Is FBXO7 p.Arg378Gly (c.1132C>G) pathogenic?

FBXO7 p.Arg378Gly (c.1132C>G) is classified Pathogenic in FBXO7 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2008-06-01). AlphaMissense: likely pathogenic (0.9513); Absent from gnomAD v4.1; Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Arg378Gly (c.1132C>G)?

FBXO7 p.Arg378Gly (c.1132C>G) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Arg378Gly (c.1132C>G) in the general population?

FBXO7 p.Arg378Gly (c.1132C>G) is absent from gnomAD v4.1 (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FBXO7 p.Arg378Gly (c.1132C>G)?

AlphaMissense predicts likely pathogenic (score 0.9513) — an in-silico prediction, not a clinical call.

FBXO7 p.Arg378Gly

c.1132C>G · rs71799110 · VCV4808

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9513 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.9513	likely pathogenic ✓ concordant with ClinVar · top 5% in FBXO7
REVEL	0.667	pathogenic-leaning
SaProt	LLR -12.89	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.28	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.1	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	27.7	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: FBXO7
Protein: p.Arg378Gly
Coding: c.1132C>G
MANE Select: NM_012179
dbSNP: rs71799110
Type: single nucleotide variant
Location: chr22:32493269 (GRCh38)
Gene constraint: LOEUF 0.955 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.13 · 2 PDB
Residue 378: a UniProt-annotated variant site (in park15; no effect on interaction with prkn; loss of sirt7 ubiquitination)

Full FBXO7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

parkinsonian-pyramidal syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Parkinsonian-pyramidal syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult

Similar variants

FBXO7 p.Arg378His Uncertain significance ★ ⚠ same residue
FBXO7 p.Arg321Ter Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg345Ter Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg381Ter Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg45Ter Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg498Ter Pathogenic ★★ same condition
FBXO7 p.Gln237Ter Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Thr22Met 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/fbxo7-p-arg378gly (accessed [today's date]).

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