Is FUS p.Ser402del (c.1204_1206del) pathogenic?

FUS p.Ser402del (c.12041206del) is classified Uncertain significance in FUS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-23). Very rare (popmax 0.00907%, nfe); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Ser402del (c.1204_1206del)?

FUS p.Ser402del (c.1204_1206del) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Ser402del (c.1204_1206del) in the general population?

FUS p.Ser402del (c.1204_1206del) is very rare (popmax 0.00907%, nfe) (gnomAD).

FUS p.Ser402del

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.1204_1206del · rs781120756 · VCV653781

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00907%, nfe)

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.58	GERP 0.067, phastCons 1
Overall
CADD	18.9	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(TGG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00907% European (non-Finnish) · 107/1,179,962 alleles

Filtering AF 0.00766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00708%

Overall 0.00762% 123/1,613,848 alleles · very rare exomes 120/1,461,872 · genomes 3/151,976 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,248
European (non-Finnish)grpmax	0.00907%	11,028
South Asian	0.00439%	22,770
East Asian	0.00223%	44,888
African / African-American	0.00134%	74,852

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Ser402del
Coding: c.1204_1206del
MANE Select: NM_004960
dbSNP: rs781120756
Type: Deletion
Location: chr16:31190310 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 402: 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 c.1541+9_1541+10del Benign/Likely benign ★★ same condition
FUS p.Gly499fs Pathogenic ★ 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-ser402del (accessed [today's date]).

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