Is FBXO7 p.Pro225Arg (c.674C>G) pathogenic?

FBXO7 p.Pro225Arg (c.674C>G) is classified Uncertain significance in FBXO7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-24). AlphaMissense: likely pathogenic (0.8346); Ultra-rare (popmax 0.0347%, afr); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Pro225Arg (c.674C>G)?

FBXO7 p.Pro225Arg (c.674C>G) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Pro225Arg (c.674C>G) in the general population?

FBXO7 p.Pro225Arg (c.674C>G) is ultra-rare (popmax 0.0347%, afr) (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.Pro225Arg (c.674C>G)?

AlphaMissense predicts likely pathogenic (score 0.8346) — an in-silico prediction, not a clinical call.

FBXO7 p.Pro225Arg

c.674C>G · rs112660869 · VCV1347968

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.8346	likely pathogenic
REVEL	0.503	indeterminate
SaProt	LLR -10.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
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	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0347% African / African-American · 26/75,022 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00266% 43/1,614,130 alleles · ultra-rare exomes 33/1,461,870 · genomes 10/152,260 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,885
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.016%	6,251
Admixed American	0.00333%	30,014
South Asian	0.00329%	30,358

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.Pro225Arg
Coding: c.674C>G
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.Pro225Leu 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-pro225arg (accessed [today's date]).

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