Is FBXO7 p.Ala198Gly (c.593C>G) pathogenic?

FBXO7 p.Ala198Gly (c.593C>G) is classified Uncertain significance in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-29). AlphaMissense: likely benign (0.2475); Absent from gnomAD v4.1; Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Ala198Gly (c.593C>G)?

FBXO7 p.Ala198Gly (c.593C>G) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Ala198Gly (c.593C>G) in the general population?

FBXO7 p.Ala198Gly (c.593C>G) is absent from gnomAD v4.1 (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.Ala198Gly (c.593C>G)?

AlphaMissense predicts likely benign (score 0.2475) — an in-silico prediction, not a clinical call.

FBXO7 p.Ala198Gly

c.593C>G · rs2057482701 · VCV962045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2475 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.2475	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -7.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FBXO7
Protein: p.Ala198Gly
Coding: c.593C>G
MANE Select: NM_012179
dbSNP: rs2057482701
Type: single nucleotide variant
Location: chr22:32484072 (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 198: an α-helix; 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

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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
FBXO7 p.Ala84Val Uncertain significance ★★ ⚠ 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-ala198gly (accessed [today's date]).

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