Is BAG3 p.Pro338Ser (c.1012C>T) pathogenic?

BAG3 p.Pro338Ser (c.1012C>T) is classified Uncertain significance in BAG3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.3789); Very rare (popmax 0.000339%, nfe); Associated with dilated cardiomyopathy 1HH.

What condition is associated with BAG3 p.Pro338Ser (c.1012C>T)?

BAG3 p.Pro338Ser (c.1012C>T) is associated with dilated cardiomyopathy 1HH, myofibrillar myopathy 6 (ClinVar).

How common is BAG3 p.Pro338Ser (c.1012C>T) in the general population?

BAG3 p.Pro338Ser (c.1012C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about BAG3 p.Pro338Ser (c.1012C>T)?

AlphaMissense predicts ambiguous (score 0.3789) — an in-silico prediction, not a clinical call.

BAG3 p.Pro338Ser

c.1012C>T · rs1319754171 · VCV1053443

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

dilated cardiomyopathy 1HH

Computational evidence

Protein change
AlphaMissense	0.3789	ambiguous
REVEL	0.449	indeterminate
SaProt	LLR -10.76	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 26 kb · p 0.29 · regional, not allelic
Overall
CADD	23.7	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 0.000339% European (non-Finnish) · 4/1,180,042 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,966 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: BAG3
Protein: p.Pro338Ser
Coding: c.1012C>T
MANE Select: NM_004281
dbSNP: rs1319754171
Type: single nucleotide variant
Location: chr10:119676566 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.92 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 57.98
Residue 338: the 'disordered' region

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

Disease context

dilated cardiomyopathy 1HH — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 6

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
BAG3 p.Gln132Ter Pathogenic ★★ same condition
BAG3 p.Gln135Ter Pathogenic ★★ same condition
BAG3 p.Gln244Ter 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-pro338ser (accessed [today's date]).

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