Is BAG3 p.Ser56Cys (c.167C>G) pathogenic?

BAG3 p.Ser56Cys (c.167C>G) is classified Conflicting classifications of pathogenicity in BAG3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-03-27). AlphaMissense: likely benign (0.0883); Ultra-rare (popmax 0.0139%, afr); Associated with BAG3-related disorder.

What condition is associated with BAG3 p.Ser56Cys (c.167C>G)?

BAG3 p.Ser56Cys (c.167C>G) is associated with BAG3-related disorder, myofibrillar myopathy 6, dilated cardiomyopathy 1HH (ClinVar).

How common is BAG3 p.Ser56Cys (c.167C>G) in the general population?

BAG3 p.Ser56Cys (c.167C>G) is ultra-rare (popmax 0.0139%, afr) (gnomAD).

What do computational predictors say about BAG3 p.Ser56Cys (c.167C>G)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

BAG3 p.Ser56Cys

c.167C>G · rs777100532 · VCV239789

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BAG3-related disorder

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -8.45	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 1.5	GERP 0.82, phastCons 0.002
Regional constraint	o/e 1.04	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	22.5	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 0.0139% African / African-American · 10/72,146 alleles

Filtering AF 0.00749% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00569%

Overall 0.000695% 11/1,583,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0139%	7,215
Remaining individualsnot grpmax-eligible	0.00164%	61,064

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: BAG3
Protein: p.Ser56Cys
Coding: c.167C>G
MANE Select: NM_004281
dbSNP: rs777100532
Type: single nucleotide variant
Location: chr10:119651842 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.92 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.98
Residue 56: the 'disordered' region

Full BAG3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BAG3-related disorder

Also linked: myofibrillar myopathy 6 dilated cardiomyopathy 1HH

Similar variants

BAG3 p.Ser56fs Pathogenic ★ same residue
BAG3 p.Ser56= Likely benign ★ same residue
BAG3 p.Ser56Pro Likely benign ★ same residue
BAG3 p.Arg121Ter Pathogenic/Likely pathogenic ★★ same condition
BAG3 p.Arg123Ter Pathogenic/Likely pathogenic ★★ same condition
BAG3 p.Arg309Ter Pathogenic ★★ same condition
BAG3 p.Arg473Ter Pathogenic/Likely pathogenic ★★ same condition
BAG3 p.Arg90Ter 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/bag3-p-ser56cys (accessed [today's date]).

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