# NM_001725.3(BPI):c.790C>T (p.Pro264Ser)

https://sugi.bio/variant/bpi-p-pro264ser

## Summary

**BPI p.Pro264Ser (c.790C>T)** is classified **Uncertain significance** in BPI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-19). AlphaMissense: likely benign (0.1457); Very rare (popmax 0.00305%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00305%, nfe)

## For patients & families {#patients}

This is a change in the BPI 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 | [BPI](https://sugi.bio/atlas/gene/BPI/) |
| Protein change (HGVS p.) | p.Pro264Ser |
| Coding change (HGVS c.) | c.790C>T |
| MANE Select transcript | [NM_001725](https://www.ncbi.nlm.nih.gov/nuccore/NM_001725) |
| Variant type | single nucleotide variant |
| Location | chr20:38323903-38323903 (GRCh38) |
| ClinVar | [VCV3992427](https://www.ncbi.nlm.nih.gov/clinvar/variation/3992427/) |

**All HGVS expressions:** `NC_000020.10:g.36952305C>T`, `NC_000020.11:g.38323903C>T`, `NG_047016.1:g.24754C>T`, `NM_001725.3:c.790C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1457)
- REVEL 0.063 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.691 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.773, GERP -4.96 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P268S** vs ClinVar **P264S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 8.11**. 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 1.07** across the covering region of the MANE Select transcript (38,304,224–38,337,181), spanning 32,957 bp. Chi-square p 0.094. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.27 acceptor loss), 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.*
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.08. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00305%** (nfe) · FAF95 0.00223% · FAF99 0.00198% · 36/1,180,014 in the highest group · 36/1,461,862 alleles overall — very rare (popmax 0.00305%, nfe).

*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}

**BPI** population constraint: LOEUF 1.011, pLI 1.4953e-13, missense-Z -0.17135. *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 **264** lies in the 'central sheet, part 2' region.

AlphaFold model confidence (whole protein): pLDDT 92.70, 89% of residues very-high.

**2 experimental structure(s)** (PDB): [1BP1](https://www.rcsb.org/structure/1BP1), [1EWF](https://www.rcsb.org/structure/1EWF).

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

*Describes the biological roles of BPI (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:** BPI's established molecular role includes lipopolysaccharide binding. p.Pro264Ser falls in the central sheet, part 2 region.


### Pathways affected {#pathways}

BPI participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antimicrobial peptides](https://reactome.org/content/detail/R-HSA-6803157) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Toll Like Receptor 4 (TLR4) Cascade](https://reactome.org/content/detail/R-HSA-166016) | curated |

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

**Molecular function:** lipopolysaccharide binding.

**Biological process:** negative regulation of interleukin-6 production, negative regulation of interleukin-8 production, negative regulation of tumor necrosis factor production, negative regulation of macrophage activation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-19.

**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 | 2025-03-19 |

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

## Similar variants {#similar}

Related BPI variant pages (same residue, condition, or type): [BPI c.664+7G>T](/variant/bpi-c-664-plus-7g-t), [BPI p.Ala12Val](/variant/bpi-p-ala12val), [BPI p.Ala192Val](/variant/bpi-p-ala192val), [BPI p.Ala333Thr](/variant/bpi-p-ala333thr), [BPI p.Ala8Thr](/variant/bpi-p-ala8thr), [BPI p.Ala8Val](/variant/bpi-p-ala8val), [BPI p.Arg86Cys](/variant/bpi-p-arg86cys), [BPI p.Glu136Gln](/variant/bpi-p-glu136gln).

### 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 2026-07-14); 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 3992427). 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.*