Is BAG3 p.Arg261Trp (c.781C>T) pathogenic?

BAG3 p.Arg261Trp (c.781C>T) is classified Conflicting classifications of pathogenicity in BAG3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-19). AlphaMissense: likely benign (0.0959); Ultra-rare (popmax 0.0198%, sas); Associated with Cardiovascular phenotype.

What condition is associated with BAG3 p.Arg261Trp (c.781C>T)?

BAG3 p.Arg261Trp (c.781C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 6, dilated cardiomyopathy 1HH (ClinVar).

How common is BAG3 p.Arg261Trp (c.781C>T) in the general population?

BAG3 p.Arg261Trp (c.781C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about BAG3 p.Arg261Trp (c.781C>T)?

AlphaMissense predicts likely benign (score 0.0959) — an in-silico prediction, not a clinical call.

BAG3 p.Arg261Trp

c.781C>T · rs548032105 · VCV162779

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0959 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0959	likely benign
REVEL	0.223	benign-leaning
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.6, phastCons 0.84
Regional constraint	o/e 1.04	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	20.5	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 0.0198% South Asian · 18/91,074 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.0039% 63/1,613,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
East Asian	0.00893%	11,195
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00297%	33,711
Remaining individualsnot grpmax-eligible	0.0016%	62,496
African / African-American	0.00133%	75,056

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.Arg261Trp
Coding: c.781C>T
MANE Select: NM_004281
dbSNP: rs548032105
Type: single nucleotide variant
Location: chr10:119672528 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.92 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.98
Residue 261: a modified residue (omega-n-methylarginine); the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 6 dilated cardiomyopathy 1HH

Similar variants

BAG3 p.Arg261Pro Uncertain significance ★★ ⚠ same residue
BAG3 p.Arg261Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
BAG3 p.Arg261= Likely benign ★ same residue
BAG3 p.Arg261_Pro265del Uncertain significance ★ 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

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-arg261trp (accessed [today's date]).

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