Is FUS p.Pro152Ser (c.454C>T) pathogenic?

FUS p.Pro152Ser (c.454C>T) is classified Uncertain significance in FUS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-19). AlphaMissense: likely benign (0.0638); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with FUS p.Pro152Ser (c.454C>T)?

FUS p.Pro152Ser (c.454C>T) is associated with Inborn genetic diseases, amyotrophic lateral sclerosis type 6, tremor, hereditary essential, 4 (ClinVar).

How common is FUS p.Pro152Ser (c.454C>T) in the general population?

FUS p.Pro152Ser (c.454C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FUS p.Pro152Ser (c.454C>T)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

FUS p.Pro152Ser

c.454C>T · rs376583452 · VCV1741417

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.565	indeterminate
SaProt	LLR -5.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 4,906 bp · p 0.12 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,902 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,614,044 alleles · very rare exomes 4/1,461,892 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,451
European (non-Finnish)	0.000339%	295,012

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.Pro152Ser
Coding: c.454C>T
MANE Select: NM_004960
dbSNP: rs376583452
Type: single nucleotide variant
Location: chr16:31184327 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 152: the 'disordered' region

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.Pro152Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro152ser (accessed [today's date]).

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