Is BACH2 p.Ser476Ile (c.1427G>T) pathogenic?

BACH2 p.Ser476Ile (c.1427G>T) is classified Uncertain significance in BACH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-29). AlphaMissense: likely benign (0.1198); Ultra-rare (popmax 0.0533%, afr); Associated with immunodeficiency 60.

What condition is associated with BACH2 p.Ser476Ile (c.1427G>T)?

BACH2 p.Ser476Ile (c.1427G>T) is associated with immunodeficiency 60 (ClinVar).

How common is BACH2 p.Ser476Ile (c.1427G>T) in the general population?

BACH2 p.Ser476Ile (c.1427G>T) is ultra-rare (popmax 0.0533%, afr) (gnomAD).

What do computational predictors say about BACH2 p.Ser476Ile (c.1427G>T)?

AlphaMissense predicts likely benign (score 0.1198) — an in-silico prediction, not a clinical call.

BACH2 p.Ser476Ile

c.1427G>T · rs200859292 · VCV2582709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1198 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0533%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 60

Computational evidence

Protein change
AlphaMissense	0.1198	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -8.25	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 2.6	GERP -0.87, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 220 bp · p 0.69 · regional, not allelic
Overall
CADD	18.35	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 0.0533% African / African-American · 40/75,036 alleles

Filtering AF 0.0401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0356%

Overall 0.0031% 50/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0533%	1,876
Remaining individualsnot grpmax-eligible	0.0032%	31,252
Admixed American	0.00167%	60,024
European (non-Finnish)	0.000593%	168,574

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.Ser476Ile
Coding: c.1427G>T
MANE Select: NM_021813
dbSNP: rs200859292
Type: single nucleotide variant
Location: chr6:89950679 (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

Disease context

immunodeficiency 60 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BACH2 p.Ser476Asn Uncertain significance ★ ⚠ same residue
BACH2 p.Ala148Val Uncertain significance ★★ ⚠ same condition
BACH2 p.Ala756Val Uncertain significance ★★ ⚠ same condition
BACH2 p.Asp34Asn Uncertain significance ★★ ⚠ same condition
BACH2 p.Gln378His Uncertain significance ★★ ⚠ same condition
BACH2 p.Gln578Lys Uncertain significance ★★ ⚠ same condition
BACH2 p.Glu788Lys Uncertain significance ★★ ⚠ same condition
BACH2 p.Pro152Leu Uncertain significance ★★ ⚠ 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/bach2-p-ser476ile (accessed [today's date]).

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