Is BRD4 p.Ile1356Val (c.4066A>G) pathogenic?

BRD4 p.Ile1356Val (c.4066A>G) is classified Uncertain significance in BRD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-15). AlphaMissense: ambiguous (0.4427); Very rare (popmax 0.000847%, nfe).

How common is BRD4 p.Ile1356Val (c.4066A>G) in the general population?

BRD4 p.Ile1356Val (c.4066A>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about BRD4 p.Ile1356Val (c.4066A>G)?

AlphaMissense predicts ambiguous (score 0.4427) — an in-silico prediction, not a clinical call.

BRD4 p.Ile1356Val

c.4066A>G · rs912468726 · VCV2895066

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4427	ambiguous
REVEL	0.153	moderately benign-leaning
SaProt	LLR -5.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 404 bp · p 4.5e-07 · regional, not allelic
Overall
CADD	23.9	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 0.000847% European (non-Finnish) · 10/1,180,002 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000684% 10/1,461,786 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: BRD4
Protein: p.Ile1356Val
Coding: c.4066A>G
MANE Select: NM_001379291
dbSNP: rs912468726
Type: single nucleotide variant
Location: chr19:15238400 (GRCh38)
Gene constraint: LOEUF 0.191 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 613 PDB
Residue 1356: the 'c-terminal (ctd) region' region; a turn; 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-ile1356val (accessed [today's date]).

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