Is FUS p.Met254Val (c.760A>G) pathogenic?

FUS p.Met254Val (c.760A>G) is classified Likely pathogenic in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2015-05-21). AlphaMissense: likely benign (0.1398); Very rare (popmax 0.00442%, sas).

How common is FUS p.Met254Val (c.760A>G) in the general population?

FUS p.Met254Val (c.760A>G) is very rare (popmax 0.00442%, sas) (gnomAD).

What do computational predictors say about FUS p.Met254Val (c.760A>G)?

AlphaMissense predicts likely benign (score 0.1398) — an in-silico prediction, not a clinical call.

FUS p.Met254Val

c.760A>G · rs752076094 · VCV427141

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00442%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1398	likely benign ⚠ discordant with ClinVar
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -9.15	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 4,022 bp · p 0.013 · regional, not allelic
Overall
CADD	22.2	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 0.00442% South Asian · 4/90,414 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000896%

Overall 0.00137% 22/1,608,436 alleles · very rare exomes 18/1,456,360 · genomes 4/152,076 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00442%	22,604
Remaining individualsnot grpmax-eligible	0.00161%	62,232
European (non-Finnish)	0.00136%	73,582
African / African-American	0.00134%	74,838

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.Met254Val
Coding: c.760A>G
MANE Select: NM_004960
dbSNP: rs752076094
Type: single nucleotide variant
Location: chr16:31185175 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 254: the 'disordered' region; a UniProt-annotated variant site (found in a patient with frontotemporal lobar degeneration)

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

Similar variants

FUS p.Met254Thr Uncertain significance ★ ⚠ same residue
FUS p.Arg481Ter Pathogenic/Likely pathogenic ★★ same type
FUS p.Arg495Ter Pathogenic ★★ same type
FUS p.Arg514Gly Pathogenic ★★ ⚠ same type
FUS p.Arg521Cys Pathogenic ★★ same type
FUS p.Arg521Gly Pathogenic ★★ same type
FUS p.Arg521His Pathogenic ★★ ⚠ same type
FUS p.Arg521Leu Pathogenic/Likely pathogenic ★★ same type

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-met254val (accessed [today's date]).

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