# NM_000944.5(PPP3CA):c.1338dup (p.Ala447fs)

https://sugi.bio/variant/ppp3ca-p-ala447fs

## Summary

**PPP3CA p.Ala447fs (c.1338dup)** is classified **Pathogenic** in PPP3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-24). Associated with developmental and epileptic encephalopathy 91.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the PPP3CA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy 91.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025189/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PPP3CA](https://sugi.bio/atlas/gene/PPP3CA/) |
| Protein change (HGVS p.) | p.Ala447fs |
| Coding change (HGVS c.) | c.1338dup |
| MANE Select transcript | [NM_000944](https://www.ncbi.nlm.nih.gov/nuccore/NM_000944) |
| Variant type | Duplication |
| Location | chr4:101032267-101032268 (GRCh38) |
| ClinVar | [VCV3900643](https://www.ncbi.nlm.nih.gov/clinvar/variation/3900643/) |

**All HGVS expressions:** `NC_000004.11:g.101953425dup`, `NC_000004.12:g.101032268dup`, `NG_077596.1:g.397dup`, `NG_077596.2:g.643dup`, `NM_000944.5:c.1338dup`, `NM_000944.5:c.1338dupC`, `NM_001130691.2:c.1338dup`, `NM_001130692.2:c.1212dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.685, GERP 2.79, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.243, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 14**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**PPP3CA** population constraint: LOEUF 0.243, pLI 1, missense-Z 4.5031. *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):

- **developmental and epileptic encephalopathy** — Definitive (AD)

## Protein context {#protein}

Residue **447** lies in a UniProt-annotated variant site (in iecee1; results in constitutive phosphatase activity in the absence of calmodulin); a UniProt-annotated variant site (in iecee1); a UniProt-annotated variant site (in iecee1; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 86.24, 61% of residues very-high.

**21 experimental structure(s)** (PDB): [1AUI](https://www.rcsb.org/structure/1AUI), [1M63](https://www.rcsb.org/structure/1M63), [1MF8](https://www.rcsb.org/structure/1MF8), [2JOG](https://www.rcsb.org/structure/2JOG), [2JZI](https://www.rcsb.org/structure/2JZI), [2P6B](https://www.rcsb.org/structure/2P6B) — incl. mutant structure 6NUU.

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

*Describes the biological roles of PPP3CA (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:** PPP3CA's established molecular role includes protein serine/threonine phosphatase activity.


### Pathways affected {#pathways}

PPP3CA participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CLEC7A (Dectin-1) induces NFAT activation](https://reactome.org/content/detail/R-HSA-5607763) | curated |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | curated |
| [FCERI mediated Ca+2 mobilization](https://reactome.org/content/detail/R-HSA-2871809) | curated |
| [Calcineurin activates NFAT](https://reactome.org/content/detail/R-HSA-2025928) | electronic |
| [DARPP-32 events](https://reactome.org/content/detail/R-HSA-180024) | electronic |

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

**Molecular function:** protein serine/threonine phosphatase activity, calmodulin binding, enzyme binding, calmodulin-dependent protein phosphatase activity, protein dimerization activity, ATPase binding.

**Biological process:** protein dephosphorylation, positive regulation of cell migration, calcineurin-NFAT signaling cascade, positive regulation of cell adhesion, positive regulation of transcription by RNA polymerase II, response to calcium ion.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-24.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Pediatric Department, Peking University First Hospital | Pathogenic | criteria provided, single submitter | research | 2025-05-24 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy 91](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-91/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy 91, EPILEPTIC ENCEPHALOPATHY, INFANTILE OR EARLY CHILDHOOD, 1.

## Same-residue context {#hotspot}

Residue **447** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PPP3CA p.Ala447Thr](/variant/ppp3ca-p-ala447thr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PPP3CA variant pages (same residue, condition, or type): [PPP3CA p.Ala447Thr](/variant/ppp3ca-p-ala447thr), [PPP3CA p.Ser438fs](/variant/ppp3ca-p-ser438fs), [PPP3CA p.Thr429fs](/variant/ppp3ca-p-thr429fs), [PPP3CA p.Gly430fs](/variant/ppp3ca-p-gly430fs), [PPP3CA p.Ser434fs](/variant/ppp3ca-p-ser434fs), [PPP3CA p.Ser446fs](/variant/ppp3ca-p-ser446fs), [PPP3CA p.Thr468fs](/variant/ppp3ca-p-thr468fs), [PPP3CA p.Val420fs](/variant/ppp3ca-p-val420fs).

### 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 3900643). 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.*