Is PTEN p.His123= (c.369C>T) pathogenic?

PTEN p.His123= (c.369C>T) is classified Conflicting classifications of pathogenicity in PTEN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with PTEN p.His123= (c.369C>T)?

PTEN p.His123= (c.369C>T) is associated with hereditary neoplastic syndrome, Cowden syndrome 1, PTEN hamartoma tumor syndrome (ClinVar).

How common is PTEN p.His123= (c.369C>T) in the general population?

PTEN p.His123= (c.369C>T) is absent from gnomAD v4.1 (gnomAD).

PTEN p.His123=

c.369C>T · rs1085308045 · VCV515681

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

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 3.1	GERP 2.4, phastCons 1
Overall
CADD	12.47	PHRED · no single calibrated threshold — expert panels disagree

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.His123=
Coding: c.369C>T
MANE Select: NM_000314
dbSNP: rs1085308045
Type: single nucleotide variant
Location: chr10:87933128 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 123: a β-strand; the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1); a UniProt-annotated variant site (in endometrial cancer; loss of protein phosphatase activity)

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.His123Arg Pathogenic ★★★ same residue
PTEN p.His123Asp Pathogenic ★★★ same residue
PTEN p.His123Gln Pathogenic/Likely pathogenic ★★ same residue
PTEN p.His123Tyr Pathogenic/Likely pathogenic ★★ same residue
PTEN p.His123Leu Likely pathogenic ★ same residue
PTEN p.His123fs Pathogenic ★ same residue
PTEN p.His123Asn Likely pathogenic ★ same residue
PTEN p.His123Pro Uncertain significance ⚠ same residue

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-his123 (accessed [today's date]).

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