Is BAG4 p.Trp186Cys (c.558G>T) pathogenic?

BAG4 p.Trp186Cys (c.558G>T) is classified Uncertain significance in BAG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-29). AlphaMissense: likely pathogenic (0.8037); Very rare (popmax 0.000169%, nfe).

How common is BAG4 p.Trp186Cys (c.558G>T) in the general population?

BAG4 p.Trp186Cys (c.558G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about BAG4 p.Trp186Cys (c.558G>T)?

AlphaMissense predicts likely pathogenic (score 0.8037) — an in-silico prediction, not a clinical call.

BAG4 p.Trp186Cys

c.558G>T · rs372261481 · VCV2489043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8037	likely pathogenic
REVEL	0.664	pathogenic-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.45	acceptor gain · deltas
Pangolin	Δ0.26	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 8.7	GERP 2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 31 kb · p 0.2 · regional, not allelic
Overall
CADD	34.0	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 0.000169% European (non-Finnish) · 2/1,180,004 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,862 alleles · very rare

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: BAG4
Protein: p.Trp186Cys
Coding: c.558G>T
MANE Select: NM_004874
dbSNP: rs372261481
Type: single nucleotide variant
Location: chr8:38207691 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.41 · 2 PDB
Residue 186: the 'disordered' region

Full BAG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BAG4 p.Ala107Val Uncertain significance ★ ⚠ same type
BAG4 p.Ala157Val Uncertain significance ★ ⚠ same type
BAG4 p.Ala248Thr Uncertain significance ★ ⚠ same type
BAG4 p.Ala447Val Uncertain significance ★ ⚠ same type
BAG4 p.Arg185His Uncertain significance ★ ⚠ same type
BAG4 p.Arg311Trp Uncertain significance ★ ⚠ same type
BAG4 p.Arg40Leu Uncertain significance ★ ⚠ same type
BAG4 p.Arg51Gln 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/bag4-p-trp186cys (accessed [today's date]).

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