Is FUS p.Arg216= (c.648C>T) pathogenic?

FUS p.Arg216= (c.648C>T) is classified Likely benign in FUS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-02). Ultra-rare (popmax 0.0447%, eas); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Arg216= (c.648C>T)?

FUS p.Arg216= (c.648C>T) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Arg216= (c.648C>T) in the general population?

FUS p.Arg216= (c.648C>T) is ultra-rare (popmax 0.0447%, eas) (gnomAD).

FUS p.Arg216=

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.648C>T · rs556586630 · VCV1630018

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0447%, eas)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -3.5
Overall
CADD	2.826	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0447% East Asian · 20/44,778 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00403% 65/1,610,978 alleles · ultra-rare exomes 51/1,459,062 · genomes 14/151,916 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0447%	2,239
African / African-American	0.0147%	6,806
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,574
Remaining individualsnot grpmax-eligible	0.00321%	31,192
European (non-Finnish)	0.00229%	43,652
South Asian	0.0022%	45,462
Admixed American	0.00169%	59,236
Finnishnot grpmax-eligible	0.00157%	63,658

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.Arg216=
Coding: c.648C>T
MANE Select: NM_004960
dbSNP: rs556586630
Type: single nucleotide variant
Location: chr16:31185063 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 216: a modified residue (asymmetric dimethylarginine; alternate); a modified residue (omega-n-methylarginine; alternate); the 'disordered' region; a UniProt-annotated variant site (in als6 and etm4)

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.Arg216His Uncertain significance ★★ ⚠ same residue
FUS p.Arg216Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
FUS p.Arg216_Gly223del 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

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-arg216 (accessed [today's date]).

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