Is PTEN p.Asp24His (c.70G>C) pathogenic?

PTEN p.Asp24His (c.70G>C) is classified Pathogenic in PTEN (ClinVar, Expert panel, 10 submitters; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.9999); Very rare (popmax 8.48e-05%, nfe); Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Asp24His (c.70G>C)?

PTEN p.Asp24His (c.70G>C) is associated with PTEN hamartoma tumor syndrome, Cowden syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Asp24His (c.70G>C) in the general population?

PTEN p.Asp24His (c.70G>C) is very rare (popmax 8.48e-05%, nfe) (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.Asp24His (c.70G>C)?

AlphaMissense predicts likely pathogenic (score 0.9999) — an in-silico prediction, not a clinical call.

PTEN p.Asp24His

c.70G>C · rs786201995 · VCV186005

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN hamartoma tumor syndrome

ClinGen expert panel — PTEN VCEP

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

PM6 PM2_Supporting PS4_Supporting PS3_Moderate PS2 PP2 PP3

Curation rationale (ClinGen, verbatim)

PTEN c.70G>C (p.Asp24His) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor(s) SCV005686053.1). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 34374989). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -3.602 (≤ -1.11) on a high throughput phosphatase assay (PMID 29706350). PP3: REVEL score > 0.7 (score of this variant = 0.98). 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID 23764071). PM2_P: Absent in large sequenced populations (PMID 27535533).

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

Computational evidence

Protein change
AlphaMissense	0.9999	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -11.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, 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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,890 alleles

Overall 6.2e-05% 1/1,614,040 alleles · very rare exomes 1/1,461,686 · genomes 0/152,354 · joint denominator

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.Asp24His
Coding: c.70G>C
MANE Select: NM_000314
dbSNP: rs786201995
Type: single nucleotide variant
Location: chr10:87864539 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 24: a β-strand; 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: Cowden syndrome 1 hereditary neoplastic syndrome glioma ovarian neoplasm

For PTEN hamartoma tumor syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

PTEN p.Asp24Asn Pathogenic ★★★ same residue
PTEN p.Asp24Gly Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Asp24Tyr Pathogenic ★★ same residue
PTEN p.Asp24Val Pathogenic/Likely pathogenic ★★ same residue
PTEN p.Asp24= Benign/Likely benign ★★ same residue
PTEN p.Asp24Ala Uncertain significance ★ ⚠ same residue
PTEN p.Asp24Glu Uncertain significance ★ ⚠ same residue
PTEN p.Asp24_Leu25insTer 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-asp24his (accessed [today's date]).

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