# NM_000314.8(PTEN):c.425G>C (p.Arg142Pro)

https://sugi.bio/variant/pten-p-arg142pro

## Summary

**PTEN p.Arg142Pro (c.425G>C)** is classified **Likely pathogenic** in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-03-27). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1; Associated with Cowden syndrome 1.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs753630034 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PTEN gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Cowden syndrome 1.

*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/0016450/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PTEN](https://sugi.bio/atlas/gene/PTEN/) |
| Protein change (HGVS p.) | p.Arg142Pro |
| Coding change (HGVS c.) | c.425G>C |
| MANE Select transcript | [NM_000314](https://www.ncbi.nlm.nih.gov/nuccore/NM_000314) |
| dbSNP | [rs753630034](https://www.ncbi.nlm.nih.gov/snp/rs753630034/) |
| Variant type | single nucleotide variant |
| Location | chr10:87933184-87933184 (GRCh38) |
| ClinVar | [VCV486225](https://www.ncbi.nlm.nih.gov/clinvar/variation/486225/) |

**All HGVS expressions:** `LRG_311:g.74746G>C`, `LRG_311t1:c.425G>C`, `NC_000010.10:g.89692941G>C`, `NC_000010.11:g.87933184G>C`, `NG_007466.2:g.74746G>C`, `NM_000314.8:c.425G>C`, `NM_001304717.5:c.944G>C`, `NM_001304718.2:c.-326G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.998) — concordant with the pathogenic call
- REVEL 0.877 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.288 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.984, GERP 2.42, 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 0.51** across the covering region of the MANE Select transcript (87,933,087–87,965,309), spanning 32,222 bp. Chi-square p 4.1e-17. 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}

**PTEN** population constraint: LOEUF 0.685, pLI 0.048668, missense-Z 4.1195; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **PTEN hamartoma tumor syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **142** lies in an α-helix; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas).

AlphaFold model confidence (whole protein): pLDDT 83.76, 70% of residues very-high.

**12 experimental structure(s)** (PDB): [1D5R](https://www.rcsb.org/structure/1D5R), [2KYL](https://www.rcsb.org/structure/2KYL), [4O1V](https://www.rcsb.org/structure/4O1V), [5BUG](https://www.rcsb.org/structure/5BUG), [5BZX](https://www.rcsb.org/structure/5BZX), [5BZZ](https://www.rcsb.org/structure/5BZZ).

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

*Describes the biological roles of PTEN (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:** PTEN's established molecular role includes phosphatidylinositol-3-phosphate phosphatase activity. p.Arg142Pro falls in the phosphatase tensin-type domain. In Reactome, PTEN is annotated in disease pathway(s) including **PTEN Loss of Function in Cancer**.

**Disease mechanism (Reactome):** PTEN loss or alteration is curated in [PTEN Loss of Function in Cancer](https://reactome.org/content/detail/R-HSA-5674404).

### Pathways affected {#pathways}

PTEN participates in **12 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [PTEN Loss of Function in Cancer](https://reactome.org/content/detail/R-HSA-5674404) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [Negative regulation of the PI3K/AKT network](https://reactome.org/content/detail/R-HSA-199418) | curated |
| [Ovarian tumor domain proteases](https://reactome.org/content/detail/R-HSA-5689896) | curated |
| [Regulation of PTEN localization](https://reactome.org/content/detail/R-HSA-8948747) | curated |
| [Regulation of PTEN mRNA translation](https://reactome.org/content/detail/R-HSA-8943723) | curated |
| [Regulation of PTEN stability and activity](https://reactome.org/content/detail/R-HSA-8948751) | curated |
| [Synthesis of IP3 and IP4 in the cytosol](https://reactome.org/content/detail/R-HSA-1855204) | curated |
| [Synthesis of PIPs at the plasma membrane](https://reactome.org/content/detail/R-HSA-1660499) | curated |
| [TP53 Regulates Metabolic Genes](https://reactome.org/content/detail/R-HSA-5628897) | curated |
| [Transcriptional Regulation by MECP2](https://reactome.org/content/detail/R-HSA-8986944) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |

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

**Molecular function:** phosphatidylinositol-3-phosphate phosphatase activity, phosphoprotein phosphatase activity, protein serine/threonine phosphatase activity, protein tyrosine phosphatase activity, beta-catenin binding, anaphase-promoting complex binding.

**Biological process:** protein dephosphorylation, spindle assembly involved in female meiosis, negative regulation of cell population proliferation, negative regulation of epithelial to mesenchymal transition, negative regulation of cell migration, regulation of protein stability.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-03-27.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-01-21 |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-03-27 |

## Associated conditions {#conditions}

[Cowden syndrome 1](https://sugi.bio/atlas/disease/cowden-syndrome-1/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Cowden syndrome 1, Hereditary cancer-predisposing syndrome, PTEN-Related Cowden Syndrome, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition.

## Same-residue context {#hotspot}

Residue **142** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PTEN p.Arg142fs](/variant/pten-p-arg142fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PTEN variant pages (same residue, condition, or type): [PTEN p.Arg142Trp](/variant/pten-p-arg142trp), [PTEN p.Arg142=](/variant/pten-p-arg142), [PTEN p.Arg142Gln](/variant/pten-p-arg142gln), [PTEN p.Arg142Gly](/variant/pten-p-arg142gly), [PTEN p.Arg142fs](/variant/pten-p-arg142fs), [PTEN c.1026+1G>A](/variant/pten-c-1026-plus-1g-a), [PTEN c.1027-1852A>G](/variant/pten-c-1027-minus-1852a-g), [PTEN c.1027-1G>A](/variant/pten-c-1027-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 486225). 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.*