Is BCL6 p.Arg445Trp (c.1333C>T) pathogenic?

BCL6 p.Arg445Trp (c.1333C>T) is classified Uncertain significance in BCL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). AlphaMissense: ambiguous (0.4157); Ultra-rare (popmax 0.0235%, sas).

How common is BCL6 p.Arg445Trp (c.1333C>T) in the general population?

BCL6 p.Arg445Trp (c.1333C>T) is ultra-rare (popmax 0.0235%, sas) (gnomAD).

What do computational predictors say about BCL6 p.Arg445Trp (c.1333C>T)?

AlphaMissense predicts ambiguous (score 0.4157) — an in-silico prediction, not a clinical call.

BCL6 p.Arg445Trp

c.1333C>T · rs967749286 · VCV2540535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4157 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4157	ambiguous
REVEL	0.25	benign-leaning
SaProt	LLR -7.11	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,447 bp · p 0.65 · regional, not allelic
Overall
CADD	27.5	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 0.0235% South Asian · 18/76,550 alleles

Filtering AF 0.0151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0125%

Overall 0.00164% 25/1,528,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0235%	4,253
Middle Eastern	0.0189%	5,298
European (non-Finnish)	0.000526%	189,983

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: BCL6
Protein: p.Arg445Trp
Coding: c.1333C>T
MANE Select: NM_001706
dbSNP: rs967749286
Type: single nucleotide variant
Location: chr3:187729072 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.89 · 222 PDB
Residue 445: the 'disordered' region

Full BCL6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BCL6 c.1356-3T>C Likely benign ★★ same type
BCL6 c.161+8A>T Benign ★★ same type
BCL6 c.1840-7C>T Likely benign ★★ same type
BCL6 p.Pro245= Likely benign ★★ same type
BCL6 p.Ser209= Benign ★★ same type
BCL6 p.Thr48= Benign ★★ same type
BCL6 p.Ala107Thr Uncertain significance ★ ⚠ same type
BCL6 p.Ala291Thr 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/bcl6-p-arg445trp (accessed [today's date]).

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