Is BRWD1 p.Ser5Pro (c.13T>C) pathogenic?

BRWD1 p.Ser5Pro (c.13T>C) is classified Uncertain significance in BRWD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0924); Ultra-rare (popmax 0.0369%, afr).

How common is BRWD1 p.Ser5Pro (c.13T>C) in the general population?

BRWD1 p.Ser5Pro (c.13T>C) is ultra-rare (popmax 0.0369%, afr) (gnomAD).

What do computational predictors say about BRWD1 p.Ser5Pro (c.13T>C)?

AlphaMissense predicts likely benign (score 0.0924) — an in-silico prediction, not a clinical call.

BRWD1 p.Ser5Pro

c.13T>C · VCV4216399

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0924 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0369%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0924	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -7.43	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 3.8	GERP 3.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 15 kb · p 0.58 · regional, not allelic
Overall
CADD	19.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0369% African / African-American · 23/62,282 alleles

Filtering AF 0.0252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.00187% 24/1,285,034 alleles · ultra-rare exomes 7/1,136,452 · genomes 17/148,582 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0369%	2,708
Remaining individualsnot grpmax-eligible	0.00213%	47,046

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: BRWD1
Protein: p.Ser5Pro
Coding: c.13T>C
MANE Select: NM_033656
Type: single nucleotide variant
Location: chr21:39313479 (GRCh38)
Gene constraint: LOEUF 0.447 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 56.20 · 1 PDB

Full BRWD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRWD1 c.50-14T>C Benign ★★ same type
BRWD1 p.Asn2173= Likely benign ★★ same type
BRWD1 p.Leu1699Pro Benign ★★ same type
BRWD1 p.Ser1511Pro Benign ★★ same type
BRWD1 p.Arg219His Likely pathogenic ★ same type
BRWD1 p.Gln1858Leu Likely pathogenic ★ ⚠ same type
BRWD1 c.2893-1G>T Uncertain significance ★ same type
BRWD1 c.*8854G>C Uncertain significance ★ ⚠ 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/brwd1-p-ser5pro (accessed [today's date]).

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