Is BRS3 p.Ser8Pro (c.22T>C) pathogenic?

BRS3 p.Ser8Pro (c.22T>C) is classified Uncertain significance in BRS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-27). AlphaMissense: likely benign (0.0661); Ultra-rare (popmax 0.0173%, nfe).

How common is BRS3 p.Ser8Pro (c.22T>C) in the general population?

BRS3 p.Ser8Pro (c.22T>C) is ultra-rare (popmax 0.0173%, nfe) (gnomAD).

What do computational predictors say about BRS3 p.Ser8Pro (c.22T>C)?

AlphaMissense predicts likely benign (score 0.0661) — an in-silico prediction, not a clinical call.

BRS3 p.Ser8Pro

c.22T>C · rs761432263 · VCV2290647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0661	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -6.86	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 0.97	GERP -4.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 179 bp · p 0.56 · regional, not allelic
Overall
CADD	14.84	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 0.0173% European (non-Finnish) · 154/890,504 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.013% 156/1,200,501 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0173%	5,782
Remaining individualsnot grpmax-eligible	0.00424%	23,593

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: BRS3
Protein: p.Ser8Pro
Coding: c.22T>C
MANE Select: NM_001727
dbSNP: rs761432263
Type: single nucleotide variant
Location: chrX:136488136 (GRCh38)
Structure: AlphaFold pLDDT 79.70 · 6 PDB

Full BRS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRS3 p.Ala319Thr Uncertain significance ★ ⚠ same type
BRS3 p.Arg155Ter Uncertain significance ★ same type
BRS3 p.Asn159Ser Uncertain significance ★ ⚠ same type
BRS3 p.Asn195Ser Uncertain significance ★ ⚠ same type
BRS3 p.Asn40Ser Uncertain significance ★ ⚠ same type
BRS3 p.Asp144Asn Uncertain significance ★ ⚠ same type
BRS3 p.Asp303Val Uncertain significance ★ ⚠ same type
BRS3 p.Asp30Asn 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/brs3-p-ser8pro (accessed [today's date]).

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