Is FBXO7 p.Val485Ile (c.1453G>A) pathogenic?

FBXO7 p.Val485Ile (c.1453G>A) is classified Conflicting classifications of pathogenicity in FBXO7 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-07-10). AlphaMissense: likely benign (0.0659); Ultra-rare (popmax 0.0929%, nfe); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Val485Ile (c.1453G>A)?

FBXO7 p.Val485Ile (c.1453G>A) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Val485Ile (c.1453G>A) in the general population?

FBXO7 p.Val485Ile (c.1453G>A) is ultra-rare (popmax 0.0929%, nfe) (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.Val485Ile (c.1453G>A)?

AlphaMissense predicts likely benign (score 0.0659) — an in-silico prediction, not a clinical call.

FBXO7 p.Val485Ile

c.1453G>A · rs141286570 · VCV597905

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0929%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.0659	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -4.9
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	0.002	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 0.0929% European (non-Finnish) · 1,096/1,180,026 alleles

Filtering AF 0.0883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0864%

Overall 0.072% 1,162/1,614,182 alleles · ultra-rare exomes 1,083/1,461,888 · genomes 79/152,294 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0929%	1,077
Remaining individualsnot grpmax-eligible	0.0464%	2,156
Admixed American	0.0333%	3,001
African / African-American	0.02%	5,003
East Asian	0.00446%	22,444

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.Val485Ile
Coding: c.1453G>A
MANE Select: NM_012179
dbSNP: rs141286570
Type: single nucleotide variant
Location: chr22:32498414 (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 485: the 'important for interaction with cdk6' region; the 'disordered' 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.Val485Leu 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-val485ile (accessed [today's date]).

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