Is FBXO7 p.Leu304His (c.911T>A) pathogenic?

FBXO7 p.Leu304His (c.911T>A) is classified Uncertain significance in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-16). AlphaMissense: likely pathogenic (0.946); No allele count reported in gnomAD v4.1 (AN 1,613,548); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Leu304His (c.911T>A)?

FBXO7 p.Leu304His (c.911T>A) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Leu304His (c.911T>A) in the general population?

FBXO7 p.Leu304His (c.911T>A) is no allele count reported in gnomAD v4.1 (AN 1,613,548) (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.Leu304His (c.911T>A)?

AlphaMissense predicts likely pathogenic (score 0.946) — an in-silico prediction, not a clinical call.

FBXO7 p.Leu304His

c.911T>A · rs2544665251 · VCV1928807

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.946 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,613,548)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.946	likely pathogenic · top 6% in FBXO7
REVEL	0.7	pathogenic-leaning
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	27.9	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

No allele count reported in gnomAD v4.1 (AN 1,613,548). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FBXO7
Protein: p.Leu304His
Coding: c.911T>A
MANE Select: NM_012179
dbSNP: rs2544665251
Type: single nucleotide variant
Location: chr22:32491125 (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 304: 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

FBXO7 p.Leu304= Likely benign ★ 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-leu304his (accessed [today's date]).

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