Is FUS p.Arg269Trp (c.805C>T) pathogenic?

FUS p.Arg269Trp (c.805C>T) is classified Uncertain significance in FUS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.7893); Very rare (popmax 0.00373%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FUS p.Arg269Trp (c.805C>T)?

FUS p.Arg269Trp (c.805C>T) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Arg269Trp (c.805C>T) in the general population?

FUS p.Arg269Trp (c.805C>T) is very rare (popmax 0.00373%, nfe) (gnomAD).

What do computational predictors say about FUS p.Arg269Trp (c.805C>T)?

AlphaMissense predicts likely pathogenic (score 0.7893) — an in-silico prediction, not a clinical call.

FUS p.Arg269Trp

c.805C>T · rs755018172 · VCV1761839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00373%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7893	likely pathogenic
REVEL	0.625	indeterminate
SaProt	LLR -12.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 4,022 bp · p 0.013 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00373% European (non-Finnish) · 44/1,179,822 alleles

Filtering AF 0.00283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00298% 48/1,612,700 alleles · very rare exomes 42/1,461,632 · genomes 6/151,068 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00373%	26,814
African / African-American	0.00269%	37,224
Admixed American	0.00167%	59,914
Remaining individualsnot grpmax-eligible	0.0016%	62,470

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FUS
Protein: p.Arg269Trp
Coding: c.805C>T
MANE Select: NM_004960
dbSNP: rs755018172
Type: single nucleotide variant
Location: chr16:31188330 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 269: the 'disordered' region; an α-helix

Full FUS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 6 tremor, hereditary essential, 4

Similar variants

FUS p.Arg269Gln Uncertain significance ★ same residue
FUS p.Arg481Ter Pathogenic/Likely pathogenic ★★ same condition
FUS p.Arg495Ter Pathogenic ★★ same condition
FUS p.Arg514Gly Pathogenic ★★ ⚠ same condition
FUS p.Arg521Cys Pathogenic ★★ same condition
FUS p.Arg521Gly Pathogenic ★★ same condition
FUS p.Arg521His Pathogenic ★★ ⚠ same condition
FUS p.Arg521Leu Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fus-p-arg269trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown