Is FBXO7 p.Leu304= (c.912C>T) pathogenic?

FBXO7 p.Leu304= (c.912C>T) is classified Likely benign in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-02). Ultra-rare (popmax 0.0294%, afr); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Leu304= (c.912C>T)?

FBXO7 p.Leu304= (c.912C>T) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Leu304= (c.912C>T) in the general population?

FBXO7 p.Leu304= (c.912C>T) is ultra-rare (popmax 0.0294%, afr) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

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

FBXO7 p.Leu304=

c.912C>T · rs377240853 · VCV2058806

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0294%, afr)

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.47	GERP -3.2, phastCons 0.044
Overall
CADD	7.098	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0294% African / African-American · 22/74,888 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00155% 25/1,613,394 alleles · ultra-rare exomes 14/1,461,248 · genomes 11/152,146 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0294%	3,404
European (non-Finnish)	0.000254%	393,182

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.Leu304=
Coding: c.912C>T
MANE Select: NM_012179
dbSNP: rs377240853
Type: single nucleotide variant
Location: chr22:32491126 (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 304: an α-helix; 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.Leu304His 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-leu304 (accessed [today's date]).

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