Is BRD1 p.Pro993Leu (c.2978C>T) pathogenic?

BRD1 p.Pro993Leu (c.2978C>T) is classified Uncertain significance in BRD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). AlphaMissense: likely benign (0.0614); Very rare (popmax 0.00272%, nfe).

How common is BRD1 p.Pro993Leu (c.2978C>T) in the general population?

BRD1 p.Pro993Leu (c.2978C>T) is very rare (popmax 0.00272%, nfe) (gnomAD).

What do computational predictors say about BRD1 p.Pro993Leu (c.2978C>T)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

BRD1 p.Pro993Leu

c.2978C>T · rs749277542 · VCV2508110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.092	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 0.68, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 12 kb · p 0.47 · regional, not allelic
Overall
CADD	20.2	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P862L vs ClinVar P993L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% European (non-Finnish) · 32/1,178,222 alleles

Filtering AF 0.00197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.0023% 37/1,607,830 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00272%	36,819
African / African-American	0.00267%	37,498
South Asian	0.00222%	45,023
Remaining individualsnot grpmax-eligible	0.00161%	62,258

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: BRD1
Protein: p.Pro993Leu
Coding: c.2978C>T
MANE Select: NM_001304808
dbSNP: rs749277542
Type: single nucleotide variant
Location: chr22:49777693 (GRCh38)
Gene constraint: LOEUF 0.337 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.54 · 318 PDB
Residue 993: the pwwp domain

Full BRD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRD1 p.Pro993Thr Uncertain significance ★ ⚠ same residue
BRD1 c.1657-4C>T Likely benign ★★ same type
BRD1 p.Ala1053= Benign ★★ same type
BRD1 p.Ala730Thr Benign ★★ same type
BRD1 p.Arg1020= Benign ★★ same type
BRD1 p.Gly620= Likely benign ★★ same type
BRD1 p.Gly776Arg Benign ★★ same type
BRD1 p.Phe193= Benign ★★ 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/brd1-p-pro993leu (accessed [today's date]).

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