Is PTEN p.Pro38= (c.114T>G) pathogenic?

PTEN p.Pro38= (c.114T>G) is classified Likely benign in PTEN (ClinVar, Expert panel, 12 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0165%, mid); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Pro38= (c.114T>G)?

PTEN p.Pro38= (c.114T>G) is associated with PTEN hamartoma tumor syndrome, breast cancer, Cowden syndrome 1 (ClinVar).

How common is PTEN p.Pro38= (c.114T>G) in the general population?

PTEN p.Pro38= (c.114T>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is PTEN hamartoma tumor syndrome inherited?

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

PTEN p.Pro38=

c.114T>G · rs748040144 · VCV184068

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

PM2_Supporting BS3 BP7

Curation rationale (ClinGen, verbatim)

PTEN c.114T>G (p.Pro38=) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS3: Intronic OR synonymous variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (internal laboratory contributor Accession: SCV000213708.7) BP7: Variant is synonymous (silent) OR intronic and at or beyond +7/-21 and no splicing impact is predicted.

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/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.6	GERP 1.5, phastCons 1
Overall
CADD	18.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,068 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,612,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,068
Admixed American	0.00167%	59,968
European (non-Finnish)	0.000509%	196,540

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.Pro38=
Coding: c.114T>G
MANE Select: NM_000314
dbSNP: rs748040144
Type: single nucleotide variant
Location: chr10:87894059 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 38: the phosphatase tensin-type domain

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: breast cancer 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.Pro38His Likely pathogenic ★★★ same residue
PTEN p.Pro38Leu Pathogenic ★★★ same residue
PTEN p.Pro38Ser Uncertain significance ★★★ ⚠ same residue
PTEN p.Pro38Thr Likely pathogenic ★★ same residue
PTEN p.Pro38fs Pathogenic ★ same residue
PTEN p.Pro38Phe Likely pathogenic ★ same residue
PTEN p.Pro38Arg Pathogenic ★ same residue
PTEN c.1026+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-pro38 (accessed [today's date]).

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