Is FUS p.Gln519fs (c.1554_1557del) pathogenic?

FUS p.Gln519fs (c.15541557del) is classified Pathogenic in FUS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-23). Absent from gnomAD; Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Gln519fs (c.1554_1557del)?

FUS p.Gln519fs (c.1554_1557del) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Gln519fs (c.1554_1557del) in the general population?

FUS p.Gln519fs (c.1554_1557del) is absent from gnomAD (gnomAD).

FUS p.Gln519fs

Q: How is Frontotemporal dementia with motor neuron disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1554_1557del · rs2144142389 · VCV1073222

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	escapes	premature termination codon in the last exon (15 of 15) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FUS
Protein: p.Gln519fs
Coding: c.1554_1557del
MANE Select: NM_004960
dbSNP: rs2144142389
Type: Microsatellite
Location: chr16:31191407 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 519: an α-helix; the 'disordered' region

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

Disease context

amyotrophic lateral sclerosis type 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tremor, hereditary essential, 4

For Frontotemporal dementia with motor neuron disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

FUS p.Gln519Ter Pathogenic ★ same residue
FUS p.Gln519Glu Uncertain significance ★ ⚠ same residue
FUS p.Gly504fs Pathogenic ★★ same condition
FUS p.Gly228_Gly231del Uncertain significance ★★ same condition
FUS p.Ser165del Uncertain significance ★★ same condition
FUS c.518_523del Benign/Likely benign ★★ same condition
FUS c.521_523+3dupGAGGTG Benign/Likely benign ★★ same condition
FUS p.Gly231del Likely benign ★★ 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-gln519fs (accessed [today's date]).

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