Is BRAT1 p.Pro753= (c.2259G>A) pathogenic?

BRAT1 p.Pro753= (c.2259G>A) is classified Likely benign in BRAT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0533%, afr); Associated with neonatal-onset encephalopathy with rigidity and seizures.

What condition is associated with BRAT1 p.Pro753= (c.2259G>A)?

BRAT1 p.Pro753= (c.2259G>A) is associated with neonatal-onset encephalopathy with rigidity and seizures (ClinVar).

How common is BRAT1 p.Pro753= (c.2259G>A) in the general population?

BRAT1 p.Pro753= (c.2259G>A) is ultra-rare (popmax 0.0533%, afr) (gnomAD).

BRAT1 p.Pro753=

c.2259G>A · rs376271902 · VCV708185

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Conditions

neonatal-onset encephalopathy with rigidity and seizures

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.79	GERP -0.99
Overall
CADD	5.155	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0533% African / African-American · 40/75,064 alleles

Filtering AF 0.0401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.00676% 109/1,611,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0533%	1,877
East Asian	0.00669%	14,952
European (non-Finnish)	0.005%	19,990
Remaining individualsnot grpmax-eligible	0.0048%	20,813
Admixed American	0.00333%	29,995
South Asian	0.0022%	45,523

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: BRAT1
Protein: p.Pro753=
Coding: c.2259G>A
MANE Select: NM_152743
dbSNP: rs376271902
Type: single nucleotide variant
Location: chr7:2538276 (GRCh38)
Gene constraint: LOEUF 1.39 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.28 · 5 PDB
Residue 753: the 'disordered' region

Full BRAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neonatal-onset encephalopathy with rigidity and seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRAT1 p.Pro753Leu Uncertain significance ★★ ⚠ same residue
BRAT1 p.Pro753Ser Uncertain significance ★ ⚠ same residue
BRAT1 c.1499-1G>T Pathogenic/Likely pathogenic ★★ same condition
BRAT1 c.283-1G>A Likely pathogenic ★★ same condition
BRAT1 p.Ala642Glu Likely pathogenic ★★ same condition
BRAT1 p.Arg268His Pathogenic/Likely pathogenic ★★ ⚠ same condition
BRAT1 p.Arg427Ter Likely pathogenic ★★ same condition
BRAT1 p.Arg562Ter Pathogenic/Likely pathogenic ★★ 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/brat1-p-pro753 (accessed [today's date]).

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