# NM_002715.4(PPP2CA):c.164G>T (p.Cys55Phe)

https://sugi.bio/variant/ppp2ca-p-cys55phe

## Summary

**PPP2CA p.Cys55Phe (c.164G>T)** is classified **Likely pathogenic** in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2149384599 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PPP2CA gene that is considered likely disease-causing, submitted by 1 submitter.

*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.Cys55Phe |
| Coding change (HGVS c.) | c.164G>T |
| MANE Select transcript | [NM_002715](https://www.ncbi.nlm.nih.gov/nuccore/NM_002715) |
| dbSNP | [rs2149384599](https://www.ncbi.nlm.nih.gov/snp/rs2149384599/) |
| Variant type | single nucleotide variant |
| Location | chr5:134206070-134206070 (GRCh38) |
| ClinVar | [VCV1409655](https://www.ncbi.nlm.nih.gov/clinvar/variation/1409655/) |

**All HGVS expressions:** `NC_000005.10:g.134206070C>A`, `NC_000005.9:g.133541761C>A`, `NG_046997.1:g.25190G>T`, `NM_001355019.2:c.-32G>T`, `NM_002715.4:c.164G>T`, `NR_149151.2:n.408G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9944) — concordant with the pathogenic call
- REVEL 0.63 (indeterminate)
- SaProt LLR -16.536 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.71, GERP 1.87, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.12** across the covering region of the MANE Select transcript (134,205,955–134,206,085), spanning 130 bp — the region is depleted of missense variation. Chi-square p 1.6e-10. 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}

**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 **55** lies in a β-strand.

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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-25.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-10-25 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PPP2CA variant pages (same residue, condition, or type): [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), [PPP2CA p.Arg108Cys](/variant/ppp2ca-p-arg108cys), [PPP2CA p.Asp57Asn](/variant/ppp2ca-p-asp57asn).

### 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 1409655). 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.*