Is BRWD3 p.Ser462Pro (c.1384T>C) pathogenic?

BRWD3 p.Ser462Pro (c.1384T>C) is classified Conflicting classifications of pathogenicity in BRWD3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-08). AlphaMissense: likely benign (0.1801); Very rare (popmax 0.00815%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BRWD3 p.Ser462Pro (c.1384T>C)?

BRWD3 p.Ser462Pro (c.1384T>C) is associated with Inborn genetic diseases, intellectual disability, X-linked 93 (ClinVar).

How common is BRWD3 p.Ser462Pro (c.1384T>C) in the general population?

BRWD3 p.Ser462Pro (c.1384T>C) is very rare (popmax 0.00815%, nfe) (gnomAD).

What do computational predictors say about BRWD3 p.Ser462Pro (c.1384T>C)?

AlphaMissense predicts likely benign (score 0.1801) — an in-silico prediction, not a clinical call.

BRWD3 p.Ser462Pro

c.1384T>C · rs202197853 · VCV912797

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1801 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00815%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1801	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -9.17	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 7.6	GERP 0.57, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 26 kb · p 4.3e-21 · regional, not allelic
Overall
CADD	24.8	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 0.00815% European (non-Finnish) · 72/883,824 alleles

Filtering AF 0.0066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00607%

Overall 0.00636% 76/1,195,469 alleles · very rare exomes 74/1,083,843 · genomes 2/111,626 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00815%	12,275
South Asian	0.00359%	27,821
Remaining individualsnot grpmax-eligible	0.00212%	47,126
African / African-American	0.00176%	56,868

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: BRWD3
Protein: p.Ser462Pro
Coding: c.1384T>C
MANE Select: NM_153252
dbSNP: rs202197853
Type: single nucleotide variant
Location: chrX:80728754 (GRCh38)
Structure: AlphaFold pLDDT 65.11

Full BRWD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, X-linked 93

Similar variants

BRWD3 p.Ser462Thr Uncertain significance ★★ ⚠ same residue
BRWD3 c.4006-1G>A Likely pathogenic ★★ same condition
BRWD3 p.Arg1240Ter Pathogenic/Likely pathogenic ★★ same condition
BRWD3 p.Arg190Ter Pathogenic ★★ same condition
BRWD3 c.2232-3T>C Uncertain significance ★★ same condition
BRWD3 c.90+5G>A Uncertain significance ★★ same condition
BRWD3 c.*2154A>G Uncertain significance ★★ same condition
BRWD3 c.*2877G>A Uncertain significance ★★ 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/brwd3-p-ser462pro (accessed [today's date]).

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