Is PTEN p.Arg130Leu (c.389G>T) pathogenic?

PTEN p.Arg130Leu (c.389G>T) is classified Pathogenic/Likely pathogenic in PTEN (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-03-23). AlphaMissense: likely pathogenic (0.9997); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.Arg130Leu (c.389G>T)?

PTEN p.Arg130Leu (c.389G>T) is associated with hereditary neoplastic syndrome, Cowden syndrome 1, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Arg130Leu (c.389G>T) in the general population?

PTEN p.Arg130Leu (c.389G>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PTEN p.Arg130Leu (c.389G>T)?

AlphaMissense predicts likely pathogenic (score 0.9997) — an in-silico prediction, not a clinical call.

PTEN p.Arg130Leu

c.389G>T · rs121909229 · VCV376509

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9997	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.987	strongly pathogenic-leaning
SaProt	LLR -13.99	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 8.48e-05% European (non-Finnish) · 1/1,179,864 alleles

Overall 6.84e-05% 1/1,461,692 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.

Variant & gene context

Gene: PTEN
Protein: p.Arg130Leu
Coding: c.389G>T
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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Cowden syndrome 1 PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Arg130Gln Pathogenic ★★★ same residue
PTEN p.Arg130Gly Pathogenic ★★★ same residue
PTEN p.Arg130Pro 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-arg130leu (accessed [today's date]).

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