Is PTEN p.Met1Val (c.1A>G) pathogenic?

PTEN p.Met1Val (c.1A>G) is classified Pathogenic in PTEN (ClinVar, Expert panel, 6 submitters; last evaluated 2019-11-22). Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Met1Val (c.1A>G)?

PTEN p.Met1Val (c.1A>G) is associated with PTEN hamartoma tumor syndrome, Cowden syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Met1Val (c.1A>G) in the general population?

PTEN p.Met1Val (c.1A>G) is absent from gnomAD v4.1 (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

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

PTEN p.Met1Val

c.1A>G · rs1554890324 · VCV484600

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

PM6 PM2 PVS1 PS4_Moderate

Curation rationale (ClinGen, verbatim)

PTEN c.1A>G (p.M1?) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 29752200) PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 29752200, 28774669; internal laboratory contributor ClinVar Organization ID: 26957)

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.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.922	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PTEN
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_000314
dbSNP: rs1554890324
Type: single nucleotide variant
Location: chr10:87864470 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB

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

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.Met1Arg Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Met1Leu Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Met1Ile Pathogenic ★ same residue
PTEN p.Met1Thr Pathogenic ★ same residue
PTEN p.Met1_Lys6del Pathogenic ★ same residue
PTEN p.Met1fs Likely 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-met1val (accessed [today's date]).

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