Is BBX p.Arg99His (c.296G>A) pathogenic?

BBX p.Arg99His (c.296G>A) is classified Uncertain significance in BBX (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely pathogenic (0.9275); Ultra-rare (popmax 0.0329%, nfe).

How common is BBX p.Arg99His (c.296G>A) in the general population?

BBX p.Arg99His (c.296G>A) is ultra-rare (popmax 0.0329%, nfe) (gnomAD).

What do computational predictors say about BBX p.Arg99His (c.296G>A)?

AlphaMissense predicts likely pathogenic (score 0.9275) — an in-silico prediction, not a clinical call.

BBX p.Arg99His

c.296G>A · rs151079480 · VCV2365266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9275 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9275	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -1.22	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 18 kb · p 0.86 · regional, not allelic
Overall
CADD	33.0	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 0.0329% European (non-Finnish) · 388/1,179,788 alleles

Filtering AF 0.0302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0291%

Overall 0.0274% 442/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0329%	3,041
African / African-American	0.028%	3,572
Remaining individualsnot grpmax-eligible	0.0272%	3,676
Admixed American	0.02%	4,998
Finnishnot grpmax-eligible	0.00625%	16,008

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.Arg99His
Coding: c.296G>A
MANE Select: NM_001142568
dbSNP: rs151079480
Type: single nucleotide variant
Location: chr3:107716740 (GRCh38)
Gene constraint: LOEUF 0.359 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.79
Residue 99: a DNA-binding 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-arg99his (accessed [today's date]).

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