# NM_000314.8(PTEN):c.424C>A (p.Arg142=)

https://sugi.bio/variant/pten-p-arg142

## Summary

**PTEN p.Arg142= (c.424C>A)** is classified **Conflicting classifications of pathogenicity** in PTEN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-08). Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs746152219 · 3 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PTEN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to PTEN hamartoma tumor syndrome.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PTEN is a diagnostic-grade gene on 34 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012800/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.Arg142= |
| Coding change (HGVS c.) | c.424C>A |
| MANE Select transcript | [NM_000314](https://www.ncbi.nlm.nih.gov/nuccore/NM_000314) |
| dbSNP | [rs746152219](https://www.ncbi.nlm.nih.gov/snp/rs746152219/) |
| Variant type | single nucleotide variant |
| Location | chr10:87933183-87933183 (GRCh38) |
| ClinVar | [VCV1213667](https://www.ncbi.nlm.nih.gov/clinvar/variation/1213667/) |

**All HGVS expressions:** `LRG_311:g.74745C>A`, `LRG_311t1:c.424C>A`, `NC_000010.10:g.89692940C>A`, `NC_000010.11:g.87933183C>A`, `NG_007466.2:g.74745C>A`, `NM_000314.8:c.424C>A`, `NM_001304717.5:c.943C>A`, `NM_001304718.2:c.-327C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.35) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 6.004, GERP 2.42, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.48**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.35**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.36**, donor gain **0.00**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- 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.Arg142= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-08-08.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Benign).

**Submission history:** 3 submissions (2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-02-12 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-05 |

## Associated conditions {#conditions}

[PTEN hamartoma tumor syndrome](https://sugi.bio/atlas/disease/pten-hamartoma-tumor-syndrome/), [Cowden syndrome 1](https://sugi.bio/atlas/disease/cowden-syndrome-1/).

**Reported phenotype names (ClinVar):** PTEN hamartoma tumor syndrome, not provided, Cowden syndrome 1, PTEN Hamartomatous Tumour Syndrome, PTEN-Related Cowden Syndrome, none provided.

## Same-residue context {#hotspot}

Residue **142** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [PTEN p.Arg142fs](/variant/pten-p-arg142fs), [PTEN p.Arg142Pro](/variant/pten-p-arg142pro). *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.Arg142Pro](/variant/pten-p-arg142pro), [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 1213667). 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.*