Is BRD2 p.Glu646Asp (c.1938G>C) pathogenic?

BRD2 p.Glu646Asp (c.1938G>C) is classified Uncertain significance in BRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). AlphaMissense: likely pathogenic (0.8845); Very rare (popmax 0.00223%, eas).

How common is BRD2 p.Glu646Asp (c.1938G>C) in the general population?

BRD2 p.Glu646Asp (c.1938G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRD2 p.Glu646Asp (c.1938G>C)?

AlphaMissense predicts likely pathogenic (score 0.8845) — an in-silico prediction, not a clinical call.

BRD2 p.Glu646Asp

c.1938G>C · VCV3261707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8845 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8845	likely pathogenic
REVEL	0.258	benign-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.15, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 180 bp · p 0.00054 · regional, not allelic
Overall
CADD	19.84	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 0.00223% East Asian · 1/44,898 alleles

Overall 0.000657% 1/152,200 alleles · very rare

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.Glu646Asp
Coding: c.1938G>C
MANE Select: NM_005104
Type: single nucleotide variant
Location: chr6:32979924 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.70 · 169 PDB
Residue 646: the net domain; the 'disordered' region; an α-helix

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-glu646asp (accessed [today's date]).

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