# NM_000314.8(PTEN):c.408T>G (p.Cys136Trp)

https://sugi.bio/variant/pten-p-cys136trp

## Summary

**PTEN p.Cys136Trp (c.408T>G)** is classified **Pathogenic** in PTEN (ClinVar, Expert panel, 6 submitters; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

**At a glance:** Pathogenic · review: Expert panel · rsID rs869312776 · 6 submitters · 3 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 disease-causing, submitted by 6 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.Cys136Trp |
| Coding change (HGVS c.) | c.408T>G |
| MANE Select transcript | [NM_000314](https://www.ncbi.nlm.nih.gov/nuccore/NM_000314) |
| dbSNP | [rs869312776](https://www.ncbi.nlm.nih.gov/snp/rs869312776/) |
| Variant type | single nucleotide variant |
| Location | chr10:87933167-87933167 (GRCh38) |
| ClinVar | [VCV224543](https://www.ncbi.nlm.nih.gov/clinvar/variation/224543/) |

**All HGVS expressions:** `LRG_311:g.74729T>G`, `LRG_311t1:c.408T>G`, `NC_000010.10:g.89692924T>G`, `NC_000010.11:g.87933167T>G`, `NG_007466.2:g.74729T>G`, `NM_000314.8:c.408T>G`, `NM_001304717.5:c.927T>G`, `NM_001304718.2:c.-343T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9999) — concordant with the pathogenic call
- REVEL 0.954 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -18.407 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 1.954, GERP -0.122, phastCons 1 — weakly conserved position
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in PTEN (of 2,391 modeled).
- CADD: **PHRED 27.8**. 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 **136** lies in an α-helix; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1; loss of phosphatase activity towards ins(1,3,4,5)p3).

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.Cys136Trp 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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-04-04.

**Submitter consensus:** conflicting (3 Likely pathogenic, 2 Pathogenic, 1 Uncertain significance).

**Submission history:** 6 submissions (2015–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — PTEN VCEP (PTEN hamartoma tumor syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PM6_Strong`, `PS3_Moderate`, `PP2`, `PP3`, `PM5`.
*Considered but not met:* `PS4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** PTEN c.408T>G (p.Cys136Trp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).  PM6_S: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history (internal laboratory contributor(s) SCV003926429.1). PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 189406, SCV000840468.3). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.54 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350). PP3: REVEL score > 0.7 (score of this variant = 0.954). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PM2_P: Absent in large sequenced populations (PMID 27535533).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50012 · approved 2025-04-04 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/a8ec82c1-a3b5-4e8c-ad81-ac59b2b541ef).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| University of Washington Department of Laboratory Medicine, University of Washington | Likely pathogenic | criteria provided, single submitter | clinical testing | 2015-11-20 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-02 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-01 |
| Clingen PTEN Variant Curation Expert Panel, Clingen | Pathogenic | reviewed by expert panel | curation | 2025-04-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-10 |
| Laboratory of Bioengineering, Higher National School of Biotechnology Taoufik Khaznadar | Likely pathogenic | criteria provided, single submitter | research | 2023-05-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** PTEN hamartoma tumor syndrome, Cowden syndrome, not provided, Hereditary cancer-predisposing syndrome, Triple-negative breast cancer, Cowden's syndrome, Cowden disease, Cowden's disease, Tumor predisposition, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **136** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [PTEN p.Cys136Phe](/variant/pten-p-cys136phe), [PTEN p.Cys136Arg](/variant/pten-p-cys136arg), [PTEN p.Cys136Tyr](/variant/pten-p-cys136tyr), [PTEN p.Cys136fs](/variant/pten-p-cys136fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PTEN variant pages (same residue, condition, or type): [PTEN p.Cys136Tyr](/variant/pten-p-cys136tyr), [PTEN p.Cys136Arg](/variant/pten-p-cys136arg), [PTEN p.Cys136Phe](/variant/pten-p-cys136phe), [PTEN p.Cys136=](/variant/pten-p-cys136), [PTEN p.Cys136Gly](/variant/pten-p-cys136gly), [PTEN p.Cys136fs](/variant/pten-p-cys136fs), [PTEN c.1026+1G>A](/variant/pten-c-1026-plus-1g-a), [PTEN c.1027-1852A>G](/variant/pten-c-1027-minus-1852a-g).

### 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 224543). 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.*