# NM_021813.4(BACH2):c.1644G>A (p.Ser548=)

https://sugi.bio/variant/bach2-p-ser548

## Summary

**BACH2 p.Ser548= (c.1644G>A)** is classified **Likely benign** in BACH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). Very rare (popmax 0.00892%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs534305159 · 1 submitter · very rare (popmax 0.00892%, eas)

## For patients & families {#patients}

This is a change in the BACH2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BACH2](https://sugi.bio/atlas/gene/BACH2/) |
| Protein change (HGVS p.) | p.Ser548= |
| Coding change (HGVS c.) | c.1644G>A |
| MANE Select transcript | [NM_021813](https://www.ncbi.nlm.nih.gov/nuccore/NM_021813) |
| dbSNP | [rs534305159](https://www.ncbi.nlm.nih.gov/snp/rs534305159/) |
| Variant type | single nucleotide variant |
| Location | chr6:89950462-89950462 (GRCh38) |
| ClinVar | [VCV1641923](https://www.ncbi.nlm.nih.gov/clinvar/variation/1641923/) |

**All HGVS expressions:** `NC_000006.11:g.90660181C>T`, `NC_000006.12:g.89950462C>T`, `NM_001170794.2:c.1644G>A`, `NM_021813.4:c.1644G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -7.753, GERP -2.79 — fast-evolving / accelerated position
- CADD: **PHRED 2.207**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.26 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00892%** (eas) · FAF95 0.00347% · FAF99 0.00228% · 4/44,868 in the highest group · 29/1,614,132 alleles overall — very rare (popmax 0.00892%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00937% | 10,671 |
| East Asian (grpmax) | 0.00892% | 11,217 |
| African / African-American | 0.00799% | 12,508 |
| South Asian | 0.00659% | 15,180 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,836 |
| Admixed American | 0.00167% | 60,016 |
| European (non-Finnish) | 0.000254% | 393,338 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BACH2** population constraint: LOEUF 0.164, pLI 1, missense-Z 3.446. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency 60** — Moderate (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 54.66, 21% of residues very-high.

**2 experimental structure(s)** (PDB): [3OHU](https://www.rcsb.org/structure/3OHU), [3OHV](https://www.rcsb.org/structure/3OHV).

## What this gene does {#gene-function}

*Describes the biological roles of BACH2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BACH2's established molecular role includes sequence-specific double-stranded DNA binding.


### Pathways affected {#pathways}

BACH2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Somatic hypermutation of immunoglobulin genes](https://reactome.org/content/detail/R-HSA-9938024) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** sequence-specific double-stranded DNA binding.

**Biological process:** primary adaptive immune response involving T cells and B cells.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-21.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-21 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related BACH2 variant pages (same residue, condition, or type): [BACH2 p.Ser548Leu](/variant/bach2-p-ser548leu), [BACH2 p.Ala148Val](/variant/bach2-p-ala148val), [BACH2 p.Ala205Thr](/variant/bach2-p-ala205thr), [BACH2 p.Ala304Glu](/variant/bach2-p-ala304glu), [BACH2 p.Ala479Val](/variant/bach2-p-ala479val), [BACH2 p.Ala529Val](/variant/bach2-p-ala529val), [BACH2 p.Ala747Val](/variant/bach2-p-ala747val), [BACH2 p.Ala756Val](/variant/bach2-p-ala756val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1641923). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*