# NM_021813.4(BACH2):c.1295TCT[1] (p.Phe433del)

https://sugi.bio/variant/bach2-p-phe433del

## Summary

**BACH2 p.Phe433del (c.1295TCT[1])** is classified **Uncertain significance** in BACH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-18). Very rare (popmax 0.000254%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the BACH2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Phe433del |
| Coding change (HGVS c.) | c.1295TCT[1] |
| MANE Select transcript | [NM_021813](https://www.ncbi.nlm.nih.gov/nuccore/NM_021813) |
| Variant type | Microsatellite |
| Location | chr6:89950806-89950808 (GRCh38) |
| ClinVar | [VCV4812104](https://www.ncbi.nlm.nih.gov/clinvar/variation/4812104/) |

**All HGVS expressions:** `NC_000006.11:g.90660525AGA[1]`, `NC_000006.12:g.89950806AGA[1]`, `NM_001170794.2:c.1295TCT[1]`, `NM_021813.4:c.1295TCT[1]`

## 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 11.888, GERP 0.538, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,180,030 in the highest group · 4/1,461,836 alleles overall — very rare (popmax 0.000254%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00156% | 63,988 |
| European (non-Finnish) (grpmax) | 0.000254% | 393,343 |

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-18.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-18 |

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

## Similar variants {#similar}

Related BACH2 variant pages (same residue, condition, or type): [BACH2 p.Arg795del](/variant/bach2-p-arg795del), [BACH2 p.Glu164del](/variant/bach2-p-glu164del), [BACH2 p.Ser247del](/variant/bach2-p-ser247del), [BACH2 p.Ser436del](/variant/bach2-p-ser436del), [BACH2 c.2044-21_2044-20del](/variant/bach2-c-2044-minus-21-2044-minus-20del), [BACH2 c.-12-18TTTC[3]](/variant/bach2-c-minus-12-minus-18tttc-3), [BACH2 c.-12-18TTTC[5]](/variant/bach2-c-minus-12-minus-18tttc-5), [BACH2 c.-12-18TTTC[6]](/variant/bach2-c-minus-12-minus-18tttc-6).

### 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 4812104). 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.*