Is BRD3 p.Pro22His (c.65C>A) pathogenic?

BRD3 p.Pro22His (c.65C>A) is classified Uncertain significance in BRD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). AlphaMissense: likely benign (0.2128); Very rare (popmax 0.0011%, sas).

How common is BRD3 p.Pro22His (c.65C>A) in the general population?

BRD3 p.Pro22His (c.65C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRD3 p.Pro22His (c.65C>A)?

AlphaMissense predicts likely benign (score 0.2128) — an in-silico prediction, not a clinical call.

BRD3 p.Pro22His

c.65C>A · VCV3825558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2128 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2128	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -11.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 80 bp · p 0.4 · regional, not allelic
Overall
CADD	24.7	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 0.0011% South Asian · 1/91,052 alleles

Overall 6.21e-05% 1/1,610,970 alleles · very rare exomes 1/1,458,658 · genomes 0/152,312 · joint denominator

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: BRD3
Protein: p.Pro22His
Coding: c.65C>A
MANE Select: NM_007371
Type: single nucleotide variant
Location: chr9:134053413 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.65 · 48 PDB
Residue 22: the 'disordered' region

Full BRD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRD3 p.Thr15= Benign ★★ same type
BRD3 c.1407+5G>A Uncertain significance ★ same type
BRD3 p.Ala10Val Uncertain significance ★ ⚠ same type
BRD3 p.Ala14Val Uncertain significance ★ ⚠ same type
BRD3 p.Ala161Val Uncertain significance ★ ⚠ same type
BRD3 p.Ala173Thr Uncertain significance ★ ⚠ same type
BRD3 p.Ala173Val Uncertain significance ★ ⚠ same type
BRD3 p.Ala198Val 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/brd3-p-pro22his (accessed [today's date]).

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