Is FBXO7 p.Leu375= (c.1125A>G) pathogenic?

FBXO7 p.Leu375= (c.1125A>G) is classified Benign/Likely benign in FBXO7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). Low-frequency (popmax 2.3%, afr); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Leu375= (c.1125A>G)?

FBXO7 p.Leu375= (c.1125A>G) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Leu375= (c.1125A>G) in the general population?

FBXO7 p.Leu375= (c.1125A>G) is low-frequency (popmax 2.3%, afr) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

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

FBXO7 p.Leu375=

c.1125A>G · rs147911892 · VCV341316

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.3%, afr)

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.21	donor loss · deltas
Constraint at this position
Conservation	phyloP -0.47	GERP -4.9, phastCons 0.001
Overall
CADD	1.767	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.3% African / African-American · 1,724/75,012 alleles

Filtering AF 2.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.17%

Overall 0.115% 1,858/1,614,032 alleles · low-frequency exomes 934/1,461,778 · genomes 924/152,254 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.3%	44
Remaining individualsnot grpmax-eligible	0.123%	812
Admixed American	0.055%	1,819
Middle Eastern	0.033%	3,031
South Asian	0.0154%	6,506
European (non-Finnish)	0.000678%	147,492

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.Leu375=
Coding: c.1125A>G
MANE Select: NM_012179
dbSNP: rs147911892
Type: single nucleotide variant
Location: chr22:32493262 (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 375: the f-box domain

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.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
FBXO7 p.Ala84Val Uncertain significance ★★ ⚠ 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-leu375 (accessed [today's date]).

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