# NM_001352913.2(PPP2R5C):c.556T>C (p.Trp186Arg)

https://sugi.bio/variant/ppp2r5c-p-trp186arg

## Summary

**PPP2R5C p.Trp186Arg (c.556T>C)** is classified **Uncertain significance** in PPP2R5C (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-19). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 0.00134%, afr); Associated with neurodevelopmental disorder.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs367794601 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the PPP2R5C gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to neurodevelopmental disorder.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 210 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PPP2R5C](https://sugi.bio/atlas/gene/PPP2R5C/) |
| Protein change (HGVS p.) | p.Trp186Arg |
| Coding change (HGVS c.) | c.556T>C |
| MANE Select transcript | [NM_001352913](https://www.ncbi.nlm.nih.gov/nuccore/NM_001352913) |
| dbSNP | [rs367794601](https://www.ncbi.nlm.nih.gov/snp/rs367794601/) |
| Variant type | single nucleotide variant |
| Location | chr14:101882257-101882257 (GRCh38) |
| ClinVar | [VCV3252059](https://www.ncbi.nlm.nih.gov/clinvar/variation/3252059/) |

**All HGVS expressions:** `NC_000014.8:g.102348594T>C`, `NC_000014.9:g.101882257T>C`, `NG_047069.1:g.126685T>C`, `NM_001161725.2:c.484T>C`, `NM_001161726.2:c.556T>C`, `NM_001352912.1:c.391T>C`, `NM_001352913.2:c.556T>C`, `NM_001352914.2:c.571T>C`, `NM_001352915.2:c.166T>C`, `NM_001352916.2:c.166T>C`, `NM_002719.4:c.391T>C`, `NM_178586.3:c.391T>C`, `NM_178587.3:c.391T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9999)
- REVEL 0.863 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.223 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.848, GERP 2.39, phastCons 1 — highly conserved (agrees)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **W131R** vs ClinVar **W186R**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in PPP2R5C (of 3,095 modeled).
- CADD: **PHRED 32.0**. 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.*
- 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 **0.00134%** (afr) · 1/74,882 in the highest group · 1/1,612,106 alleles overall — very rare (popmax 0.00134%, 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}

**PPP2R5C** population constraint: LOEUF 0.198, pLI 1, missense-Z 4.0695. *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 **131** lies in a UniProt-annotated variant site (in hjs4; likely pathogenic; decreased interaction with ppp2ca and ppp2r1a); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.15, 71% of residues very-high.

**22 experimental structure(s)** (PDB): [2IAE](https://www.rcsb.org/structure/2IAE), [2JAK](https://www.rcsb.org/structure/2JAK), [2NPP](https://www.rcsb.org/structure/2NPP), [2NYL](https://www.rcsb.org/structure/2NYL), [2NYM](https://www.rcsb.org/structure/2NYM), [3FGA](https://www.rcsb.org/structure/3FGA).

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

*Describes the biological roles of PPP2R5C (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:** PPP2R5C's established molecular role includes protein phosphatase regulator activity. In Reactome, PPP2R5C is annotated in disease pathway(s) including **APC truncation mutants have impaired AXIN binding**, **AXIN missense mutants destabilize the destruction complex**.

**Disease mechanism (Reactome):** PPP2R5C 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}

PPP2R5C participates in **24 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 |
| [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 |
| [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 |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | 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 |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |

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

**Molecular function:** protein phosphatase regulator activity.

**Biological process:** negative regulation of cell population proliferation, DNA damage response, signal transduction by p53 class mediator, intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator, proteasome-mediated ubiquitin-dependent protein catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Uncertain Significance | criteria provided, single submitter | curation | 2024-06-19 |

## Associated conditions {#conditions}

[neurodevelopmental disorder](https://sugi.bio/atlas/disease/neurodevelopmental-disorder/).

**Reported phenotype names (ClinVar):** Neurodevelopmental disorder.

## Similar variants {#similar}

Related PPP2R5C variant pages (same residue, condition, or type): [PPP2R5C p.Cys104Arg](/variant/ppp2r5c-p-cys104arg), [PPP2R5C p.Leu307Ile](/variant/ppp2r5c-p-leu307ile), [PPP2R5C p.Met153Val](/variant/ppp2r5c-p-met153val), [PPP2R5C p.Phe110Ser](/variant/ppp2r5c-p-phe110ser), [PPP2R5C p.Pro180Ser](/variant/ppp2r5c-p-pro180ser), [PPP2R5C c.1017+19G>A](/variant/ppp2r5c-c-1017-plus-19g-a), [PPP2R5C c.1018-4G>C](/variant/ppp2r5c-c-1018-minus-4g-c), [PPP2R5C c.1491+11A>C](/variant/ppp2r5c-c-1491-plus-11a-c).

### 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 3252059). 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.*