Is FUS p.Gly499fs (c.1496del) pathogenic?

FUS p.Gly499fs (c.1496del) is classified Pathogenic in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Gly499fs (c.1496del)?

FUS p.Gly499fs (c.1496del) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

FUS p.Gly499fs

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.1496del · VCV3760171

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 within the last 50 nt of the penultimate exon (14 of 15, 48 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 0.093, phastCons 1

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

Variant & gene context

Gene: FUS
Protein: p.Gly499fs
Coding: c.1496del
MANE Select: NM_004960
Type: Deletion
Location: chr16:31191062 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 499: 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 c.1394-2del Pathogenic/Likely pathogenic ★★ same condition
FUS p.Asp470fs Pathogenic/Likely pathogenic ★★ same condition
FUS p.Ser402del Uncertain significance ★★ same condition
FUS c.1541+9_1541+10del Benign/Likely benign ★★ same condition
FUS p.Gly509fs Likely pathogenic ★ same condition
FUS p.Tyr484fs Pathogenic ★ same condition
FUS c.13+11_13+13del Uncertain significance ★ same condition
FUS p.Arg216_Gly223del Uncertain significance ★ 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-gly499fs (accessed [today's date]).

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