Is FUS p.His463Arg (c.1388A>G) pathogenic?

FUS p.His463Arg (c.1388A>G) is classified Uncertain significance in FUS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-01). AlphaMissense: ambiguous (0.3492); Absent from gnomAD v4.1.

How common is FUS p.His463Arg (c.1388A>G) in the general population?

FUS p.His463Arg (c.1388A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FUS p.His463Arg (c.1388A>G)?

AlphaMissense predicts ambiguous (score 0.3492) — an in-silico prediction, not a clinical call.

FUS p.His463Arg

c.1388A>G · rs2144138846 · VCV1694795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3492 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3492	ambiguous
REVEL	0.263	benign-leaning
SaProt	LLR -4.26	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 644 bp · p 0.025 · regional, not allelic
Overall
CADD	21.9	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.His463Arg
Coding: c.1388A>G
MANE Select: NM_004960
dbSNP: rs2144138846
Type: single nucleotide variant
Location: chr16:31190837 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.96 · 23 PDB
Residue 463: 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-his463arg (accessed [today's date]).

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