Is PTEN p.Pro246Leu (c.737C>T) pathogenic?

PTEN p.Pro246Leu (c.737C>T) is classified Pathogenic in PTEN (ClinVar, Expert panel, 23 submitters; last evaluated 2017-10-18). AlphaMissense: likely pathogenic (0.9408); Very rare (popmax 0.000254%, nfe); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Pro246Leu (c.737C>T)?

PTEN p.Pro246Leu (c.737C>T) is associated with PTEN hamartoma tumor syndrome, gastric cancer, Cowden syndrome 1 (ClinVar).

How common is PTEN p.Pro246Leu (c.737C>T) in the general population?

PTEN p.Pro246Leu (c.737C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PTEN p.Pro246Leu (c.737C>T)?

AlphaMissense predicts likely pathogenic (score 0.9408) — an in-silico prediction, not a clinical call.

PTEN p.Pro246Leu

c.737C>T · rs587782350 · VCV142269

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 23 submitters

AlphaMissense

likely pathogenic

0.9408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

Pathogenic for PTEN hamartoma tumor syndrome. Applied ACMG criteria (verbatim):

PM2 PS2_VeryStrong PS4 PP2

Curation rationale (ClinGen, verbatim)

PTEN c.737C>T (p.P246L) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 23934111, internal laboratory contributor(s) SCV000222227.10) PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10) PM2: Absent in large sequenced populations. (PMID 27535533). 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.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9408	likely pathogenic ✓ concordant with ClinVar
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -10.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,986 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,802 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PTEN
Protein: p.Pro246Leu
Coding: c.737C>T
MANE Select: NM_000314
dbSNP: rs587782350
Type: single nucleotide variant
Location: chr10:87957955 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 246: a β-strand; the c2 tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1)

Full PTEN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PTEN hamartoma tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: gastric cancer Cowden syndrome 1 macrocephaly-autism syndrome familial meningioma glioma susceptibility 2 hereditary neoplastic syndrome prostate cancer, hereditary

For PTEN hamartoma tumor syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PTEN p.Pro246Gln Uncertain significance ★★ ⚠ same residue
PTEN p.Pro246= Benign/Likely benign ★★ same residue
PTEN p.Pro246Arg Uncertain significance ★ ⚠ same residue
PTEN p.Pro246Thr Uncertain significance ★ ⚠ same residue
PTEN p.Pro246fs Pathogenic ★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G Likely pathogenic ★★★ same condition
PTEN c.1027-1G>A Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pten-p-pro246leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown