, none provided.

## Same-residue context {#hotspot}

Residue **495** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FUS p.Arg495fs](/variant/fus-p-arg495fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FUS variant pages (same residue, condition, or type): [FUS p.Arg495Gln](/variant/fus-p-arg495gln), [FUS p.Arg495=](/variant/fus-p-arg495), [FUS p.Arg481Ter](/variant/fus-p-arg481ter), [FUS p.Arg514Gly](/variant/fus-p-arg514gly), [FUS p.Arg521Cys](/variant/fus-p-arg521cys), [FUS p.Arg521Gly](/variant/fus-p-arg521gly), [FUS p.Arg521His](/variant/fus-p-arg521his), [FUS p.Arg521Leu](/variant/fus-p-arg521leu).

### 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 29707). 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.*