Is FUS p.Ser221del (c.661_663del) pathogenic?

FUS p.Ser221del (c.661663del) is classified Conflicting classifications of pathogenicity in FUS (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-11-12). Ultra-rare (popmax 0.012%, afr); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Ser221del (c.661_663del)?

FUS p.Ser221del (c.661_663del) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Ser221del (c.661_663del) in the general population?

FUS p.Ser221del (c.661_663del) is ultra-rare (popmax 0.012%, afr) (gnomAD).

FUS p.Ser221del

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.661_663del · rs746633090 · VCV503718

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

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 -0.33	GERP -0.85, phastCons 0.008
Overall
CADD	0.555	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(GGC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,710 alleles

Filtering AF 0.00682% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00677% 109/1,609,824 alleles · ultra-rare exomes 94/1,458,078 · genomes 15/151,746 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,301
European (non-Finnish)	0.00815%	12,272
East Asian	0.00447%	22,387
South Asian	0.0022%	45,448

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.Ser221del
Coding: c.661_663del
MANE Select: NM_004960
dbSNP: rs746633090
Type: Deletion
Location: chr16:31185076 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 221: a modified residue (phosphoserine); 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.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

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-ser221del (accessed [today's date]).

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