Is BAG3 p.Pro209Leu (c.626C>T) pathogenic?

BAG3 p.Pro209Leu (c.626C>T) is classified Pathogenic in BAG3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.9624); Absent from gnomAD v4.1; Associated with BAG3-related disorder.

What condition is associated with BAG3 p.Pro209Leu (c.626C>T)?

BAG3 p.Pro209Leu (c.626C>T) is associated with BAG3-related disorder, peripheral neuropathy, myofibrillar myopathy 6 (ClinVar).

How common is BAG3 p.Pro209Leu (c.626C>T) in the general population?

BAG3 p.Pro209Leu (c.626C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BAG3 p.Pro209Leu (c.626C>T)?

AlphaMissense predicts likely pathogenic (score 0.9624) — an in-silico prediction, not a clinical call.

BAG3 p.Pro209Leu

c.626C>T · rs121918312 · VCV5981

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9624 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BAG3-related disorder

Computational evidence

Protein change
AlphaMissense	0.9624	likely pathogenic ✓ concordant with ClinVar · top 9% in BAG3
REVEL	0.724	pathogenic-leaning
SaProt	LLR -13.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	28.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BAG3
Protein: p.Pro209Leu
Coding: c.626C>T
MANE Select: NM_004281
dbSNP: rs121918312
Type: single nucleotide variant
Location: chr10:119672373 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.92 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.98
Residue 209: a UniProt-annotated variant site (in mfm6; pathogenic; affects function in protein folding; results in decreased adenyl-nucleotide exchange factor activity; results in aggregation of hsp70 chaperones and proteasomal substrates; reduced thermal stability; affects quaternary structure and the mutant forms non-native oligomers); a UniProt-annotated variant site (in mfm6; likely pathogenic); a UniProt-annotated variant site (in cmt2jj; likely pathogenic)

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

Disease context

BAG3-related disorder

Also linked: peripheral neuropathy myofibrillar myopathy 6 dilated cardiomyopathy 1HH

Similar variants

BAG3 p.Pro209Ser Pathogenic/Likely pathogenic ★★ same residue
BAG3 p.Pro209= Benign/Likely benign ★★ same residue
BAG3 p.Pro209Gln Pathogenic ★ same residue
BAG3 p.Pro209Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro209leu (accessed [today's date]).

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