Is BRD2 p.Arg406Cys (c.1216C>T) pathogenic?

BRD2 p.Arg406Cys (c.1216C>T) is classified Uncertain significance in BRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-02). AlphaMissense: likely pathogenic (0.9491); Very rare (popmax 0.0011%, sas).

How common is BRD2 p.Arg406Cys (c.1216C>T) in the general population?

BRD2 p.Arg406Cys (c.1216C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRD2 p.Arg406Cys (c.1216C>T)?

AlphaMissense predicts likely pathogenic (score 0.9491) — an in-silico prediction, not a clinical call.

BRD2 p.Arg406Cys

c.1216C>T · VCV3825549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9491	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -10.79	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 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 3,274 bp · p 0.26 · regional, not allelic
Overall
CADD	32.0	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 0.0011% South Asian · 1/91,082 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,914 alleles · very rare exomes 4/1,461,634 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,082
European (non-Finnish)	0.000254%	393,345

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.Arg406Cys
Coding: c.1216C>T
MANE Select: NM_005104
Type: single nucleotide variant
Location: chr6:32977457 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.70 · 169 PDB
Residue 406: the bromo 2 domain; a turn

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-arg406cys (accessed [today's date]).

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