# NM_138761.4(BAX):c.501G>A (p.Thr167=)

https://sugi.bio/variant/bax-p-thr167

## Summary

**BAX p.Thr167= (c.501G>A)** is classified **Likely benign** in BAX (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-10). Very rare (popmax 0.00802%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs373493221 · 1 submitter · very rare (popmax 0.00802%, afr)

## For patients & families {#patients}

This is a change in the BAX 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 | [BAX](https://sugi.bio/atlas/gene/BAX/) |
| Protein change (HGVS p.) | p.Thr167= |
| Coding change (HGVS c.) | c.501G>A |
| MANE Select transcript | [NM_138761](https://www.ncbi.nlm.nih.gov/nuccore/NM_138761) |
| dbSNP | [rs373493221](https://www.ncbi.nlm.nih.gov/snp/rs373493221/) |
| Variant type | single nucleotide variant |
| Location | chr19:48961558-48961558 (GRCh38) |
| ClinVar | [VCV742552](https://www.ncbi.nlm.nih.gov/clinvar/variation/742552/) |

**All HGVS expressions:** `NC_000019.10:g.48961558G>A`, `NC_000019.9:g.49464815G>A`, `NG_008152.1:g.1250G>A`, `NG_012191.1:g.11699G>A`, `NM_001291428.2:c.550G>A`, `NM_001291429.2:c.*461G>A`, `NM_001291431.2:c.267G>A`, `NM_004324.4:c.*461G>A`, `NM_138761.4:c.501G>A`, `NM_138763.4:c.354G>A`, `NM_138764.5:c.475-13G>A`, `NR_027882.2:n.653G>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 -0.606, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.489**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00802%** (afr) · FAF95 0.00606% · FAF99 0.00566% · 6/74,814 in the highest group · 106/1,610,722 alleles overall — very rare (popmax 0.00802%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00941% | 10,630 |
| African / African-American (grpmax) | 0.00802% | 12,469 |
| European (non-Finnish) | 0.00738% | 13,547 |
| Remaining individuals (not grpmax-eligible) | 0.00642% | 15,587 |
| Admixed American | 0.00335% | 29,826 |
| East Asian | 0.00223% | 44,828 |

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}

**BAX** population constraint: LOEUF 1.245, pLI 4.5107e-07, missense-Z 0.24728. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **167** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 86.71, 61% of residues very-high.

**37 experimental structure(s)** (PDB): [1F16](https://www.rcsb.org/structure/1F16), [2G5B](https://www.rcsb.org/structure/2G5B), [2K7W](https://www.rcsb.org/structure/2K7W), [2LR1](https://www.rcsb.org/structure/2LR1), [3PK1](https://www.rcsb.org/structure/3PK1), [3PL7](https://www.rcsb.org/structure/3PL7).

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

*Describes the biological roles of BAX (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:** BAX's established molecular role includes lipid binding.


### Pathways affected {#pathways}

BAX participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation, translocation and oligomerization of BAX](https://reactome.org/content/detail/R-HSA-114294) | curated |
| [Pyroptosis](https://reactome.org/content/detail/R-HSA-5620971) | curated |
| [Release of apoptotic factors from the mitochondria](https://reactome.org/content/detail/R-HSA-111457) | curated |
| [TP53 Regulates Transcription of Genes Involved in Cytochrome C Release](https://reactome.org/content/detail/R-HSA-6803204) | curated |
| [TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest](https://reactome.org/content/detail/R-HSA-6804114) | curated |
| [Transcriptional regulation by RUNX2](https://reactome.org/content/detail/R-HSA-8878166) | curated |
| [NTRK3 as a dependence receptor](https://reactome.org/content/detail/R-HSA-9603505) | electronic |

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

**Molecular function:** lipid binding, channel activity, identical protein binding, protein homodimerization activity, protein heterodimerization activity, BH3 domain binding.

**Biological process:** B cell apoptotic process, release of cytochrome c from mitochondria, apoptotic process, mitochondrial fusion, intrinsic apoptotic signaling pathway in response to DNA damage, apoptotic mitochondrial changes.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-04-10.

**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 | 2018-04-10 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related BAX variant pages (same residue, condition, or type): [BAX p.Asp102=](/variant/bax-p-asp102), [BAX c.474+151G>A](/variant/bax-c-474-plus-151g-a), [BAX c.474+20C>A](/variant/bax-c-474-plus-20c-a), [BAX c.474+34C>T](/variant/bax-c-474-plus-34c-t), [BAX c.474+76G>A](/variant/bax-c-474-plus-76g-a), [BAX c.474+95G>C](/variant/bax-c-474-plus-95g-c), [BAX p.Ala81Pro](/variant/bax-p-ala81pro), [BAX p.Arg134Gly](/variant/bax-p-arg134gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 742552). 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.*