Is BRD4 p.Pro649Arg (c.1946C>G) pathogenic?

BRD4 p.Pro649Arg (c.1946C>G) is classified Uncertain significance in BRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-16). AlphaMissense: likely pathogenic (0.9982); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome.

What condition is associated with BRD4 p.Pro649Arg (c.1946C>G)?

BRD4 p.Pro649Arg (c.1946C>G) is associated with Cornelia de Lange syndrome (ClinVar).

How common is BRD4 p.Pro649Arg (c.1946C>G) in the general population?

BRD4 p.Pro649Arg (c.1946C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRD4 p.Pro649Arg (c.1946C>G)?

AlphaMissense predicts likely pathogenic (score 0.9982) — an in-silico prediction, not a clinical call.

BRD4 p.Pro649Arg

c.1946C>G · rs2145570115 · VCV1992306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cornelia de Lange syndrome

Computational evidence

Protein change
AlphaMissense	0.9982	likely pathogenic · top 5% in BRD4
REVEL	0.479	indeterminate
SaProt	LLR -13.64	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 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 1,281 bp · p 8.7e-10 · regional, not allelic
Overall
CADD	25.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRD4
Protein: p.Pro649Arg
Coding: c.1946C>G
MANE Select: NM_001379291
dbSNP: rs2145570115
Type: single nucleotide variant
Location: chr19:15255398 (GRCh38)
Gene constraint: LOEUF 0.191 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 613 PDB
Residue 649: the net domain; a UniProt-annotated variant site (found in a patient with a neurodevelopmental syndrome; likely pathogenic)

Full BRD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cornelia de Lange syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRD4 c.4020+1G>A Pathogenic ★ same condition
BRD4 p.His388Gln Uncertain significance ★ ⚠ same condition
BRD4 p.Ser503Thr Uncertain significance ★ ⚠ same condition
BRD4 p.Ser712Phe Uncertain significance ★ ⚠ same condition
BRD4 p.Thr942Met Uncertain significance ★ ⚠ same condition
BRD4 p.Gln934_Gln936del Uncertain significance ★★ same condition
BRD4 p.Tyr430Cys Likely pathogenic ★★ same type
BRD4 p.Ala220Thr 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/brd4-p-pro649arg (accessed [today's date]).

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