# NM_006219.3(PIK3CB):c.2175A>T (p.Leu725Phe)

https://sugi.bio/variant/pik3cb-p-leu725phe

## Summary

**PIK3CB p.Leu725Phe (c.2175A>T)** is classified **Uncertain significance** in PIK3CB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: likely benign (0.2043); Very rare (popmax 0.00267%, afr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the PIK3CB 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 | [PIK3CB](https://sugi.bio/atlas/gene/PIK3CB/) |
| Protein change (HGVS p.) | p.Leu725Phe |
| Coding change (HGVS c.) | c.2175A>T |
| MANE Select transcript | [NM_006219](https://www.ncbi.nlm.nih.gov/nuccore/NM_006219) |
| Variant type | single nucleotide variant |
| Location | chr3:138684765-138684765 (GRCh38) |
| ClinVar | [VCV3306611](https://www.ncbi.nlm.nih.gov/clinvar/variation/3306611/) |

**All HGVS expressions:** `NC_000003.11:g.138403607T>A`, `NC_000003.12:g.138684765T>A`, `NM_001256045.2:c.711A>T`, `NM_006219.3:c.2175A>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** (0.2043)
- REVEL 0.383 (indeterminate)
- SaProt LLR -5.926 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 2.701, GERP -4.01, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.21**. 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 0.56** across the covering region of the MANE Select transcript (138,663,938–138,691,019), spanning 27,081 bp. Chi-square p 3.3e-14. 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 (T>G, 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 **0.00267%** (afr) · FAF95 0.00122% · FAF99 0.00104% · 2/74,910 in the highest group · 25/1,613,766 alleles overall — very rare (popmax 0.00267%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00267% | 37,455 |
| European (non-Finnish) | 0.00186% | 53,630 |
| Admixed American | 0.00167% | 59,954 |

*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}

**PIK3CB** population constraint: LOEUF 0.319, pLI 1, missense-Z 3.3831. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.62, 61% of residues very-high.

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

*Describes the biological roles of PIK3CB (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:** PIK3CB's established molecular role includes 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity. In Reactome, PIK3CB is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Signaling by ALK fusions and activated point mutants**.

**Disease mechanism (Reactome):** PIK3CB loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370), [Signaling by LTK in cancer](https://reactome.org/content/detail/R-HSA-9842640).

### Pathways affected {#pathways}

PIK3CB participates in **32 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Signaling by LTK in cancer](https://reactome.org/content/detail/R-HSA-9842640) | curated |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | curated |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | curated |
| [CD28 dependent PI3K/Akt signaling](https://reactome.org/content/detail/R-HSA-389357) | curated |
| [Co-stimulation by ICOS](https://reactome.org/content/detail/R-HSA-9927354) | curated |
| [DAP12 signaling](https://reactome.org/content/detail/R-HSA-2424491) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |
| [IRS-mediated signalling](https://reactome.org/content/detail/R-HSA-112399) | curated |
| [Interleukin receptor SHC signaling](https://reactome.org/content/detail/R-HSA-912526) | curated |
| [Interleukin-3, Interleukin-5 and GM-CSF signaling](https://reactome.org/content/detail/R-HSA-512988) | curated |
| [PI3K Cascade](https://reactome.org/content/detail/R-HSA-109704) | curated |
| [PI3K/AKT activation](https://reactome.org/content/detail/R-HSA-198203) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [Role of LAT2/NTAL/LAB on calcium mobilization](https://reactome.org/content/detail/R-HSA-2730905) | curated |
| [Role of phospholipids in phagocytosis](https://reactome.org/content/detail/R-HSA-2029485) | curated |
| [Signaling by ALK](https://reactome.org/content/detail/R-HSA-201556) | curated |
| [Signaling by LTK](https://reactome.org/content/detail/R-HSA-9842663) | curated |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | curated |
| [Tie2 Signaling](https://reactome.org/content/detail/R-HSA-210993) | curated |
| [Erythropoietin activates Phosphoinositide-3-kinase (PI3K)](https://reactome.org/content/detail/R-HSA-9027276) | electronic |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | electronic |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | electronic |

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

**Molecular function:** 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity, protein serine kinase activity.

**Biological process:** regulation of cell-matrix adhesion, sphingosine-1-phosphate receptor signaling pathway, positive regulation of endothelial cell migration, positive regulation of gene expression, positive regulation of neutrophil apoptotic process, positive regulation of Rac protein signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-17.

**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 | 2024-04-17 |

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

## Similar variants {#similar}

Related PIK3CB variant pages (same residue, condition, or type): [PIK3CB c.1302+10T>C](/variant/pik3cb-c-1302-plus-10t-c), [PIK3CB p.Arg1069=](/variant/pik3cb-p-arg1069), [PIK3CB p.Arg811=](/variant/pik3cb-p-arg811), [PIK3CB p.Asn717Ser](/variant/pik3cb-p-asn717ser), [PIK3CB p.Gln644=](/variant/pik3cb-p-gln644), [PIK3CB p.Phe508=](/variant/pik3cb-p-phe508), [PIK3CB p.Tyr618=](/variant/pik3cb-p-tyr618), [PIK3CB p.Ala490Val](/variant/pik3cb-p-ala490val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3306611). 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.*