Is FBXO7 p.Gly126fs (c.377del) pathogenic?

FBXO7 p.Gly126fs (c.377del) is classified Pathogenic in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-05). Very rare (popmax 0.000254%, nfe); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Gly126fs (c.377del)?

FBXO7 p.Gly126fs (c.377del) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Gly126fs (c.377del) in the general population?

FBXO7 p.Gly126fs (c.377del) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

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

FBXO7 p.Gly126fs

c.377del · rs2057448454 · VCV2884317

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.7	GERP -5.1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,158 alleles · very rare exomes 3/1,461,886 · genomes 0/152,272 · 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: FBXO7
Protein: p.Gly126fs
Coding: c.377del
MANE Select: NM_012179
dbSNP: rs2057448454
Type: Deletion
Location: chr22:32479234 (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 126: the 'disordered' region; the 'important for interaction with pink1' region

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.Gly126= Likely benign ★ same residue
FBXO7 p.Pro484fs Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg513fs Uncertain significance ★★ same condition
FBXO7 c.1183-2_1183-1del Likely pathogenic ★ same condition
FBXO7 p.Asn51fs Pathogenic ★ same condition
FBXO7 p.Asp348fs Pathogenic ★ same condition
FBXO7 p.Cys192fs Pathogenic ★ same condition
FBXO7 p.Leu106fs 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-gly126fs (accessed [today's date]).

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