Is BCO2 p.Glu423Lys (c.1267G>A) pathogenic?

BCO2 p.Glu423Lys (c.1267G>A) is classified Uncertain significance in BCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-17). AlphaMissense: likely benign (0.0749); Very rare (popmax 0.00446%, eas).

How common is BCO2 p.Glu423Lys (c.1267G>A) in the general population?

BCO2 p.Glu423Lys (c.1267G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BCO2 p.Glu423Lys (c.1267G>A)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

BCO2 p.Glu423Lys

c.1267G>A · rs553884859 · VCV2524280

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -6.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.1	GERP -0.11, phastCons 0.73
Regional constraint	o/e 0.97	unconstrained · MANE · 42 kb · p 0.37 · regional, not allelic
Overall
CADD	16.57	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 0.00446% East Asian · 2/44,836 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000372% 6/1,613,456 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,418
Remaining individualsnot grpmax-eligible	0.0032%	31,239
South Asian	0.0022%	45,525

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: BCO2
Protein: p.Glu423Lys
Coding: c.1267G>A
MANE Select: NM_031938
dbSNP: rs553884859
Type: single nucleotide variant
Location: chr11:112213796 (GRCh38)
Gene constraint: LOEUF 1.047 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.41

Full BCO2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCO2 p.Arg472Ter Likely benign ★★ same type
BCO2 p.Ala115Val Uncertain significance ★ ⚠ same type
BCO2 p.Ala223Gly Uncertain significance ★ ⚠ same type
BCO2 p.Ala318Val Uncertain significance ★ ⚠ same type
BCO2 p.Ala437Ser Uncertain significance ★ ⚠ same type
BCO2 p.Arg184Trp Uncertain significance ★ ⚠ same type
BCO2 p.Arg253Gln Uncertain significance ★ ⚠ same type
BCO2 p.Arg27Trp 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/bco2-p-glu423lys (accessed [today's date]).

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