Is PTEN p.His93Pro (c.278A>C) pathogenic?

PTEN p.His93Pro (c.278A>C) is classified Likely pathogenic in PTEN (ClinVar, Expert panel, 3 submitters; last evaluated 2024-02-09). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.His93Pro (c.278A>C)?

PTEN p.His93Pro (c.278A>C) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.His93Pro (c.278A>C) in the general population?

PTEN p.His93Pro (c.278A>C) 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.

What do computational predictors say about PTEN p.His93Pro (c.278A>C)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

PTEN p.His93Pro

c.278A>C · rs121909238 · VCV468680

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

PM2_Supporting PS3_Moderate PM1 PP2 PP3 PM5

Curation rationale (ClinGen, verbatim)

NM_000314.8(PTEN):c.278A>C (p.His93Pro) variant meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_Moderate: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.95 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7848, SCV000886857.1). PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP3: REVEL score > 0.7 (score of this variant =0.974).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.974	strongly pathogenic-leaning
SaProt	LLR -15.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

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.His93Pro
Coding: c.278A>C
MANE Select: NM_000314
dbSNP: rs121909238
Type: single nucleotide variant
Location: chr10:87933037 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 93: the phosphatase tensin-type domain; a UniProt-annotated variant site (in mcephas); a UniProt-annotated variant site (in cws1)

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: 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.His93Arg Pathogenic ★★★ same residue
PTEN p.His93Tyr Pathogenic/Likely pathogenic ★★ same residue
PTEN p.His93= Benign/Likely benign ★★ same residue
PTEN p.His93Asp Likely pathogenic ★ same residue
PTEN p.His93Leu Uncertain significance ★ ⚠ same residue
PTEN p.His93fs Pathogenic ★ same residue
PTEN p.His93Asn Likely pathogenic ★★ same residue
PTEN p.His93Gln Likely pathogenic ★ 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-his93pro (accessed [today's date]).

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