Is BRD2 p.Phe149Leu (c.447C>G) pathogenic?

BRD2 p.Phe149Leu (c.447C>G) is classified Uncertain significance in BRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9998); Very rare (popmax 8.48e-05%, nfe).

How common is BRD2 p.Phe149Leu (c.447C>G) in the general population?

BRD2 p.Phe149Leu (c.447C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BRD2 p.Phe149Leu (c.447C>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

BRD2 p.Phe149Leu

c.447C>G · VCV4646593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 5% in BRD2
REVEL	0.358	indeterminate
SaProt	LLR -11.34	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP 0.89, phastCons 0.98
Regional constraint	o/e 1.23	unconstrained · MANE · 3,664 bp · p 2.1e-05 · regional, not allelic
Overall
CADD	22.8	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 8.48e-05% European (non-Finnish) · 1/1,179,758 alleles

Overall 6.85e-05% 1/1,460,184 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.Phe149Leu
Coding: c.447C>G
MANE Select: NM_005104
Type: single nucleotide variant
Location: chr6:32975497 (GRCh38)
Gene constraint: LOEUF 0.28 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 65.70 · 169 PDB
Residue 149: the bromo 1 domain; 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-phe149leu (accessed [today's date]).

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