# NM_138761.4(BAX):c.10T>C (p.Ser4Pro)

https://sugi.bio/variant/bax-p-ser4pro

## Summary

**BAX p.Ser4Pro (c.10T>C)** is classified **Uncertain significance** in BAX (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-12). AlphaMissense: likely benign (0.1331); No allele count reported in gnomAD v4.1 (AN 1,236,952).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs894774952 · 1 submitter · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,236,952)

## For patients & families {#patients}

This is a change in the BAX 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 | [BAX](https://sugi.bio/atlas/gene/BAX/) |
| Protein change (HGVS p.) | p.Ser4Pro |
| Coding change (HGVS c.) | c.10T>C |
| MANE Select transcript | [NM_138761](https://www.ncbi.nlm.nih.gov/nuccore/NM_138761) |
| dbSNP | [rs894774952](https://www.ncbi.nlm.nih.gov/snp/rs894774952/) |
| Variant type | single nucleotide variant |
| Location | chr19:48954938-48954938 (GRCh38) |
| ClinVar | [VCV2260655](https://www.ncbi.nlm.nih.gov/clinvar/variation/2260655/) |

**All HGVS expressions:** `NC_000019.10:g.48954938T>C`, `NC_000019.9:g.49458195T>C`, `NG_012191.1:g.5079T>C`, `NG_141788.1:g.485T>C`, `NM_001291428.2:c.10T>C`, `NM_001291429.2:c.-50T>C`, `NM_001291430.2:c.-26T>C`, `NM_001291431.2:c.-26T>C`, `NM_004324.4:c.10T>C`, `NM_138761.4:c.10T>C`, `NM_138763.4:c.10T>C`, `NM_138764.5:c.10T>C`, `NM_138765.3:c.10T>C`, `NR_027882.2:n.64T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1331)
- REVEL 0.146 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.258 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.624, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.4**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (48,954,929–48,961,633), spanning 6,704 bp. Chi-square p 0.24. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.26**, acceptor gain **0.00**, donor gain **0.01**.
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,236,952)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **4** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-12 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## 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 2026-10-11); 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 2260655). 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.*