Is BRD4 p.Ala565Val (c.1694C>T) pathogenic?

BRD4 p.Ala565Val (c.1694C>T) is classified Uncertain significance in BRD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-10). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with BRD4 p.Ala565Val (c.1694C>T)?

BRD4 p.Ala565Val (c.1694C>T) is associated with Inborn genetic diseases (ClinVar).

How common is BRD4 p.Ala565Val (c.1694C>T) in the general population?

BRD4 p.Ala565Val (c.1694C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about BRD4 p.Ala565Val (c.1694C>T)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

BRD4 p.Ala565Val

c.1694C>T · rs971737368 · VCV2352746

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	GERP 2.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 672 bp · p 0.42 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00446% East Asian · 2/44,892 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000496% 8/1,611,712 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00963%	10,382
East Asiangrpmax	0.00446%	22,446

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala565Val
Coding: c.1694C>T
MANE Select: NM_001379291
dbSNP: rs971737368
Type: single nucleotide variant
Location: chr19:15256121 (GRCh38)
Gene constraint: LOEUF 0.191 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 613 PDB
Residue 565: a UniProt-annotated variant site (found in a patient with a neurodevelopmental syndrome; likely pathogenic); the 'disordered' region; the 'bid region' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRD4 p.Ala220Thr Uncertain significance ★★ ⚠ same condition
BRD4 p.Ala409Thr Uncertain significance ★★ ⚠ same condition
BRD4 p.Asp497Gly Uncertain significance ★★ ⚠ same condition
BRD4 p.Gln32Arg Uncertain significance ★★ ⚠ same condition
BRD4 p.Glu715Lys Uncertain significance ★★ ⚠ same condition
BRD4 p.Glu718Gln Uncertain significance ★★ ⚠ same condition
BRD4 p.Gly6Ala Uncertain significance ★★ ⚠ same condition
BRD4 p.Ile300Val Uncertain significance ★★ ⚠ same condition

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-ala565val (accessed [today's date]).

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