Is BACH1 p.Thr74Ser (c.221C>G) pathogenic?

BACH1 p.Thr74Ser (c.221C>G) is classified Uncertain significance in BACH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1046); Very rare (popmax 0.00267%, afr).

How common is BACH1 p.Thr74Ser (c.221C>G) in the general population?

BACH1 p.Thr74Ser (c.221C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BACH1 p.Thr74Ser (c.221C>G)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

BACH1 p.Thr74Ser

c.221C>G · rs1322576331 · VCV3132785

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -7.33	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 5.9	GERP 0.18, phastCons 0.91
Overall
CADD	18.13	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 0.00267% African / African-American · 2/74,918 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,796 alleles · very rare

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: BACH1
Protein: p.Thr74Ser
Coding: c.221C>G
MANE Select: NM_032043 · reported on NM_001186
dbSNP: rs1322576331
Type: single nucleotide variant
Location: chr21:29321501 (GRCh38)
Structure: AlphaFold pLDDT 64.19 · 6 PDB
Residue 74: the helicase atp-binding domain

Full BACH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BRIP1 p.Glu74= Benign/Likely benign ★★ same residue
BRIP1 p.Glu74Asp Uncertain significance ★ ⚠ same residue
BRIP1 p.Glu74Gln Uncertain significance ★ ⚠ same residue
BRIP1 p.Glu74fs Pathogenic same residue
BRIP1 c.1140+1G>A Likely pathogenic ★★ same type
BRIP1 c.1141-2A>C Likely pathogenic ★★ same type
BRIP1 c.1141-2A>G Likely pathogenic ★★ same type
BRIP1 c.1141-2A>T Likely pathogenic ★★ 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/bach1-p-thr74ser (accessed [today's date]).

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