Is FBXO7 p.Ser93Ala (c.277T>G) pathogenic?

FBXO7 p.Ser93Ala (c.277T>G) is classified Conflicting classifications of pathogenicity in FBXO7 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-09-09). AlphaMissense: likely benign (0.083); Rare (popmax 0.22%, amr); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Ser93Ala (c.277T>G)?

FBXO7 p.Ser93Ala (c.277T>G) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Ser93Ala (c.277T>G) in the general population?

FBXO7 p.Ser93Ala (c.277T>G) is rare (popmax 0.22%, amr) (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.Ser93Ala (c.277T>G)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

FBXO7 p.Ser93Ala

c.277T>G · rs143041875 · VCV901598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.22%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -6.21	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 2.4	GERP 0.19, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	19.36	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 0.22% Admixed American · 132/60,022 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.0341% 550/1,614,176 alleles · rare exomes 501/1,461,892 · genomes 49/152,284 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.22%	455
South Asian	0.0615%	1,627
Remaining individualsnot grpmax-eligible	0.0368%	2,718
European (non-Finnish)	0.0285%	3,512
African / African-American	0.004%	25,014

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.Ser93Ala
Coding: c.277T>G
MANE Select: NM_012179
dbSNP: rs143041875
Type: single nucleotide variant
Location: chr22:32479135 (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 93: the 'disordered' region; the 'important for interaction with pink1' 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.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
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-ser93ala (accessed [today's date]).

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