Is FBXO7 p.Met1Leu (c.1A>C) pathogenic?

FBXO7 p.Met1Leu (c.1A>C) is classified Pathogenic in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-15). Ultra-rare (popmax 0.0204%, sas); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Met1Leu (c.1A>C)?

FBXO7 p.Met1Leu (c.1A>C) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Met1Leu (c.1A>C) in the general population?

FBXO7 p.Met1Leu (c.1A>C) is ultra-rare (popmax 0.0204%, sas) (gnomAD).

How is Parkinsonian-pyramidal syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

FBXO7 p.Met1Leu

c.1A>C · rs753392528 · VCV2887235

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0204%, sas)

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.354	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0204% South Asian · 17/83,466 alleles

Filtering AF 0.013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00117% 18/1,536,094 alleles · ultra-rare exomes 18/1,383,780 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0204%	4,910
European (non-Finnish)	8.74e-05%	1,144,348

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.Met1Leu
Coding: c.1A>C
MANE Select: NM_012179
dbSNP: rs753392528
Type: single nucleotide variant
Location: chr22:32475003 (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 1: the 'ubiquitin-like' 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.Met1Arg Pathogenic ★ same residue
FBXO7 p.Met1Lys Pathogenic ★ same residue
FBXO7 p.Met1Val Pathogenic ★ 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

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-met1leu (accessed [today's date]).

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