Is PTEN p.Pro204= (c.612A>G) pathogenic?

PTEN p.Pro204= (c.612A>G) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-05-17). Ultra-rare (popmax 0.0307%, sas); Associated with Cowden syndrome 1.

What condition is associated with PTEN p.Pro204= (c.612A>G)?

PTEN p.Pro204= (c.612A>G) is associated with Cowden syndrome 1, hereditary neoplastic syndrome, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.Pro204= (c.612A>G) in the general population?

PTEN p.Pro204= (c.612A>G) is ultra-rare (popmax 0.0307%, sas) (gnomAD).

PTEN p.Pro204=

c.612A>G · rs539074063 · VCV760194

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0307%, sas)

Conditions

Cowden syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 0.52, phastCons 1
Overall
CADD	11.87	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0307% South Asian · 28/91,060 alleles

Filtering AF 0.0218% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0018% 29/1,613,518 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0307%	3,252
Middle Eastern	0.0165%	6,058

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.Pro204=
Coding: c.612A>G
MANE Select: NM_000314
dbSNP: rs539074063
Type: single nucleotide variant
Location: chr10:87952237 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 204: 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: hereditary neoplastic syndrome PTEN hamartoma tumor syndrome

Similar variants

PTEN p.Pro204Ala Pathogenic ★★★ same residue
PTEN p.Pro204Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Pro204Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Pro204fs Pathogenic ★ same residue
PTEN p.Pro204Gln Uncertain significance ★ ⚠ 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

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-pro204 (accessed [today's date]).

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