Is PTEN p.Val53= (c.159A>G) pathogenic?

PTEN p.Val53= (c.159A>G) is classified Likely benign in PTEN (ClinVar, Expert panel, 5 submitters; last evaluated 2024-02-09). Ultra-rare (popmax 0.0107%, afr); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Val53= (c.159A>G)?

PTEN p.Val53= (c.159A>G) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Val53= (c.159A>G) in the general population?

PTEN p.Val53= (c.159A>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

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

PTEN p.Val53=

c.159A>G · rs189583426 · VCV184020

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

BP4 BS1_Supporting

Curation rationale (ClinGen, verbatim)

NM_000314.8(PTEN):c.159A>G (p.Val53=) 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 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1_P: To be applied for variants with filtering allele frequency of 0.0000043 up to 0.000043 (0.00043% up to 0.0043%) in gnomAD. Popmax FAF of this variant=0.00004593 (9 alleles v4 gnomAD). BP4: Synonymous variant where SpliceAI model predict no splicing impact (acceptor gain 0.08, donor gain 0.13).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 2.4, phastCons 1
Overall
CADD	12.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,958 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000559% 9/1,609,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,370
European (non-Finnish)	8.5e-05%	1,175,784

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.Val53=
Coding: c.159A>G
MANE Select: NM_000314
dbSNP: rs189583426
Type: single nucleotide variant
Location: chr10:87894104 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 53: an α-helix; the phosphatase tensin-type domain

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: hereditary neoplastic syndrome

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Val53Ile Pathogenic ★★★ same residue
PTEN p.Val53Glu Uncertain significance ★★ ⚠ same residue
PTEN p.Val53Gly Uncertain significance ★ ⚠ same residue
PTEN p.Val53Asp Uncertain significance ★★ same residue
PTEN p.Val53Ala Conflicting classifications of pathogenicity ★ 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-val53 (accessed [today's date]).

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