Is FUS p.Arg371Cys (c.1111C>T) pathogenic?

FUS p.Arg371Cys (c.1111C>T) is classified Uncertain significance in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 0.00223%, eas); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Arg371Cys (c.1111C>T)?

FUS p.Arg371Cys (c.1111C>T) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Arg371Cys (c.1111C>T) in the general population?

FUS p.Arg371Cys (c.1111C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FUS p.Arg371Cys (c.1111C>T)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

FUS p.Arg371Cys

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.1111C>T · rs773141319 · VCV566220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 7% in FUS
REVEL	0.23	benign-leaning
SaProt	LLR -13.61	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.9, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 949 bp · p 1.6e-15 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,886 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000547% 8/1,461,734 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
Admixed American	0.00167%	59,988
European (non-Finnish)	0.000508%	196,659

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.Arg371Cys
Coding: c.1111C>T
MANE Select: NM_004960
dbSNP: rs773141319
Type: single nucleotide variant
Location: chr16:31190084 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 371: the rrm domain

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.Arg371His 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
FUS p.Arg521Leu Pathogenic/Likely 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-arg371cys (accessed [today's date]).

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