Is FBXO7 p.Arg306His (c.917G>A) pathogenic?

FBXO7 p.Arg306His (c.917G>A) is classified Uncertain significance in FBXO7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-05). AlphaMissense: likely benign (0.1276); Ultra-rare (popmax 0.0138%, nfe); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Arg306His (c.917G>A)?

FBXO7 p.Arg306His (c.917G>A) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Arg306His (c.917G>A) in the general population?

FBXO7 p.Arg306His (c.917G>A) is ultra-rare (popmax 0.0138%, nfe) (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.Arg306His (c.917G>A)?

AlphaMissense predicts likely benign (score 0.1276) — an in-silico prediction, not a clinical call.

FBXO7 p.Arg306His

c.917G>A · rs771599282 · VCV1484666

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1276 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.1276	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	29.7	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

Grpmax group 0.0138% European (non-Finnish) · 163/1,179,452 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.0105% 170/1,613,258 alleles · ultra-rare exomes 159/1,461,132 · genomes 11/152,126 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0138%	7,236
African / African-American	0.00534%	18,718
Remaining individualsnot grpmax-eligible	0.0048%	20,820

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.Arg306His
Coding: c.917G>A
MANE Select: NM_012179
dbSNP: rs771599282
Type: single nucleotide variant
Location: chr22:32491131 (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 306: 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.Arg306fs 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
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-arg306his (accessed [today's date]).

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