Is BRAT1 p.Pro680= (c.2040C>T) pathogenic?

BRAT1 p.Pro680= (c.2040C>T) is classified Likely benign in BRAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-31). Very rare (popmax 0.00223%, eas); Associated with neonatal-onset encephalopathy with rigidity and seizures.

What condition is associated with BRAT1 p.Pro680= (c.2040C>T)?

BRAT1 p.Pro680= (c.2040C>T) is associated with neonatal-onset encephalopathy with rigidity and seizures (ClinVar).

How common is BRAT1 p.Pro680= (c.2040C>T) in the general population?

BRAT1 p.Pro680= (c.2040C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

BRAT1 p.Pro680=

c.2040C>T · rs1018617325 · VCV749466

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -6.1	GERP -2.7
Overall
CADD	0.718	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000754% 11/1,459,050 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
Remaining individualsnot grpmax-eligible	0.0016%	62,462
South Asian	0.0011%	91,076
European (non-Finnish)	0.000678%	147,479

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.Pro680=
Coding: c.2040C>T
MANE Select: NM_152743
dbSNP: rs1018617325
Type: single nucleotide variant
Location: chr7:2538495 (GRCh38)
Gene constraint: LOEUF 1.39 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.28 · 5 PDB

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.Pro680fs Pathogenic ★ 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
BRAT1 p.Gln196Ter 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-pro680 (accessed [today's date]).

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