Is BRD4 p.Pro331Leu (c.992C>T) pathogenic?

BRD4 p.Pro331Leu (c.992C>T) is classified Uncertain significance in BRD4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-25). AlphaMissense: likely benign (0.1849); Very rare (popmax 0.0011%, sas); Associated with BRD4-related disorder.

What condition is associated with BRD4 p.Pro331Leu (c.992C>T)?

BRD4 p.Pro331Leu (c.992C>T) is associated with BRD4-related disorder (ClinVar).

How common is BRD4 p.Pro331Leu (c.992C>T) in the general population?

BRD4 p.Pro331Leu (c.992C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRD4 p.Pro331Leu (c.992C>T)?

AlphaMissense predicts likely benign (score 0.1849) — an in-silico prediction, not a clinical call.

BRD4 p.Pro331Leu

c.992C>T · VCV3348310

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1849 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BRD4-related disorder

Computational evidence

Protein change
AlphaMissense	0.1849	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -12.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.6, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 174 bp · p 0.5 · regional, not allelic
Overall
CADD	23.4	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 0.0011% South Asian · 1/91,078 alleles

Overall 0.000124% 2/1,613,986 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	8.47e-05%	1,180,026

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.Pro331Leu
Coding: c.992C>T
MANE Select: NM_001379291
Type: single nucleotide variant
Location: chr19:15264624 (GRCh38)
Gene constraint: LOEUF 0.191 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 613 PDB
Residue 331: 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

Disease context

BRD4-related disorder

Similar variants

BRD4 p.Pro331= Likely benign ★ same residue
BRD4 c.3282+2T>C Likely pathogenic ★ same condition
BRD4 p.Pro681Ser Uncertain significance ★ ⚠ same condition
BRD4 p.Thr210Ser Uncertain significance ★ ⚠ same condition
BRD4 p.Tyr390Cys Uncertain significance ★ ⚠ same condition
BRD4 p.Val193Leu Uncertain significance ★ ⚠ same condition
BRD4 p.Arg10Gly Uncertain significance ⚠ same condition
BRD4 p.Pro797Ser 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-pro331leu (accessed [today's date]).

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