Is FBXO7 p.Asp516His (c.1546G>C) pathogenic?

FBXO7 p.Asp516His (c.1546G>C) is classified Conflicting classifications of pathogenicity in FBXO7 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.3217); Rare (popmax 0.2%, nfe); Associated with parkinsonian-pyramidal syndrome.

What condition is associated with FBXO7 p.Asp516His (c.1546G>C)?

FBXO7 p.Asp516His (c.1546G>C) is associated with parkinsonian-pyramidal syndrome (ClinVar).

How common is FBXO7 p.Asp516His (c.1546G>C) in the general population?

FBXO7 p.Asp516His (c.1546G>C) is rare (popmax 0.2%, 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.Asp516His (c.1546G>C)?

AlphaMissense predicts likely benign (score 0.3217) — an in-silico prediction, not a clinical call.

FBXO7 p.Asp516His

c.1546G>C · rs34316445 · VCV444586

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3217 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.2%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

parkinsonian-pyramidal syndrome

Computational evidence

Protein change
AlphaMissense	0.3217	likely benign
REVEL	0.551	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	24.2	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 0.2% European (non-Finnish) · 2,356/1,180,014 alleles

Filtering AF 0.193% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.19%

Overall 0.187% 3,025/1,613,818 alleles · rare exomes 2,814/1,461,530 · genomes 211/152,288 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.392%	255
Ashkenazi Jewishnot grpmax-eligible	0.351%	285
Remaining individualsnot grpmax-eligible	0.208%	481
European (non-Finnish)grpmax	0.2%	501
South Asian	0.152%	660
Admixed American	0.05%	2,001
Middle Eastern	0.033%	3,031
African / African-American	0.02%	5,003

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp516His
Coding: c.1546G>C
MANE Select: NM_012179
dbSNP: rs34316445
Type: single nucleotide variant
Location: chr22:32498507 (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 516: the 'important for interaction with cdk6' region; the 'disordered' 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.Asp516Tyr Uncertain significance ★ ⚠ 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-asp516his (accessed [today's date]).

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