Is FBXO7 p.Arg481Cys (c.1441C>T) pathogenic?

FBXO7 p.Arg481Cys (c.1441C>T) is classified Conflicting classifications of pathogenicity in FBXO7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1296); Rare (popmax 0.346%, mid); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Arg481Cys (c.1441C>T)?

FBXO7 p.Arg481Cys (c.1441C>T) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Arg481Cys (c.1441C>T) in the general population?

FBXO7 p.Arg481Cys (c.1441C>T) is rare (popmax 0.346%, 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.Arg481Cys (c.1441C>T)?

AlphaMissense predicts likely benign (score 0.1296) — an in-silico prediction, not a clinical call.

FBXO7 p.Arg481Cys

c.1441C>T · rs148272407 · VCV767123

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1296 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.346%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.1296	likely benign
REVEL	0.522	indeterminate
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	26.4	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 0.346% Middle Eastern · 21/6,062 alleles

Filtering AF 0.279% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.267%

Overall 0.025% 404/1,614,174 alleles · rare exomes 378/1,461,892 · genomes 26/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.346%	289
South Asian	0.309%	324
Remaining individualsnot grpmax-eligible	0.0416%	2,404
African / African-American	0.0107%	9,379
Admixed American	0.00833%	12,004
Finnishnot grpmax-eligible	0.00781%	12,806
European (non-Finnish)	0.00483%	20,702
East Asian	0.00223%	44,886

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.Arg481Cys
Coding: c.1441C>T
MANE Select: NM_012179
dbSNP: rs148272407
Type: single nucleotide variant
Location: chr22:32498402 (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 481: a UniProt-annotated variant site (found in two patients with kufor-rakeb syndrome also carrying r-877 in atp13a2); the 'important for interaction with cdk6' 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.Arg481His 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-arg481cys (accessed [today's date]).

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