Is BAG1 p.Leu271Pro (c.812T>C) pathogenic?

BAG1 p.Leu271Pro (c.812T>C) is classified Uncertain significance in BAG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.9484); Very rare (popmax 0.0011%, sas).

How common is BAG1 p.Leu271Pro (c.812T>C) in the general population?

BAG1 p.Leu271Pro (c.812T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BAG1 p.Leu271Pro (c.812T>C)?

AlphaMissense predicts likely pathogenic (score 0.9484) — an in-silico prediction, not a clinical call.

BAG1 p.Leu271Pro

c.812T>C · VCV4645063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9484	likely pathogenic · top 4% in BAG1
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -14.32	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 9,452 bp · p 0.63 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,082 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000424%	236,007

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: BAG1
Protein: p.Leu271Pro
Coding: c.812T>C
MANE Select: NM_004323
Type: single nucleotide variant
Location: chr9:33256874 (GRCh38)
Gene constraint: LOEUF 1.477 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.89 · 29 PDB
Residue 271: the 'interaction with ppp1r15a' region; an α-helix; the bag domain

Full BAG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BAG1 p.Ser304Gly Benign ★★ same type
BAG1 p.Ala110Thr Uncertain significance ★ ⚠ same type
BAG1 p.Ala270Val Uncertain significance ★ ⚠ same type
BAG1 p.Ala280Thr Uncertain significance ★ ⚠ same type
BAG1 p.Ala317Val Uncertain significance ★ ⚠ same type
BAG1 p.Ala49Gly Uncertain significance ★ ⚠ same type
BAG1 p.Ala64Thr Uncertain significance ★ ⚠ same type
BAG1 p.Ala65Val 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/bag1-p-leu271pro (accessed [today's date]).

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