# NM_000314.8(PTEN):c.114T>G (p.Pro38=)

https://sugi.bio/variant/pten-p-pro38

## Summary

**PTEN p.Pro38= (c.114T>G)** is classified **Likely benign** in PTEN (ClinVar, Expert panel, 12 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0165%, mid); Associated with PTEN hamartoma tumor syndrome.

**At a glance:** Likely benign · review: Expert panel · rsID rs748040144 · 12 submitters · 4 linked conditions · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the PTEN gene that is classified as likely benign — not considered disease-causing, submitted by 12 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.Pro38= |
| Coding change (HGVS c.) | c.114T>G |
| MANE Select transcript | [NM_000314](https://www.ncbi.nlm.nih.gov/nuccore/NM_000314) |
| dbSNP | [rs748040144](https://www.ncbi.nlm.nih.gov/snp/rs748040144/) |
| Variant type | single nucleotide variant |
| Location | chr10:87894059-87894059 (GRCh38) |
| ClinVar | [VCV184068](https://www.ncbi.nlm.nih.gov/clinvar/variation/184068/) |

**All HGVS expressions:** `LRG_311:g.35621T>G`, `LRG_311t1:c.114T>G`, `NC_000010.10:g.89653816T>G`, `NC_000010.11:g.87894059T>G`, `NG_007466.2:g.35621T>G`, `NM_000314.8:c.114T>G`, `NM_001304717.5:c.633T>G`, `NM_001304718.2:c.-592T>G`

## 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 0.32) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.589, GERP 1.49, phastCons 1 — weakly conserved position
- CADD: **PHRED 18.07**. 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 **0.15**, donor loss **0.00**, acceptor gain **0.32**, donor gain **0.08**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.32**, donor gain **0.08**.
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.000183% · FAF99 0.00012% · 1/6,068 in the highest group · 8/1,612,786 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,068 |
| Admixed American | 0.00167% | 59,968 |
| European (non-Finnish) | 0.000509% | 196,540 |

*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 **38** lies in the phosphatase tensin-type domain.

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.Pro38= 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 benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2026-01-21.

**Submitter consensus:** conflicting (6 Likely benign, 3 Uncertain significance, 2 Likely Benign, 1 Benign).

**Submission history:** 12 submissions (2014–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — PTEN VCEP (PTEN hamartoma tumor syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `BS3`, `BP7`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `PP3`, `PP4`, `BS2`, `PM3`, `BS1`, `BS4`, `BP5`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** PTEN c.114T>G (p.Pro38=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0).  Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).  BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (internal laboratory contributor Accession: SCV000213708.7)  BP7: Variant is synonymous (silent) OR intronic and at or beyond +7/-21 and no splicing impact is predicted.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50012 · approved 2026-01-21 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/a06a1116-f26c-4129-8a43-c1ecbda9bc38).*
*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 |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-29 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-05-15 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2014-10-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-04-27 |
| Molecular Diagnostics Laboratory, Catalan Institute of Oncology | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-23 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2021-12-27 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-10-08 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-13 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-02-11 |
| Clingen PTEN Variant Curation Expert Panel, Clingen | Likely Benign | reviewed by expert panel | curation | 2026-01-21 |

## Associated conditions {#conditions}

[PTEN hamartoma tumor syndrome](https://sugi.bio/atlas/disease/pten-hamartoma-tumor-syndrome/), [breast cancer](https://sugi.bio/atlas/disease/breast-cancer/), [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):** PTEN hamartoma tumor syndrome, Hereditary cancer-predisposing syndrome, not specified, Malignant tumor of breast, not provided, PTEN-related disorder, Cowden syndrome 1, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **38** carries **6 other pathogenic ClinVar variants** — a recurrently-mutated position: [PTEN p.Pro38His](/variant/pten-p-pro38his), [PTEN p.Pro38fs](/variant/pten-p-pro38fs), [PTEN p.Pro38Thr](/variant/pten-p-pro38thr), [PTEN p.Pro38Arg](/variant/pten-p-pro38arg), [PTEN p.Pro38Phe](/variant/pten-p-pro38phe), [PTEN p.Pro38Leu](/variant/pten-p-pro38leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PTEN variant pages (same residue, condition, or type): [PTEN p.Pro38His](/variant/pten-p-pro38his), [PTEN p.Pro38Leu](/variant/pten-p-pro38leu), [PTEN p.Pro38Ser](/variant/pten-p-pro38ser), [PTEN p.Pro38Thr](/variant/pten-p-pro38thr), [PTEN p.Pro38fs](/variant/pten-p-pro38fs), [PTEN p.Pro38Phe](/variant/pten-p-pro38phe), [PTEN p.Pro38Arg](/variant/pten-p-pro38arg), [PTEN c.1026+1G>A](/variant/pten-c-1026-plus-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 184068). 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.*