Is PTEN p.Arg130Gln (c.389G>A) pathogenic?

PTEN p.Arg130Gln (c.389G>A) is classified Pathogenic in PTEN (ClinVar, Expert panel, 23 submitters; last evaluated 2017-10-18). AlphaMissense: likely pathogenic (0.9996); Very rare (popmax 0.00017%, nfe); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Arg130Gln (c.389G>A)?

PTEN p.Arg130Gln (c.389G>A) is associated with PTEN hamartoma tumor syndrome, Cowden syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Arg130Gln (c.389G>A) in the general population?

PTEN p.Arg130Gln (c.389G>A) is very rare (popmax 0.00017%, 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.Arg130Gln (c.389G>A)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

PTEN p.Arg130Gln

c.389G>A · rs121909229 · VCV7829

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 23 submitters

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.976	strongly pathogenic-leaning
SaProt	LLR -13.33	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 10	GERP 2.4, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	34.0	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 0.00017% European (non-Finnish) · 2/1,179,864 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,692 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.

ClinGen expert panel — PTEN VCEP

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

PM2 PM6_VeryStrong PS3 PS4 PM1 PP2

Curation rationale (ClinGen, verbatim)

PTEN c.389G>A (p.R130Q) 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). PM6_VS: At least four assumed de novo observations in a patient with the disease and no family history. (PMID 22595938, PMID 22327138, internal laboratory contributor(s) SCV000222111.11) PS3: Phosphatase activity <50% of wild type (PMID 10866302) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 26798346, PMID 17526801, PMID 23335809, PMID 22266152) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. 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.

Variant & gene context

Gene: PTEN
Protein: p.Arg130Gln
Coding: c.389G>A
MANE Select: NM_000314
dbSNP: rs121909229
Type: single nucleotide variant
Location: chr10:87933148 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 130: 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)p4 and ptdins(3,4,5)p3); a UniProt-annotated variant site (in cws1; also found in endometrial hyperplasia; loss of phosphatase activity towards ins(1,3,4,5)p4; retains ability to bind phospholipid membranes); a UniProt-annotated variant site (in cws1; loss of phosphatase activity towards ins(1,3,4,5)p4; retains ability to bind phospholipid membranes)

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: Cowden syndrome 1 hereditary neoplastic syndrome Cowden disease ovarian neoplasm

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Arg130Gly Pathogenic ★★★ same residue
PTEN p.Arg130Pro Pathogenic ★★★ same residue
PTEN p.Arg130Leu Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Arg130Ter Pathogenic ★★ same residue
PTEN p.Arg130= Likely benign ★ same residue
PTEN p.Arg130fs Pathogenic ★★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G Likely 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-arg130gln (accessed [today's date]).

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