Is BAG4 p.Ser433Phe (c.1298C>T) pathogenic?

BAG4 p.Ser433Phe (c.1298C>T) is classified Uncertain significance in BAG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.4116); Ultra-rare (popmax 0.0605%, sas).

How common is BAG4 p.Ser433Phe (c.1298C>T) in the general population?

BAG4 p.Ser433Phe (c.1298C>T) is ultra-rare (popmax 0.0605%, sas) (gnomAD).

What do computational predictors say about BAG4 p.Ser433Phe (c.1298C>T)?

AlphaMissense predicts ambiguous (score 0.4116) — an in-silico prediction, not a clinical call.

BAG4 p.Ser433Phe

c.1298C>T · VCV4645070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4116 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0605%, sas)

Computational evidence

Protein change
AlphaMissense	0.4116	ambiguous
REVEL	0.433	indeterminate
SaProt	LLR -9.07	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.39, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 2,740 bp · p 0.00011 · regional, not allelic
Overall
CADD	26.1	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

Grpmax group 0.0605% South Asian · 55/90,962 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0431%

Overall 0.0039% 63/1,613,348 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0605%	1,654
Admixed American	0.00167%	59,814
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.000509%	196,647

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.Ser433Phe
Coding: c.1298C>T
MANE Select: NM_004874
Type: single nucleotide variant
Location: chr8:38210417 (GRCh38)
Gene constraint: LOEUF 0.704 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.41 · 2 PDB
Residue 433: 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.Ala447Val 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

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-ser433phe (accessed [today's date]).

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