Is BRD4 p.Pro1019His (c.3056C>A) pathogenic?

BRD4 p.Pro1019His (c.3056C>A) is classified Conflicting classifications of pathogenicity in BRD4 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0855); Ultra-rare (popmax 0.0143%, eas).

How common is BRD4 p.Pro1019His (c.3056C>A) in the general population?

BRD4 p.Pro1019His (c.3056C>A) is ultra-rare (popmax 0.0143%, eas) (gnomAD).

What do computational predictors say about BRD4 p.Pro1019His (c.3056C>A)?

AlphaMissense predicts likely benign (score 0.0855) — an in-silico prediction, not a clinical call.

BRD4 p.Pro1019His

c.3056C>A · rs200799369 · VCV2713250

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0855	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 0.86, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 15 kb · p 0.05 · regional, not allelic
Overall
CADD	20.7	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 0.0143% East Asian · 6/41,828 alleles

Filtering AF 0.00876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00819%

Overall 0.00927% 143/1,542,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0143%	6,971
South Asian	0.0108%	9,292
European (non-Finnish)	0.0103%	9,708
Admixed American	0.00596%	16,777
African / African-American	0.00554%	18,063
Remaining individualsnot grpmax-eligible	0.00335%	29,859
Finnishnot grpmax-eligible	0.00181%	55,298

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: BRD4
Protein: p.Pro1019His
Coding: c.3056C>A
MANE Select: NM_001379291
dbSNP: rs200799369
Type: single nucleotide variant
Location: chr19:15243013 (GRCh38)
Gene constraint: LOEUF 0.191 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 613 PDB
Residue 1019: the 'disordered' region; 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

Similar variants

BRD4 p.Pro1019= Likely benign ★★ same residue
BRD4 p.Pro1019Leu Uncertain significance ★ ⚠ same residue
BRD4 p.Pro1019Ser Uncertain significance ★ ⚠ same residue
BRD4 p.Tyr430Cys Likely pathogenic ★★ same type
BRD4 p.Ala220Thr Uncertain significance ★★ ⚠ same type
BRD4 p.Ala409Thr Uncertain significance ★★ ⚠ same type
BRD4 p.Ala565Val Uncertain significance ★★ ⚠ same type
BRD4 p.Asp337Asn 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-pro1019his (accessed [today's date]).

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