Is BCL3 p.Arg222Gln (c.665G>A) pathogenic?

BCL3 p.Arg222Gln (c.665G>A) is classified Uncertain significance in BCL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.0676); Ultra-rare (popmax 0.0196%, amr).

How common is BCL3 p.Arg222Gln (c.665G>A) in the general population?

BCL3 p.Arg222Gln (c.665G>A) is ultra-rare (popmax 0.0196%, amr) (gnomAD).

What do computational predictors say about BCL3 p.Arg222Gln (c.665G>A)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

BCL3 p.Arg222Gln

c.665G>A · rs763828094 · VCV2456325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -3.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -0.13, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 561 bp · p 0.72 · regional, not allelic
Overall
CADD	19.57	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 0.0196% Admixed American · 11/56,004 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00846%

Overall 0.00214% 34/1,585,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0196%	5,091
Middle Eastern	0.0168%	5,936
South Asian	0.00341%	29,359
African / African-American	0.0027%	37,046
Remaining individualsnot grpmax-eligible	0.00163%	61,316
European (non-Finnish)	0.00137%	72,905

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: BCL3
Protein: p.Arg222Gln
Coding: c.665G>A
MANE Select: NM_005178
dbSNP: rs763828094
Type: single nucleotide variant
Location: chr19:44757162 (GRCh38)
Gene constraint: LOEUF 0.702 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 71.86 · 2 PDB
Residue 222: an α-helix

Full BCL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCL3 p.Val258Met Uncertain significance ★★ ⚠ same type
BCL3 p.Leu294= Benign ★★ same type
BCL3 p.Ala126Thr Uncertain significance ★ ⚠ same type
BCL3 p.Ala22Thr Uncertain significance ★ ⚠ same type
BCL3 p.Ala270Gly Uncertain significance ★ ⚠ same type
BCL3 p.Ala45Asp Uncertain significance ★ ⚠ same type
BCL3 p.Ala45Thr Uncertain significance ★ ⚠ same type
BCL3 p.Ala45Val 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/bcl3-p-arg222gln (accessed [today's date]).

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