# NM_000314.8(PTEN):c.731del (p.Pro244fs)

https://sugi.bio/variant/pten-p-pro244fs

## Summary

**PTEN p.Pro244fs (c.731del)** is classified **Pathogenic** in PTEN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-24). No gnomAD frequency available for this variant; Associated with macrocephaly-autism syndrome.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2493767037 · 3 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PTEN gene that is considered disease-causing, submitted by 3 submitters, and is linked to macrocephaly-autism 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) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PTEN is a diagnostic-grade gene on 34 Genomics England panels |

**Commonly reported features of Macrocephaly-intellectual disability-autism syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Macrocephaly — Very frequent (99-80%)
- Autistic behavior — Very frequent (99-80%)
- Delayed speech and language development — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Motor delay — Frequent (79-30%)
- Cafe-au-lait spot — Occasional (29-5%)
- Multiple lipomas — Occasional (29-5%)
- Numerous nevi — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017112/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.Pro244fs |
| Coding change (HGVS c.) | c.731del |
| MANE Select transcript | [NM_000314](https://www.ncbi.nlm.nih.gov/nuccore/NM_000314) |
| dbSNP | [rs2493767037](https://www.ncbi.nlm.nih.gov/snp/rs2493767037/) |
| Variant type | Deletion |
| Location | chr10:87957947-87957947 (GRCh38) |
| ClinVar | [VCV2674416](https://www.ncbi.nlm.nih.gov/clinvar/variation/2674416/) |

**All HGVS expressions:** `LRG_311:g.99511del`, `LRG_311t1:c.731del`, `NC_000010.10:g.89717706del`, `NC_000010.11:g.87957949del`, `NG_007466.2:g.99511del`, `NM_000314.8:c.731del`, `NM_001304717.5:c.1250del`, `NM_001304718.2:c.140del`

## Computational & population evidence {#evidence}

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

- **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 7.875, GERP 2.46, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 9**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **244** lies in a β-strand; the c2 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.Pro244fs falls in the c2 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-24.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-29 |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-24 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Macrocephaly-autism syndrome, Cowden syndrome 1, PTEN hamartoma tumor syndrome, Macrocephaly/autism syndrome, PTEN Hamartomatous Tumour Syndrome, PTEN-Related Cowden Syndrome.

## Similar variants {#similar}

Related PTEN variant pages (same residue, condition, or type): [PTEN p.Pro244Leu](/variant/pten-p-pro244leu), [PTEN p.Pro244=](/variant/pten-p-pro244), [PTEN c.209+4_209+7del](/variant/pten-c-209-plus-4-209-plus-7del), [PTEN c.210-2_211del](/variant/pten-c-210-minus-2-211del), [PTEN c.801+1del](/variant/pten-c-801-plus-1del), [PTEN c.802-2del](/variant/pten-c-802-minus-2del), [PTEN p.Asn329fs](/variant/pten-p-asn329fs), [PTEN p.Gln17fs](/variant/pten-p-gln17fs).

### 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 2674416). 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.*