# NM_002715.4(PPP2CA):c.438del (p.Phe146fs)

https://sugi.bio/variant/ppp2ca-p-phe146fs

## Summary

**PPP2CA p.Phe146fs (c.438del)** is classified **Pathogenic** in PPP2CA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-10). No gnomAD frequency available for this variant; Associated with Houge-Janssens syndrome 3.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1561734750 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PPP2CA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Houge-Janssens syndrome 3.

*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 | [PPP2CA](https://sugi.bio/atlas/gene/PPP2CA/) |
| Protein change (HGVS p.) | p.Phe146fs |
| Coding change (HGVS c.) | c.438del |
| MANE Select transcript | [NM_002715](https://www.ncbi.nlm.nih.gov/nuccore/NM_002715) |
| dbSNP | [rs1561734750](https://www.ncbi.nlm.nih.gov/snp/rs1561734750/) |
| Variant type | Deletion |
| Location | chr5:134201896-134201896 (GRCh38) |
| ClinVar | [VCV620079](https://www.ncbi.nlm.nih.gov/clinvar/variation/620079/) |

**All HGVS expressions:** `NC_000005.10:g.134201899del`, `NC_000005.9:g.133537590del`, `NG_046997.1:g.29364del`, `NM_001355019.2:c.243del`, `NM_002715.4:c.438del`, `NR_149151.2:n.682del`

## 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 7.923, GERP 1.87, 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 0.315, pLI 0.99995), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 7**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PPP2CA** population constraint: LOEUF 0.315, pLI 0.99995, missense-Z 5.568. *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **146** lies in a UniProt-annotated variant site (in hjs3; may be expressed at very low levels, if any); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.86, 92% of residues very-high.

**50 experimental structure(s)** (PDB): [2IAE](https://www.rcsb.org/structure/2IAE), [2IE3](https://www.rcsb.org/structure/2IE3), [2IE4](https://www.rcsb.org/structure/2IE4), [2NPP](https://www.rcsb.org/structure/2NPP), [2NYL](https://www.rcsb.org/structure/2NYL), [2NYM](https://www.rcsb.org/structure/2NYM) — incl. mutant structure 8U1X.

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

*Describes the biological roles of PPP2CA (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:** PPP2CA's established molecular role includes protein serine/threonine phosphatase activity. In Reactome, PPP2CA is annotated in disease pathway(s) including **APC truncation mutants have impaired AXIN binding**, **AXIN missense mutants destabilize the destruction complex**.

**Disease mechanism (Reactome):** PPP2CA loss or alteration is curated in [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337), [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340), [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747).

### Pathways affected {#pathways}

PPP2CA participates in **38 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337) | curated |
| ⚕ [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340) | curated |
| ⚕ [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747) | curated |
| ⚕ [CTNNB1 S37 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358749) | curated |
| ⚕ [CTNNB1 S45 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358751) | curated |
| ⚕ [CTNNB1 T41 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358752) | curated |
| ⚕ [Signaling by GSK3beta mutants](https://reactome.org/content/detail/R-HSA-5339716) | curated |
| ⚕ [Truncations of AMER1 destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467348) | curated |
| [Amplification  of signal from unattached  kinetochores via a MAD2  inhibitory signal](https://reactome.org/content/detail/R-HSA-141444) | curated |
| [Beta-catenin phosphorylation cascade](https://reactome.org/content/detail/R-HSA-196299) | curated |
| [Co-inhibition by CTLA4](https://reactome.org/content/detail/R-HSA-389513) | curated |
| [Co-stimulation by CD28](https://reactome.org/content/detail/R-HSA-389356) | curated |
| [Cyclin A/B1/B2 associated events during G2/M transition](https://reactome.org/content/detail/R-HSA-69273) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [DARPP-32 events](https://reactome.org/content/detail/R-HSA-180024) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [EML4 and NUDC in mitotic spindle formation](https://reactome.org/content/detail/R-HSA-9648025) | curated |
| [ERK/MAPK targets](https://reactome.org/content/detail/R-HSA-198753) | curated |
| [ERKs are inactivated](https://reactome.org/content/detail/R-HSA-202670) | curated |
| [Inhibition of replication initiation of damaged DNA by RB1/E2F1](https://reactome.org/content/detail/R-HSA-113501) | curated |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | curated |
| [Mitotic Prometaphase](https://reactome.org/content/detail/R-HSA-68877) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)](https://reactome.org/content/detail/R-HSA-975957) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PKR-mediated signaling](https://reactome.org/content/detail/R-HSA-9833482) | curated |
| [Platelet sensitization by LDL](https://reactome.org/content/detail/R-HSA-432142) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [RHO GTPases Activate Formins](https://reactome.org/content/detail/R-HSA-5663220) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Resolution of Sister Chromatid Cohesion](https://reactome.org/content/detail/R-HSA-2500257) | curated |
| [Separation of Sister Chromatids](https://reactome.org/content/detail/R-HSA-2467813) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |
| [MASTL Facilitates Mitotic Progression](https://reactome.org/content/detail/R-HSA-2465910) | electronic |
| [PP2A-mediated dephosphorylation of key metabolic factors](https://reactome.org/content/detail/R-HSA-163767) | electronic |
| [Regulation of glycolysis by fructose 2,6-bisphosphate metabolism](https://reactome.org/content/detail/R-HSA-9634600) | electronic |
| [Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells](https://reactome.org/content/detail/R-HSA-9860927) | electronic |

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

**Molecular function:** protein serine/threonine phosphatase activity, protein tyrosine phosphatase activity, protein heterodimerization activity, RNA polymerase II CTD heptapeptide repeat S2 phosphatase activity, RNA polymerase II CTD heptapeptide repeat S5 phosphatase activity, RNA polymerase II CTD heptapeptide repeat S7 phosphatase activity.

**Biological process:** protein dephosphorylation, negative regulation of epithelial to mesenchymal transition, regulation of transcription elongation by RNA polymerase II, negative regulation of hippo signaling, negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction, negative regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-11-10.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2023-11-10 |

## Associated conditions {#conditions}

[Houge-Janssens syndrome 3](https://sugi.bio/atlas/disease/houge-janssens-syndrome-3/).

**Reported phenotype names (ClinVar):** Houge-Janssens syndrome 3, NEURODEVELOPMENTAL DISORDER AND LANGUAGE DELAY WITH OR WITHOUT STRUCTURAL BRAIN ABNORMALITIES.

## Similar variants {#similar}

Related PPP2CA variant pages (same residue, condition, or type): [PPP2CA p.Phe164fs](/variant/ppp2ca-p-phe164fs), [PPP2CA p.Tyr127fs](/variant/ppp2ca-p-tyr127fs), [PPP2CA p.Asp223His](/variant/ppp2ca-p-asp223his), [PPP2CA p.Asp88Gly](/variant/ppp2ca-p-asp88gly), [PPP2CA p.Gln122His](/variant/ppp2ca-p-gln122his), [PPP2CA p.His191Arg](/variant/ppp2ca-p-his191arg), [PPP2CA p.Tyr127Cys](/variant/ppp2ca-p-tyr127cys), [PPP2CA p.Tyr265Cys](/variant/ppp2ca-p-tyr265cys).

### 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 620079). 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.*