# NM_004960.4(FUS):c.1453C>T (p.Arg485Trp)

https://sugi.bio/variant/fus-p-arg485trp

## Summary

**FUS p.Arg485Trp (c.1453C>T)** is classified **Conflicting classifications of pathogenicity** in FUS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.9028); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201772423 · 6 submitters · 3 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0167%, mid)

## For patients & families {#patients}

This is a change in the FUS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Inborn genetic diseases.

*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.Arg485Trp |
| Coding change (HGVS c.) | c.1453C>T |
| MANE Select transcript | [NM_004960](https://www.ncbi.nlm.nih.gov/nuccore/NM_004960) |
| dbSNP | [rs201772423](https://www.ncbi.nlm.nih.gov/snp/rs201772423/) |
| Variant type | single nucleotide variant |
| Location | chr16:31191022-31191022 (GRCh38) |
| ClinVar | [VCV1773001](https://www.ncbi.nlm.nih.gov/clinvar/variation/1773001/) |

**All HGVS expressions:** `LRG_655:g.15891C>T`, `LRG_655t1:c.1453C>T`, `NC_000016.10:g.31191022C>T`, `NC_000016.9:g.31202343C>T`, `NG_012889.2:g.15891C>T`, `NM_001170634.1:c.1450C>T`, `NM_001170937.1:c.1441C>T`, `NM_004960.4:c.1453C>T`, `NR_028388.2:n.1523C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9028)
- REVEL 0.529 (indeterminate)
- SaProt LLR -15.446 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 6.013, GERP -2.19, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.80** across the covering region of the MANE Select transcript (31,190,791–31,191,435), spanning 644 bp. Chi-square p 0.025. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 (gnomAD v4.1): grpmax **0.0167%** (mid) · FAF95 0.00674% · FAF99 0.00626% · 1/5,986 in the highest group · 156/1,607,122 alleles overall — ultra-rare (popmax 0.0167%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0731% | 1,368 |
| Remaining individuals (not grpmax-eligible) | 0.0177% | 5,647 |
| Middle Eastern (grpmax) | 0.0167% | 5,986 |
| European (non-Finnish) | 0.00808% | 12,384 |
| African / African-American | 0.00403% | 24,796 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **485** 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.Arg485Trp 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-12.

**Submitter consensus:** conflicting (3 Likely benign, 2 Uncertain significance, 1 Benign).

**Submission history:** 6 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-11-19 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-08-22 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-04 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-06-12 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-01 |

## Associated conditions {#conditions}

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

## Similar variants {#similar}

Related FUS variant pages (same residue, condition, or type): [FUS p.Arg485Gln](/variant/fus-p-arg485gln), [FUS p.Arg481Ter](/variant/fus-p-arg481ter), [FUS p.Arg495Ter](/variant/fus-p-arg495ter), [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 2026-10-14); 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 1773001). 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.*