# NM_002715.4(PPP2CA):c.513G>A (p.Ser171=)

https://sugi.bio/variant/ppp2ca-p-ser171

## Summary

**PPP2CA p.Ser171= (c.513G>A)** is classified **Likely benign** in PPP2CA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-13). Very rare (popmax 0.00935%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs778165477 · 1 submitter · very rare (popmax 0.00935%, afr)

## For patients & families {#patients}

This is a change in the PPP2CA gene that is classified as likely benign — not considered 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.Ser171= |
| Coding change (HGVS c.) | c.513G>A |
| MANE Select transcript | [NM_002715](https://www.ncbi.nlm.nih.gov/nuccore/NM_002715) |
| dbSNP | [rs778165477](https://www.ncbi.nlm.nih.gov/snp/rs778165477/) |
| Variant type | single nucleotide variant |
| Location | chr5:134201048-134201048 (GRCh38) |
| ClinVar | [VCV1508428](https://www.ncbi.nlm.nih.gov/clinvar/variation/1508428/) |

**All HGVS expressions:** `NC_000005.10:g.134201048C>T`, `NC_000005.9:g.133536739C>T`, `NG_046997.1:g.30212G>A`, `NM_001355019.2:c.318G>A`, `NM_002715.4:c.513G>A`, `NR_149151.2:n.757G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -2.163, GERP -3.75 — fast-evolving / accelerated position
- CADD: **PHRED 9.414**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, C>A, IS in the release and scores Δ0.51 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00935%** (afr) · FAF95 0.00438% · FAF99 0.00309% · 7/74,856 in the highest group · 12/1,612,520 alleles overall — very rare (popmax 0.00935%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00935% | 10,694 |
| Admixed American | 0.00167% | 59,990 |
| European (non-Finnish) | 0.000339% | 294,674 |

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

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 benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-13.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-13 |

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

## Similar variants {#similar}

Related PPP2CA variant pages (same residue, condition, or type): [PPP2CA p.Ser171Leu](/variant/ppp2ca-p-ser171leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1508428). 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.*