Is FUS p.Pro450Ser (c.1348C>T) pathogenic?

FUS p.Pro450Ser (c.1348C>T) is classified Conflicting classifications of pathogenicity in FUS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-03-08). AlphaMissense: ambiguous (0.5307); Ultra-rare (popmax 0.0571%, sas); Associated with amyotrophic lateral sclerosis type 6.

What condition is associated with FUS p.Pro450Ser (c.1348C>T)?

FUS p.Pro450Ser (c.1348C>T) is associated with amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Pro450Ser (c.1348C>T) in the general population?

FUS p.Pro450Ser (c.1348C>T) is ultra-rare (popmax 0.0571%, sas) (gnomAD).

What do computational predictors say about FUS p.Pro450Ser (c.1348C>T)?

AlphaMissense predicts ambiguous (score 0.5307) — an in-silico prediction, not a clinical call.

FUS p.Pro450Ser

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.1348C>T · rs201533156 · VCV886474

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5307 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0571%, sas)

Conditions

amyotrophic lateral sclerosis type 6

Computational evidence

Protein change
AlphaMissense	0.5307	ambiguous
REVEL	0.414	indeterminate
SaProt	LLR -11.99	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 644 bp · p 0.025 · regional, not allelic
Overall
CADD	24.7	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 0.0571% South Asian · 52/91,086 alleles

Filtering AF 0.0447% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0403%

Overall 0.00682% 110/1,614,072 alleles · ultra-rare exomes 104/1,461,882 · genomes 6/152,190 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0571%	1,752
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	0.00415%	24,083
Admixed American	0.00333%	30,000
Finnishnot grpmax-eligible	0.00312%	32,017

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.Pro450Ser
Coding: c.1348C>T
MANE Select: NM_004960
dbSNP: rs201533156
Type: single nucleotide variant
Location: chr16:31190797 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 450: a β-strand; 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 p.Pro450= 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-pro450ser (accessed [today's date]).

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