Is BACH2 p.Ser409Leu (c.1226C>T) pathogenic?

BACH2 p.Ser409Leu (c.1226C>T) is classified Uncertain significance in BACH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-16). AlphaMissense: likely benign (0.0753); Ultra-rare (popmax 0.0118%, amr).

How common is BACH2 p.Ser409Leu (c.1226C>T) in the general population?

BACH2 p.Ser409Leu (c.1226C>T) is ultra-rare (popmax 0.0118%, amr) (gnomAD).

What do computational predictors say about BACH2 p.Ser409Leu (c.1226C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

BACH2 p.Ser409Leu

c.1226C>T · rs763363335 · VCV1498452

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -7.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.58, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 534 bp · p 0.87 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0118% Admixed American · 7/59,376 alleles

Filtering AF 0.00548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00384%

Overall 0.000747% 12/1,605,902 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0118%	8,482
East Asian	0.00446%	22,414
Remaining individualsnot grpmax-eligible	0.00161%	62,100
European (non-Finnish)	0.00017%	587,782

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: BACH2
Protein: p.Ser409Leu
Coding: c.1226C>T
MANE Select: NM_021813
dbSNP: rs763363335
Type: single nucleotide variant
Location: chr6:89950880 (GRCh38)
Gene constraint: LOEUF 0.164 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.66 · 2 PDB

Full BACH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BACH2 p.Ser409= Benign/Likely benign ★★ same residue
BACH2 p.Ala148Val Uncertain significance ★★ ⚠ same type
BACH2 p.Ala205Thr Uncertain significance ★★ ⚠ same type
BACH2 p.Ala304Glu Uncertain significance ★★ ⚠ same type
BACH2 p.Ala479Val Uncertain significance ★★ ⚠ same type
BACH2 p.Ala529Val Uncertain significance ★★ same type
BACH2 p.Ala747Val Uncertain significance ★★ ⚠ same type
BACH2 p.Ala756Val 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/bach2-p-ser409leu (accessed [today's date]).

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