Is BRD2 p.Arg708His (c.2123G>A) pathogenic?

BRD2 p.Arg708His (c.2123G>A) is classified Uncertain significance in BRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely pathogenic (0.6776); Ultra-rare (popmax 0.0164%, mid).

How common is BRD2 p.Arg708His (c.2123G>A) in the general population?

BRD2 p.Arg708His (c.2123G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about BRD2 p.Arg708His (c.2123G>A)?

AlphaMissense predicts likely pathogenic (score 0.6776) — an in-silico prediction, not a clinical call.

BRD2 p.Arg708His

c.2123G>A · rs768036257 · VCV2398353

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6776 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6776	likely pathogenic
REVEL	0.209	benign-leaning
SaProt	LLR -13.85	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.40	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP -0.18, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 654 bp · p 0.61 · regional, not allelic
Overall
CADD	26.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00174% 28/1,612,088 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00223%	44,900
European (non-Finnish)	0.00186%	53,632
Finnishnot grpmax-eligible	0.0016%	62,386
Remaining individualsnot grpmax-eligible	0.0016%	62,452
African / African-American	0.00134%	74,848
South Asian	0.0011%	91,066

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.Arg708His
Coding: c.2123G>A
MANE Select: NM_005104
dbSNP: rs768036257
Type: single nucleotide variant
Location: chr6:32980109 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.70 · 169 PDB
Residue 708: the net domain

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-arg708his (accessed [today's date]).

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