Is FUS p.Arg522= (c.1566G>A) pathogenic?

FUS p.Arg522= (c.1566G>A) is classified Benign/Likely benign in FUS (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-04-01). Rare (popmax 0.354%, sas); Associated with Inborn genetic diseases.

What condition is associated with FUS p.Arg522= (c.1566G>A)?

FUS p.Arg522= (c.1566G>A) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Arg522= (c.1566G>A) in the general population?

FUS p.Arg522= (c.1566G>A) is rare (popmax 0.354%, sas) (gnomAD).

FUS p.Arg522=

c.1566G>A · rs138901914 · VCV540280

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.354%, sas)

Conditions

Inborn genetic diseases

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 5.9	GERP -0.048, phastCons 1
Overall
CADD	12.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.354% South Asian · 322/91,018 alleles

Filtering AF 0.322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.31%

Overall 0.174% 2,801/1,613,152 alleles · rare exomes 2,649/1,461,730 · genomes 152/151,422 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.354%	283
European (non-Finnish)	0.195%	514
Middle Eastern	0.182%	550
Remaining individualsnot grpmax-eligible	0.114%	880
Admixed American	0.107%	936
African / African-American	0.0308%	3,247
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,288
Finnishnot grpmax-eligible	0.00939%	10,650

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.Arg522=
Coding: c.1566G>A
MANE Select: NM_004960
dbSNP: rs138901914
Type: single nucleotide variant
Location: chr16:31191423 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 522: the 'disordered' region; a UniProt-annotated variant site (in als6)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyotrophic lateral sclerosis type 6 tremor, hereditary essential, 4

Similar variants

FUS p.Arg522Gly Likely pathogenic ★ same residue
FUS p.Arg522Ser 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
FUS p.Arg521His 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-arg522 (accessed [today's date]).

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