Is FBXO7 p.Tyr425fs (c.1268_1272dup) pathogenic?

FBXO7 p.Tyr425fs (c.12681272dup) is classified Pathogenic/Likely pathogenic in FBXO7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-29). Very rare (popmax 0.00534%, nfe); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Tyr425fs (c.1268_1272dup)?

FBXO7 p.Tyr425fs (c.1268_1272dup) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Tyr425fs (c.1268_1272dup) in the general population?

FBXO7 p.Tyr425fs (c.1268_1272dup) is very rare (popmax 0.00534%, nfe) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

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

FBXO7 p.Tyr425fs

c.1268_1272dup · rs749534144 · VCV631891

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, 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	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.62	GERP -2.7, phastCons 0.027
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% European (non-Finnish) · 63/1,180,024 alleles

Filtering AF 0.00426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00387%

Overall 0.00434% 70/1,614,174 alleles · very rare exomes 63/1,461,880 · genomes 7/152,294 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,930
European (non-Finnish)grpmax	0.00534%	18,731

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr425fs
Coding: c.1268_1272dup
MANE Select: NM_012179
dbSNP: rs749534144
Type: Microsatellite
Location: chr22:32498222 (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 425: the 'important for interaction with cdk6' 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.Cys243fs Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg306fs Pathogenic ★ same condition
FBXO7 p.Leu250fs Pathogenic ★ same condition
FBXO7 p.Ser189fs Pathogenic ★ same condition
FBXO7 p.Val274fs Pathogenic ★ same condition
FBXO7 c.1181_1182+1del Uncertain significance ★ same condition
FBXO7 c.645+22_645+23del Likely benign ★ same condition
FBXO7 c.871+15_871+17del Likely benign ★ 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-tyr425fs (accessed [today's date]).

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