Is BCL6 p.Arg692Cys (c.2074C>T) pathogenic?

BCL6 p.Arg692Cys (c.2074C>T) is classified Uncertain significance in BCL6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.5414); Very rare (popmax 0.00446%, eas).

How common is BCL6 p.Arg692Cys (c.2074C>T) in the general population?

BCL6 p.Arg692Cys (c.2074C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BCL6 p.Arg692Cys (c.2074C>T)?

AlphaMissense predicts ambiguous (score 0.5414) — an in-silico prediction, not a clinical call.

BCL6 p.Arg692Cys

c.2074C>T · VCV3991021

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5414 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.5414	ambiguous
REVEL	0.532	indeterminate
SaProt	LLR -7.29	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 2,556 bp · p 1.4e-09 · regional, not allelic
Overall
CADD	34.0	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 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00235% 38/1,613,804 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
South Asian	0.00329%	30,352
European (non-Finnish)	0.00254%	39,333
Remaining individualsnot grpmax-eligible	0.0016%	62,462
Finnishnot grpmax-eligible	0.00156%	64,040
African / African-American	0.00133%	74,928

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.Arg692Cys
Coding: c.2074C>T
MANE Select: NM_001706
Type: single nucleotide variant
Location: chr3:187722505 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.89 · 222 PDB

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

Similar variants

BCL6 p.Arg692His Uncertain significance ★ ⚠ same residue
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

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-arg692cys (accessed [today's date]).

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