Is BRD2 p.Pro641Leu (c.1922C>T) pathogenic?

BRD2 p.Pro641Leu (c.1922C>T) is classified Uncertain significance in BRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely pathogenic (0.8181); Very rare (popmax 0.00333%, amr).

How common is BRD2 p.Pro641Leu (c.1922C>T) in the general population?

BRD2 p.Pro641Leu (c.1922C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about BRD2 p.Pro641Leu (c.1922C>T)?

AlphaMissense predicts likely pathogenic (score 0.8181) — an in-silico prediction, not a clinical call.

BRD2 p.Pro641Leu

c.1922C>T · VCV4646587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8181 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8181	likely pathogenic
REVEL	0.415	indeterminate
SaProt	LLR -12.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 180 bp · p 0.00054 · regional, not allelic
Overall
CADD	26.1	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 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,613,174 alleles · very rare exomes 10/1,460,914 · genomes 3/152,260 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,492
European (non-Finnish)	0.000763%	131,114

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: BRD2
Protein: p.Pro641Leu
Coding: c.1922C>T
MANE Select: NM_005104
Type: single nucleotide variant
Location: chr6:32979908 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.70 · 169 PDB
Residue 641: the net domain; the 'disordered' region

Full BRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRD2 p.Pro12Leu Uncertain significance ★★ ⚠ same type
BRD2 p.Ala766Thr Benign/Likely benign ★★ same type
BRD2 p.Gln533= Likely benign ★★ same type
BRD2 p.Leu383= Likely benign ★★ same type
BRD2 p.Ser397= Benign/Likely benign ★★ same type
BRD2 p.Val465= Likely benign ★★ same type
BRD2 p.Ala263Val Uncertain significance ★ ⚠ same type
BRD2 p.Ala295Pro 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/brd2-p-pro641leu (accessed [today's date]).

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