Is FBXO7 p.Val274fs (c.821_822del) pathogenic?

FBXO7 p.Val274fs (c.821822del) is classified Pathogenic in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-12). Very rare (popmax 0.000255%, nfe); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Val274fs (c.821_822del)?

FBXO7 p.Val274fs (c.821_822del) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Val274fs (c.821_822del) in the general population?

FBXO7 p.Val274fs (c.821_822del) is very rare (popmax 0.000255%, nfe) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

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

FBXO7 p.Val274fs

c.821_822del · rs1157030138 · VCV2900056

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000255%, 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 5 of 9
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.1	GERP 2.6, phastCons 1
Overall
CADD	32.0	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 0.000255% European (non-Finnish) · 3/1,176,532 alleles

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

Overall 0.000186% 3/1,609,598 alleles · very rare exomes 2/1,457,386 · genomes 1/152,212 · 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.Val274fs
Coding: c.821_822del
MANE Select: NM_012179
dbSNP: rs1157030138
Type: Microsatellite
Location: chr22:32487775 (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 274: a β-strand; the 'important for dimerization and interaction with psmf1' 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.Tyr425fs Pathogenic/Likely pathogenic ★★ same condition
FBXO7 p.Arg306fs Pathogenic ★ same condition
FBXO7 p.Leu250fs Pathogenic ★ same condition
FBXO7 p.Ser189fs 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-val274fs (accessed [today's date]).

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