Is BRD1 p.Pro491His (c.1472C>A) pathogenic?

BRD1 p.Pro491His (c.1472C>A) is classified Uncertain significance in BRD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: likely pathogenic (0.8941); Very rare (popmax 0.00445%, sas).

How common is BRD1 p.Pro491His (c.1472C>A) in the general population?

BRD1 p.Pro491His (c.1472C>A) is very rare (popmax 0.00445%, sas) (gnomAD).

What do computational predictors say about BRD1 p.Pro491His (c.1472C>A)?

AlphaMissense predicts likely pathogenic (score 0.8941) — an in-silico prediction, not a clinical call.

BRD1 p.Pro491His

c.1472C>A · VCV3992893

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8941	likely pathogenic
REVEL	0.581	indeterminate
SaProt	LLR -13.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 17 kb · p 6.5e-07 · regional, not allelic
Overall
CADD	28.7	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 0.00445% South Asian · 4/89,974 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000899%

Overall 0.000275% 4/1,457,100 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: BRD1
Protein: p.Pro491His
Coding: c.1472C>A
MANE Select: NM_001304808
Type: single nucleotide variant
Location: chr22:49804256 (GRCh38)
Gene constraint: LOEUF 0.337 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.54 · 318 PDB

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

Similar variants

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
BRD1 p.Pro111= 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-pro491his (accessed [today's date]).

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