Is PTEN p.Met205Val (c.613A>G) pathogenic?

PTEN p.Met205Val (c.613A>G) is classified Uncertain significance in PTEN (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.2764); Very rare (popmax 0.00223%, eas); Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Met205Val (c.613A>G)?

PTEN p.Met205Val (c.613A>G) is associated with Cowden syndrome 1, macrocephaly-autism syndrome, familial meningioma (ClinVar).

How common is PTEN p.Met205Val (c.613A>G) in the general population?

PTEN p.Met205Val (c.613A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PTEN p.Met205Val (c.613A>G)?

AlphaMissense predicts likely benign (score 0.2764) — an in-silico prediction, not a clinical call.

PTEN p.Met205Val

c.613A>G · rs776763121 · VCV404146

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.2764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cowden syndrome 1

Computational evidence

Protein change
AlphaMissense	0.2764	likely benign
REVEL	0.542	indeterminate
SaProt	LLR -4.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	22.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,866 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,613,336 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00315%	31,723
East Asiangrpmax	0.00223%	44,866
European (non-Finnish)	0.00127%	78,666
South Asian	0.0011%	91,054

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Met205Val
Coding: c.613A>G
MANE Select: NM_000314
dbSNP: rs776763121
Type: single nucleotide variant
Location: chr10:87952238 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 205: 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

Cowden syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: macrocephaly-autism syndrome familial meningioma glioma susceptibility 2 hereditary neoplastic syndrome PTEN hamartoma tumor syndrome prostate cancer, hereditary

Similar variants

PTEN p.Met205Ile Uncertain significance ★ ⚠ same residue
PTEN p.Met205Leu Uncertain significance ★ ⚠ same residue
PTEN p.Met205Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Met205fs Pathogenic ★ 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
PTEN c.165-1G>A 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-met205val (accessed [today's date]).

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