Is BAG4 p.Ala447Val (c.1340C>T) pathogenic?

BAG4 p.Ala447Val (c.1340C>T) is classified Uncertain significance in BAG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely pathogenic (0.6317); Very rare (popmax 0.000256%, nfe).

How common is BAG4 p.Ala447Val (c.1340C>T) in the general population?

BAG4 p.Ala447Val (c.1340C>T) is very rare (popmax 0.000256%, nfe) (gnomAD).

What do computational predictors say about BAG4 p.Ala447Val (c.1340C>T)?

AlphaMissense predicts likely pathogenic (score 0.6317) — an in-silico prediction, not a clinical call.

BAG4 p.Ala447Val

c.1340C>T · VCV3817306

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6317	likely pathogenic
REVEL	0.511	indeterminate
SaProt	LLR -8.08	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 2,740 bp · p 0.00011 · regional, not allelic
Overall
CADD	25.5	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 0.000256% European (non-Finnish) · 3/1,170,612 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00056% 8/1,429,212 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00634%	15,768
Remaining individualsnot grpmax-eligible	0.00164%	60,966
European (non-Finnish)grpmax	0.000256%	390,204

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala447Val
Coding: c.1340C>T
MANE Select: NM_004874
Type: single nucleotide variant
Location: chr8:38210459 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.41 · 2 PDB
Residue 447: the bag domain; an α-helix

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.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
BAG4 p.Arg84Gln 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-ala447val (accessed [today's date]).

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