Is BRDT p.Leu280Pro (c.839T>C) pathogenic?

BRDT p.Leu280Pro (c.839T>C) is classified Uncertain significance in BRDT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-16). AlphaMissense: likely pathogenic (0.9548); Very rare (popmax 0.000847%, nfe).

How common is BRDT p.Leu280Pro (c.839T>C) in the general population?

BRDT p.Leu280Pro (c.839T>C) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about BRDT p.Leu280Pro (c.839T>C)?

AlphaMissense predicts likely pathogenic (score 0.9548) — an in-silico prediction, not a clinical call.

BRDT p.Leu280Pro

c.839T>C · rs761903112 · VCV2261867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9548 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9548	likely pathogenic · top 2% in BRDT
REVEL	0.72	pathogenic-leaning
SaProt	LLR -15.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 52 kb · p 0.018 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000847% European (non-Finnish) · 10/1,179,994 alleles

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

Overall 0.000684% 10/1,461,756 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: BRDT
Protein: p.Leu280Pro
Coding: c.839T>C
MANE Select: NM_207189
dbSNP: rs761903112
Type: single nucleotide variant
Location: chr1:91977263 (GRCh38)
Gene constraint: LOEUF 0.801 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.40 · 22 PDB
Residue 280: the bromo 2 domain; an α-helix

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

Similar variants

BRDT p.Gln795Ter Likely pathogenic ★ same type
BRDT p.Ala241Val Uncertain significance ★ ⚠ same type
BRDT p.Ala405Thr Uncertain significance ★ ⚠ same type
BRDT p.Ala898Gly Uncertain significance ★ ⚠ same type
BRDT p.Arg419Gln Uncertain significance ★ ⚠ same type
BRDT p.Arg422Cys Uncertain significance ★ ⚠ same type
BRDT p.Arg422Leu Uncertain significance ★ ⚠ same type
BRDT p.Arg446Cys 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/brdt-p-leu280pro (accessed [today's date]).

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