Is FUS p.Phe265Val (c.793T>G) pathogenic?

FUS p.Phe265Val (c.793T>G) is classified Uncertain significance in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-13). AlphaMissense: likely pathogenic (0.909); Very rare (popmax 0.000339%, nfe).

How common is FUS p.Phe265Val (c.793T>G) in the general population?

FUS p.Phe265Val (c.793T>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about FUS p.Phe265Val (c.793T>G)?

AlphaMissense predicts likely pathogenic (score 0.909) — an in-silico prediction, not a clinical call.

FUS p.Phe265Val

c.793T>G · VCV3777645

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.909 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.909	likely pathogenic
REVEL	0.555	indeterminate
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 4,022 bp · p 0.013 · regional, not allelic
Overall
CADD	25.8	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 0.000339% European (non-Finnish) · 4/1,179,920 alleles

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

Overall 0.000248% 4/1,614,112 alleles · very rare exomes 4/1,461,742 · genomes 0/152,370 · 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.Phe265Val
Coding: c.793T>G
MANE Select: NM_004960
Type: single nucleotide variant
Location: chr16:31186830 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 265: the 'disordered' region

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

Similar variants

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
FUS p.Lys510Glu 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-phe265val (accessed [today's date]).

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