# NM_005026.5(PIK3CD):c.2173C>G (p.Leu725Val)

https://sugi.bio/variant/pik3cd-p-leu725val

## Summary

**PIK3CD p.Leu725Val (c.2173C>G)** is classified **Uncertain significance** in PIK3CD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-29). AlphaMissense: likely benign (0.0698); Very rare (popmax 0.004%, afr); Associated with immunodeficiency 14.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs143471703 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.004%, afr)

## For patients & families {#patients}

This is a change in the PIK3CD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to immunodeficiency 14.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Diagnostic panels | PIK3CD is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Activated PI3K-delta syndrome 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Recurrent respiratory infections — Very frequent (99-80%)
- Splenomegaly — Frequent (79-30%)
- Bronchiectasis — Frequent (79-30%)
- Hepatomegaly — Frequent (79-30%)
- Lymphadenopathy — Frequent (79-30%)
- Autoimmunity — Frequent (79-30%)
- Decreased total B cell count — Frequent (79-30%)
- Intestinal lymphoid nodular hyperplasia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015979/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PIK3CD](https://sugi.bio/atlas/gene/PIK3CD/) |
| Protein change (HGVS p.) | p.Leu725Val |
| Coding change (HGVS c.) | c.2173C>G |
| MANE Select transcript | [NM_005026](https://www.ncbi.nlm.nih.gov/nuccore/NM_005026) |
| dbSNP | [rs143471703](https://www.ncbi.nlm.nih.gov/snp/rs143471703/) |
| Variant type | single nucleotide variant |
| Location | chr1:9722092-9722092 (GRCh38) |
| ClinVar | [VCV1479527](https://www.ncbi.nlm.nih.gov/clinvar/variation/1479527/) |

**All HGVS expressions:** `LRG_191:g.75361C>G`, `NC_000001.10:g.9782150C>G`, `NC_000001.11:g.9722092C>G`, `NG_023434.1:g.75361C>G`, `NM_001350234.2:c.2170C>G`, `NM_001350235.1:c.2086C>G`, `NM_005026.5:c.2173C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0698)
- REVEL 0.122 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.487 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.713, GERP -0.088, phastCons 0.869 — weakly conserved position
- CADD: **PHRED 16.89**. 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 0.67** across the covering region of the MANE Select transcript (9,721,983–9,722,253), spanning 270 bp. Chi-square p 0.0049. 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 (gnomAD v4.1): grpmax **0.004%** (afr) · FAF95 0.00106% · FAF99 0.000495% · 3/74,934 in the highest group · 3/1,613,348 alleles overall — very rare (popmax 0.004%, afr).

*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}

**PIK3CD** population constraint: LOEUF 0.23, pLI 1, missense-Z 6.3956. *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):

- **immunodeficiency 14b, autosomal recessive** — Definitive (AR)
- **immunodeficiency 14** — Definitive (AD)

## Protein context {#protein}

Residue **725** lies in a UniProt-annotated variant site (in rochis; no protein can be detected by western blot in patient cells); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 88.21, 69% of residues very-high.

**20 experimental structure(s)** (PDB): [5DXU](https://www.rcsb.org/structure/5DXU), [5M6U](https://www.rcsb.org/structure/5M6U), [5T8F](https://www.rcsb.org/structure/5T8F), [5UBT](https://www.rcsb.org/structure/5UBT), [5VLR](https://www.rcsb.org/structure/5VLR), [6G6W](https://www.rcsb.org/structure/6G6W).

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

*Describes the biological roles of PIK3CD (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:** PIK3CD participates in disease-associated pathways. In Reactome, PIK3CD is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** PIK3CD loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

PIK3CD participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | 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 |
| [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 |
| [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 |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | curated |
| [Antigen activates B Cell Receptor (BCR) leading to generation of second messengers](https://reactome.org/content/detail/R-HSA-983695) | 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 |
| [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 |

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

**Biological process:** positive regulation of endothelial cell proliferation, positive regulation of endothelial cell migration, positive regulation of gene expression, positive regulation of cell migration, positive regulation of neutrophil apoptotic process, vascular endothelial growth factor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-03-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-03-29 |

## Associated conditions {#conditions}

[immunodeficiency 14](https://sugi.bio/atlas/disease/immunodeficiency-14/).

**Reported phenotype names (ClinVar):** Immunodeficiency 14, Activated PI3K Delta Syndrome Type 1 (APDS1), IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT, ACTIVATED PI3K-DELTA SYNDROME 1, p110-DELTA-ACTIVATING MUTATION CAUSING SENESCENT T CELLS, LYMPHADENOPATHY, AND IMMUNODEFICIENCY.

## Similar variants {#similar}

Related PIK3CD variant pages (same residue, condition, or type): [PIK3CD p.Asn334Lys](/variant/pik3cd-p-asn334lys), [PIK3CD p.Glu1021Lys](/variant/pik3cd-p-glu1021lys), [PIK3CD p.Glu1025Gly](/variant/pik3cd-p-glu1025gly), [PIK3CD p.Glu525Ala](/variant/pik3cd-p-glu525ala), [PIK3CD p.Glu525Gly](/variant/pik3cd-p-glu525gly), [PIK3CD p.Glu525Lys](/variant/pik3cd-p-glu525lys), [PIK3CD p.Glu81Lys](/variant/pik3cd-p-glu81lys), [PIK3CD p.Gly124Asp](/variant/pik3cd-p-gly124asp).

### 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 1479527). 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.*