Is FBXO7 c.122+254G>A pathogenic?

FBXO7 c.122+254G>A is classified Benign in FBXO7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-25). Common (popmax 10.8%, amr) — too common for a highly-penetrant pathogenic allele.

FBXO7 c.122+254G>A

Q: How common is FBXO7 c.122+254G>A in the general population?

FBXO7 c.122+254G>A is common (popmax 10.8%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs9621461 · VCV1244096

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 10.8%, amr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.044	moderately benign-leaning
Splicing
Splice region	donor +254	deep intronic (+254 nt into the intron)
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.14	GERP -3.2, phastCons 0.001
Overall
CADD	6.578	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.8% Admixed American · 6,484/59,828 alleles

Filtering AF 10.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.5%

Overall 9.49% 152,939/1,611,018 alleles · common exomes 140,741/1,458,772 · genomes 12,198/152,246 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	13.1%	8
Admixed Americangrpmax	10.8%	9
Finnishnot grpmax-eligible	10.8%	9
European (non-Finnish)	10.2%	10
Remaining individualsnot grpmax-eligible	8.98%	11
South Asian	7.79%	13
East Asian	6.43%	16
Middle Eastern	6.03%	17
Ashkenazi Jewishnot grpmax-eligible	4.34%	23
African / African-American	3.48%	29

Amish 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
Coding: c.122+254G>A
MANE Select: NM_012179
dbSNP: rs9621461
Type: single nucleotide variant
Location: chr22:32475378 (GRCh38)
Gene constraint: LOEUF 0.955 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.13 · 2 PDB

Full FBXO7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FBXO7 p.Arg321Ter Pathogenic/Likely pathogenic ★★ same type
FBXO7 p.Arg345Ter Pathogenic/Likely pathogenic ★★ same type
FBXO7 p.Arg381Ter Pathogenic/Likely pathogenic ★★ same type
FBXO7 p.Arg45Ter Pathogenic/Likely pathogenic ★★ same type
FBXO7 p.Arg498Ter Pathogenic ★★ same type
FBXO7 p.Gln237Ter Pathogenic/Likely pathogenic ★★ same type
FBXO7 p.Thr22Met Pathogenic/Likely pathogenic ★★ same type
FBXO7 p.Ala84Val Uncertain significance ★★ ⚠ same type

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-c-122-plus-254g-a (accessed [today's date]).

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