Is FBXO7 p.Arg350Cys (c.1048C>T) pathogenic?

FBXO7 p.Arg350Cys (c.1048C>T) is classified Uncertain significance in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.125); Ultra-rare (popmax 0.0164%, mid); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Arg350Cys (c.1048C>T)?

FBXO7 p.Arg350Cys (c.1048C>T) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Arg350Cys (c.1048C>T) in the general population?

FBXO7 p.Arg350Cys (c.1048C>T) is ultra-rare (popmax 0.0164%, 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.Arg350Cys (c.1048C>T)?

AlphaMissense predicts likely benign (score 0.125) — an in-silico prediction, not a clinical call.

FBXO7 p.Arg350Cys

c.1048C>T · rs780834791 · VCV2040372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.125 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.125	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -9.90	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.54 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00266% 43/1,614,024 alleles · ultra-rare exomes 40/1,461,832 · genomes 3/152,192 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.0133%	7,501
Finnishnot grpmax-eligible	0.0125%	8,004
East Asian	0.00446%	22,446
African / African-American	0.00267%	37,464
European (non-Finnish)	0.00178%	56,190
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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.Arg350Cys
Coding: c.1048C>T
MANE Select: NM_012179
dbSNP: rs780834791
Type: single nucleotide variant
Location: chr22:32493185 (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 350: 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.Arg350His 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-arg350cys (accessed [today's date]).

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