Is BRD4 p.Arg1256Trp (c.3766C>T) pathogenic?

BRD4 p.Arg1256Trp (c.3766C>T) is classified Uncertain significance in BRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). AlphaMissense: ambiguous (0.4604); Very rare (popmax 0.00222%, sas).

How common is BRD4 p.Arg1256Trp (c.3766C>T) in the general population?

BRD4 p.Arg1256Trp (c.3766C>T) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about BRD4 p.Arg1256Trp (c.3766C>T)?

AlphaMissense predicts ambiguous (score 0.4604) — an in-silico prediction, not a clinical call.

BRD4 p.Arg1256Trp

c.3766C>T · rs759358078 · VCV2712176

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4604	ambiguous
REVEL	0.137	moderately benign-leaning
SaProt	LLR -10.59	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 321 bp · p 0.41 · regional, not allelic
Overall
CADD	25.7	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 0.00222% South Asian · 2/90,192 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000438% 7/1,596,972 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00222%	45,096
Finnishnot grpmax-eligible	0.00183%	54,654
European (non-Finnish)	0.00034%	293,808

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.Arg1256Trp
Coding: c.3766C>T
MANE Select: NM_001379291
dbSNP: rs759358078
Type: single nucleotide variant
Location: chr19:15239075 (GRCh38)
Gene constraint: LOEUF 0.191 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 613 PDB
Residue 1256: the 'c-terminal (ctd) region' region; 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.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
BRD4 p.Asp497Gly Uncertain significance ★★ ⚠ same type
BRD4 p.Gln32Arg Uncertain significance ★★ ⚠ same type
BRD4 p.Glu1123Lys 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-arg1256trp (accessed [today's date]).

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