Is FUS p.Arg248His (c.743G>A) pathogenic?

FUS p.Arg248His (c.743G>A) is classified Uncertain significance in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: likely benign (0.3233); Very rare (popmax 0.00034%, nfe); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Arg248His (c.743G>A)?

FUS p.Arg248His (c.743G>A) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Arg248His (c.743G>A) in the general population?

FUS p.Arg248His (c.743G>A) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about FUS p.Arg248His (c.743G>A)?

AlphaMissense predicts likely benign (score 0.3233) — an in-silico prediction, not a clinical call.

FUS p.Arg248His

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.743G>A · rs760351730 · VCV581527

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3233 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
AlphaMissense	0.3233	likely benign
REVEL	0.396	indeterminate
SaProt	LLR -10.86	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 4,022 bp · p 0.013 · regional, not allelic
Overall
CADD	23.5	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 0.00034% European (non-Finnish) · 4/1,178,164 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,610,376 alleles · very rare exomes 4/1,458,116 · genomes 0/152,260 · joint denominator

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.Arg248His
Coding: c.743G>A
MANE Select: NM_004960
dbSNP: rs760351730
Type: single nucleotide variant
Location: chr16:31185158 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 248: the 'disordered' region; a modified residue (asymmetric dimethylarginine)

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.Arg248= Likely benign ★ 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-arg248his (accessed [today's date]).

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