Is FBXO7 p.Pro225Leu (c.674C>T) pathogenic?

FBXO7 p.Pro225Leu (c.674C>T) is classified Uncertain significance in FBXO7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-24). AlphaMissense: ambiguous (0.4763); Ultra-rare (popmax 0.0493%, mid); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Pro225Leu (c.674C>T)?

FBXO7 p.Pro225Leu (c.674C>T) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Pro225Leu (c.674C>T) in the general population?

FBXO7 p.Pro225Leu (c.674C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

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

What do computational predictors say about FBXO7 p.Pro225Leu (c.674C>T)?

AlphaMissense predicts ambiguous (score 0.4763) — an in-silico prediction, not a clinical call.

FBXO7 p.Pro225Leu

c.674C>T · rs112660869 · VCV1301697

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.4763	ambiguous
REVEL	0.396	indeterminate
SaProt	LLR -8.03	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.0013% 21/1,614,012 alleles · ultra-rare exomes 20/1,461,870 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
East Asian	0.0178%	5,611
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00134%	74,900
European (non-Finnish)	0.000593%	168,576

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.Pro225Leu
Coding: c.674C>T
MANE Select: NM_012179
dbSNP: rs112660869
Type: single nucleotide variant
Location: chr22:32485096 (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 225: 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.Pro225Arg Uncertain significance ★★ ⚠ same residue
FBXO7 p.Pro225= Likely benign ★ 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

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-pro225leu (accessed [today's date]).

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