Is FUS p.Ala423Val (c.1268C>T) pathogenic?

FUS p.Ala423Val (c.1268C>T) is classified Uncertain significance in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-17). AlphaMissense: likely pathogenic (0.9073); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FUS p.Ala423Val (c.1268C>T)?

FUS p.Ala423Val (c.1268C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FUS p.Ala423Val (c.1268C>T) in the general population?

FUS p.Ala423Val (c.1268C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FUS p.Ala423Val (c.1268C>T)?

AlphaMissense predicts likely pathogenic (score 0.9073) — an in-silico prediction, not a clinical call.

FUS p.Ala423Val

c.1268C>T · rs2144136586 · VCV1764597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9073 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9073	likely pathogenic
REVEL	0.334	indeterminate
SaProt	LLR -8.65	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 647 bp · p 0.028 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FUS
Protein: p.Ala423Val
Coding: c.1268C>T
MANE Select: NM_004960
dbSNP: rs2144136586
Type: single nucleotide variant
Location: chr16:31190374 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 423: 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

Similar variants

FUS c.833-6A>G Uncertain significance ★★ same condition
FUS p.Arg269Trp Uncertain significance ★★ ⚠ same condition
FUS p.Arg472Cys Uncertain significance ★★ ⚠ same condition
FUS p.Arg498Gln Uncertain significance ★★ same condition
FUS p.Gln199Glu Uncertain significance ★★ ⚠ same condition
FUS p.Gly515Ser Uncertain significance ★★ ⚠ same condition
FUS p.Pro152Ser Uncertain significance ★★ ⚠ same condition
FUS p.Tyr397Cys Uncertain significance ★★ ⚠ 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-ala423val (accessed [today's date]).

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