Is FBXO7 p.Met115Ile (c.345G>A) pathogenic?

FBXO7 p.Met115Ile (c.345G>A) is classified Benign in FBXO7 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0795); Common (popmax 73.1%, eas) — too common for a highly-penetrant pathogenic allele; Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Met115Ile (c.345G>A)?

FBXO7 p.Met115Ile (c.345G>A) is associated with parkinsonian-pyramidal syndrome (ClinVar).

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.Met115Ile (c.345G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

FBXO7 p.Met115Ile

Q: How common is FBXO7 p.Met115Ile (c.345G>A) in the general population?

FBXO7 p.Met115Ile (c.345G>A) is common (popmax 73.1%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.345G>A · rs11107 · VCV195275

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 73.1%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -5.66	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 -0.51	GERP -5.1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	2.565	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 73.1% East Asian · 32,742/44,810 alleles

Filtering AF 72.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 72.1%

Overall 40.4% 651,428/1,613,402 alleles · common exomes 588,283/1,461,758 · genomes 63,145/151,644 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	73.1%	1
Admixed American	57.2%	2
Finnishnot grpmax-eligible	47.3%	2
South Asian	46.6%	2
Middle Eastern	42.2%	2
Remaining individualsnot grpmax-eligible	41.6%	2
Ashkenazi Jewishnot grpmax-eligible	40.8%	2
African / African-American	38.4%	3
European (non-Finnish)	37.5%	3
Amishnot grpmax-eligible	34.6%	3

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.Met115Ile
Coding: c.345G>A
MANE Select: NM_012179
dbSNP: rs11107
Type: single nucleotide variant
Location: chr22:32479203 (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 115: a UniProt-annotated variant site (in); 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-met115ile (accessed [today's date]).

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