Is BBX p.Lys764Glu (c.2290A>G) pathogenic?

BBX p.Lys764Glu (c.2290A>G) is classified Uncertain significance in BBX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.2877); Rare (popmax 0.183%, mid).

How common is BBX p.Lys764Glu (c.2290A>G) in the general population?

BBX p.Lys764Glu (c.2290A>G) is rare (popmax 0.183%, mid) (gnomAD).

What do computational predictors say about BBX p.Lys764Glu (c.2290A>G)?

AlphaMissense predicts likely benign (score 0.2877) — an in-silico prediction, not a clinical call.

BBX p.Lys764Glu

c.2290A>G · VCV3990812

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2877 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.183%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2877	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.88	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 8.1	GERP 1.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 25 kb · p 0.8 · regional, not allelic
Overall
CADD	22.9	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 0.183% Middle Eastern · 11/6,008 alleles

Filtering AF 0.103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0793%

Overall 0.00155% 24/1,547,408 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.183%	546
Remaining individualsnot grpmax-eligible	0.00668%	14,981
East Asian	0.00244%	40,906
Admixed American	0.00196%	50,894
African / African-American	0.00137%	72,912
European (non-Finnish)	0.000525%	190,609

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: BBX
Protein: p.Lys764Glu
Coding: c.2290A>G
MANE Select: NM_001142568
Type: single nucleotide variant
Location: chr3:107789873 (GRCh38)
Gene constraint: LOEUF 0.359 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.79
Residue 764: the 'disordered' region

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

Similar variants

BBX p.Ala442Thr Benign ★★ same type
BBX p.Ala60= Likely benign ★★ same type
BBX p.Ala892= Benign ★★ same type
BBX p.Ala139Thr Uncertain significance ★ ⚠ same type
BBX p.Ala143Gly Uncertain significance ★ ⚠ same type
BBX p.Ala269Pro Uncertain significance ★ ⚠ same type
BBX p.Ala354Thr Uncertain significance ★ ⚠ same type
BBX p.Ala375Thr 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/bbx-p-lys764glu (accessed [today's date]).

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