Is FBXO7 p.Arg378His (c.1133G>A) pathogenic?

FBXO7 p.Arg378His (c.1133G>A) is classified Uncertain significance in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: likely pathogenic (0.6218); Ultra-rare (popmax 0.0329%, sas).

How common is FBXO7 p.Arg378His (c.1133G>A) in the general population?

FBXO7 p.Arg378His (c.1133G>A) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

What do computational predictors say about FBXO7 p.Arg378His (c.1133G>A)?

AlphaMissense predicts likely pathogenic (score 0.6218) — an in-silico prediction, not a clinical call.

FBXO7 p.Arg378His

c.1133G>A · VCV3907199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6218 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6218	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -11.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
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 8.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0329% South Asian · 30/91,080 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00223% 36/1,613,836 alleles · ultra-rare exomes 33/1,461,580 · genomes 3/152,256 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,036
European (non-Finnish)	0.000509%	196,627

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.Arg378His
Coding: c.1133G>A
MANE Select: NM_012179
Type: single nucleotide variant
Location: chr22:32493270 (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 378: a UniProt-annotated variant site (in park15; no effect on interaction with prkn; loss of sirt7 ubiquitination)

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

Similar variants

FBXO7 p.Arg378Gly Pathogenic same residue
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

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-arg378his (accessed [today's date]).

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