Is BRAT1 p.Ser462Pro (c.1384T>C) pathogenic?

BRAT1 p.Ser462Pro (c.1384T>C) is classified Uncertain significance in BRAT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-11). AlphaMissense: likely benign (0.2659); Ultra-rare (popmax 0.0186%, amr); Associated with neonatal-onset encephalopathy with rigidity and seizures.

What condition is associated with BRAT1 p.Ser462Pro (c.1384T>C)?

BRAT1 p.Ser462Pro (c.1384T>C) is associated with neonatal-onset encephalopathy with rigidity and seizures (ClinVar).

How common is BRAT1 p.Ser462Pro (c.1384T>C) in the general population?

BRAT1 p.Ser462Pro (c.1384T>C) is ultra-rare (popmax 0.0186%, amr) (gnomAD).

What do computational predictors say about BRAT1 p.Ser462Pro (c.1384T>C)?

AlphaMissense predicts likely benign (score 0.2659) — an in-silico prediction, not a clinical call.

BRAT1 p.Ser462Pro

c.1384T>C · rs761704986 · VCV540157

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neonatal-onset encephalopathy with rigidity and seizures

Computational evidence

Protein change
AlphaMissense	0.2659	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -11.19	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 16 kb · p 0.0016 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0186% Admixed American · 8/42,968 alleles

Filtering AF 0.00917% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00675%

Overall 0.000644% 10/1,552,456 alleles · ultra-rare exomes 8/1,400,340 · genomes 2/152,116 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0186%	5,371
African / African-American	0.00142%	70,652
European (non-Finnish)	8.61e-05%	1,161,168

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.Ser462Pro
Coding: c.1384T>C
MANE Select: NM_152743
dbSNP: rs761704986
Type: single nucleotide variant
Location: chr7:2540990 (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.Ser462Phe 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
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-ser462pro (accessed [today's date]).

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