Is BCO2 p.Arg410Trp (c.1228A>T) pathogenic?

BCO2 p.Arg410Trp (c.1228A>T) is classified Uncertain significance in BCO2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely pathogenic (0.8379); Ultra-rare (popmax 0.0491%, nfe).

How common is BCO2 p.Arg410Trp (c.1228A>T) in the general population?

BCO2 p.Arg410Trp (c.1228A>T) is ultra-rare (popmax 0.0491%, nfe) (gnomAD).

What do computational predictors say about BCO2 p.Arg410Trp (c.1228A>T)?

AlphaMissense predicts likely pathogenic (score 0.8379) — an in-silico prediction, not a clinical call.

BCO2 p.Arg410Trp

c.1228A>T · rs78952668 · VCV3133531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8379 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0491%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8379	likely pathogenic
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -14.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.44	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 42 kb · p 0.37 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0491% European (non-Finnish) · 579/1,179,720 alleles

Filtering AF 0.0458% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0444%

Overall 0.0426% 687/1,613,468 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.127%	789
European (non-Finnish)grpmax	0.0491%	2,038
Remaining individualsnot grpmax-eligible	0.0272%	3,675
African / African-American	0.00935%	10,701
South Asian	0.0022%	45,532
Admixed American	0.00167%	59,940

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg410Trp
Coding: c.1228A>T
MANE Select: NM_031938
dbSNP: rs78952668
Type: single nucleotide variant
Location: chr11:112213757 (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-arg410trp (accessed [today's date]).

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