Is PTEN p.Met199Val (c.595A>G) pathogenic?

PTEN p.Met199Val (c.595A>G) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-10). AlphaMissense: likely benign (0.0637); Very rare (popmax 8.48e-05%, nfe); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Met199Val (c.595A>G)?

PTEN p.Met199Val (c.595A>G) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Met199Val (c.595A>G) in the general population?

PTEN p.Met199Val (c.595A>G) is very rare (popmax 8.48e-05%, 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.Met199Val (c.595A>G)?

AlphaMissense predicts likely benign (score 0.0637) — an in-silico prediction, not a clinical call.

PTEN p.Met199Val

c.595A>G · rs1434191423 · VCV629479

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0637 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.0637	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -3.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 32 kb · p 4.1e-17 · regional, not allelic
Overall
CADD	20.3	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) · 1/1,179,936 alleles

Overall 6.84e-05% 1/1,461,406 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.Met199Val
Coding: c.595A>G
MANE Select: NM_000314
dbSNP: rs1434191423
Type: single nucleotide variant
Location: chr10:87952220 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 199: a β-strand; the c2 tensin-type domain; a UniProt-annotated variant site (in mcephas)

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.Met199Ile Uncertain significance ★★ ⚠ same residue
PTEN p.Met199Lys Uncertain significance ★★ ⚠ same residue
PTEN p.Met199Thr Uncertain significance ★★ ⚠ same residue
PTEN p.Met199Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Met199del Uncertain significance ★★★ same residue
PTEN p.Met199_Phe200delinsIle 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-met199val (accessed [today's date]).

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