Is FBXO7 p.Thr44Asn (c.131C>A) pathogenic?

FBXO7 p.Thr44Asn (c.131C>A) is classified Uncertain significance in FBXO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). AlphaMissense: likely benign (0.1692); Ultra-rare (popmax 0.0178%, eas); Associated with FBXO7-related disorder.

What condition is associated with FBXO7 p.Thr44Asn (c.131C>A)?

FBXO7 p.Thr44Asn (c.131C>A) is associated with FBXO7-related disorder (ClinVar).

How common is FBXO7 p.Thr44Asn (c.131C>A) in the general population?

FBXO7 p.Thr44Asn (c.131C>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about FBXO7 p.Thr44Asn (c.131C>A)?

AlphaMissense predicts likely benign (score 0.1692) — an in-silico prediction, not a clinical call.

FBXO7 p.Thr44Asn

c.131C>A · rs762999184 · VCV2635086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FBXO7-related disorder

Computational evidence

Protein change
AlphaMissense	0.1692	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -9.52	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 24 kb · p 0.42 · regional, not allelic
Overall
CADD	24.0	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 0.0178% East Asian · 8/44,882 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000558% 9/1,614,154 alleles · ultra-rare exomes 9/1,461,852 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
European (non-Finnish)	8.47e-05%	1,179,994

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.Thr44Asn
Coding: c.131C>A
MANE Select: NM_012179
dbSNP: rs762999184
Type: single nucleotide variant
Location: chr22:32478989 (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 44: the 'ubiquitin-like' region

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

Disease context

FBXO7-related disorder

Similar variants

FBXO7 c.122+245G>A Likely benign same condition
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-thr44asn (accessed [today's date]).

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