Is BBX p.Asn760Ser (c.2279A>G) pathogenic?

BBX p.Asn760Ser (c.2279A>G) is classified Uncertain significance in BBX (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.0721); Ultra-rare (popmax 0.0318%, eas).

How common is BBX p.Asn760Ser (c.2279A>G) in the general population?

BBX p.Asn760Ser (c.2279A>G) is ultra-rare (popmax 0.0318%, eas) (gnomAD).

What do computational predictors say about BBX p.Asn760Ser (c.2279A>G)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

BBX p.Asn760Ser

c.2279A>G · rs374206549 · VCV3133190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.482	indeterminate
SaProt	LLR -4.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 25 kb · p 0.8 · regional, not allelic
Overall
CADD	20.7	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 0.0318% East Asian · 13/40,908 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00536% 83/1,549,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0318%	3,147
Admixed American	0.0314%	3,184
African / African-American	0.0274%	3,654
Remaining individualsnot grpmax-eligible	0.005%	20,008
Ashkenazi Jewishnot grpmax-eligible	0.0035%	28,604
European (non-Finnish)	0.00253%	39,493
South Asian	0.00119%	83,848

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.Asn760Ser
Coding: c.2279A>G
MANE Select: NM_001142568
dbSNP: rs374206549
Type: single nucleotide variant
Location: chr3:107789862 (GRCh38)
Gene constraint: LOEUF 0.359 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.79
Residue 760: 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-asn760ser (accessed [today's date]).

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