# NM_006218.4(PIK3CA):c.3076C>G (p.Leu1026Val)

https://sugi.bio/variant/pik3ca-p-leu1026val

## Summary

**PIK3CA p.Leu1026Val (c.3076C>G)** is classified **Uncertain significance** in PIK3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-27). AlphaMissense: likely pathogenic (0.8837); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2108429587 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PIK3CA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [PIK3CA](https://sugi.bio/atlas/gene/PIK3CA/) |
| Protein change (HGVS p.) | p.Leu1026Val |
| Coding change (HGVS c.) | c.3076C>G |
| MANE Select transcript | [NM_006218](https://www.ncbi.nlm.nih.gov/nuccore/NM_006218) |
| dbSNP | [rs2108429587](https://www.ncbi.nlm.nih.gov/snp/rs2108429587/) |
| Variant type | single nucleotide variant |
| Location | chr3:179234233-179234233 (GRCh38) |
| ClinVar | [VCV2587511](https://www.ncbi.nlm.nih.gov/clinvar/variation/2587511/) |

**All HGVS expressions:** `LRG_310:g.90711C>G`, `LRG_310t1:c.3076C>G`, `NC_000003.11:g.178952021C>G`, `NC_000003.12:g.179234233C>G`, `NG_012113.2:g.90711C>G`, `NM_006218.4:c.3076C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8837)
- REVEL 0.721 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.988 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 0.134, GERP -2.63, phastCons 0.06 — weakly conserved position
- CADD: **PHRED 21.3**. 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 0.16** across the covering region of the MANE Select transcript (179,234,172–179,234,361), spanning 189 bp — the region is depleted of missense variation. Chi-square p 3e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PIK3CA** population constraint: LOEUF 0.221, pLI 1, missense-Z 6.1494; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **hereditary breast carcinoma** — Refuted (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}

Residue **1026** lies in a turn; the pi3k/pi4k catalytic domain.

AlphaFold model confidence (whole protein): pLDDT 92.50, 83% of residues very-high.

**135 experimental structure(s)** (PDB): [2ENQ](https://www.rcsb.org/structure/2ENQ), [2RD0](https://www.rcsb.org/structure/2RD0), [3HHM](https://www.rcsb.org/structure/3HHM), [3HIZ](https://www.rcsb.org/structure/3HIZ), [3ZIM](https://www.rcsb.org/structure/3ZIM), [4JPS](https://www.rcsb.org/structure/4JPS) — incl. mutant structure 3HHM.

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

*Describes the biological roles of PIK3CA (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:** PIK3CA's established molecular role includes 1-phosphatidylinositol-3-kinase activity. p.Leu1026Val falls in the pi3k/pi4k catalytic domain. In Reactome, PIK3CA is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Constitutive Signaling by EGFRvIII**.

**Disease mechanism (Reactome):** PIK3CA loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810), [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382).

### Pathways affected {#pathways}

PIK3CA participates in **60 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | curated |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | curated |
| ⚕ [Signaling by ALK fusions and activated point mutants](https://reactome.org/content/detail/R-HSA-9725370) | curated |
| ⚕ [Signaling by ERBB2 ECD mutants](https://reactome.org/content/detail/R-HSA-9665348) | curated |
| ⚕ [Signaling by ERBB2 KD Mutants](https://reactome.org/content/detail/R-HSA-9664565) | curated |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | curated |
| ⚕ [Signaling by FGFR2 in disease](https://reactome.org/content/detail/R-HSA-5655253) | curated |
| ⚕ [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332) | curated |
| ⚕ [Signaling by FGFR4 in disease](https://reactome.org/content/detail/R-HSA-5655291) | curated |
| ⚕ [Signaling by FLT3 ITD and TKD mutants](https://reactome.org/content/detail/R-HSA-9703648) | curated |
| ⚕ [Signaling by FLT3 fusion proteins](https://reactome.org/content/detail/R-HSA-9703465) | 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 |
| ⚕ [Signaling by cytosolic FGFR1 fusion mutants](https://reactome.org/content/detail/R-HSA-1839117) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | 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 |
| [Extra-nuclear estrogen signaling](https://reactome.org/content/detail/R-HSA-9009391) | curated |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [GAB1 signalosome](https://reactome.org/content/detail/R-HSA-180292) | 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 |
| [MET activates PI3K/AKT signaling](https://reactome.org/content/detail/R-HSA-8851907) | curated |
| [PI-3K cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654689) | curated |
| [PI-3K cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654695) | curated |
| [PI-3K cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654710) | curated |
| [PI-3K cascade:FGFR4](https://reactome.org/content/detail/R-HSA-5654720) | curated |
| [PI3K Cascade](https://reactome.org/content/detail/R-HSA-109704) | curated |
| [PI3K events in ERBB2 signaling](https://reactome.org/content/detail/R-HSA-1963642) | curated |
| [PI3K events in ERBB4 signaling](https://reactome.org/content/detail/R-HSA-1250342) | 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 |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | 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 |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | 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 |
| [Activated NTRK2 signals through PI3K](https://reactome.org/content/detail/R-HSA-9028335) | electronic |
| [Activated NTRK3 signals through PI3K](https://reactome.org/content/detail/R-HSA-9603381) | electronic |
| [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-3-kinase activity, 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity.

**Biological process:** cellular response to insulin stimulus, vascular endothelial growth factor signaling pathway, TORC2 signaling, phosphatidylinositol 3-kinase/protein kinase B signal transduction, positive regulation of protein kinase activity, positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-27.

**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 | 2023-07-27 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related PIK3CA variant pages (same residue, condition, or type): [PIK3CA p.Cys378Arg](/variant/pik3ca-p-cys378arg), [PIK3CA p.Glu542Gly](/variant/pik3ca-p-glu542gly), [PIK3CA p.His1047Leu](/variant/pik3ca-p-his1047leu), [PIK3CA p.Arg401Gln](/variant/pik3ca-p-arg401gln), [PIK3CA p.Arg740Lys](/variant/pik3ca-p-arg740lys), [PIK3CA p.Arg808Trp](/variant/pik3ca-p-arg808trp), [PIK3CA p.Arg899His](/variant/pik3ca-p-arg899his), [PIK3CA p.Asn212Ser](/variant/pik3ca-p-asn212ser).

### 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 2587511). 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.*