Is BBX p.Val893Met (c.2677G>A) pathogenic?

BBX p.Val893Met (c.2677G>A) is classified Uncertain significance in BBX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely pathogenic (0.5692); Ultra-rare (popmax 0.0602%, eas).

How common is BBX p.Val893Met (c.2677G>A) in the general population?

BBX p.Val893Met (c.2677G>A) is ultra-rare (popmax 0.0602%, eas) (gnomAD).

What do computational predictors say about BBX p.Val893Met (c.2677G>A)?

AlphaMissense predicts likely pathogenic (score 0.5692) — an in-silico prediction, not a clinical call.

BBX p.Val893Met

c.2677G>A · rs200844510 · VCV3133194

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0602%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5692	likely pathogenic
REVEL	0.518	indeterminate
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 6,762 bp · p 0.014 · regional, not allelic
Overall
CADD	25.9	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 0.0602% East Asian · 27/44,878 alleles

Filtering AF 0.0424% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00458% 74/1,614,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0602%	1,662
Remaining individualsnot grpmax-eligible	0.0544%	1,839
African / African-American	0.00666%	15,014
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Admixed American	0.00167%	60,034
European (non-Finnish)	0.000508%	196,673

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.Val893Met
Coding: c.2677G>A
MANE Select: NM_001142568
dbSNP: rs200844510
Type: single nucleotide variant
Location: chr3:107801220 (GRCh38)
Gene constraint: LOEUF 0.359 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.79

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-val893met (accessed [today's date]).

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