Is PTEN p.His75Arg (c.224A>G) pathogenic?

PTEN p.His75Arg (c.224A>G) is classified Uncertain significance in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-13). AlphaMissense: likely benign (0.1814); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.His75Arg (c.224A>G)?

PTEN p.His75Arg (c.224A>G) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.His75Arg (c.224A>G) in the general population?

PTEN p.His75Arg (c.224A>G) 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.His75Arg (c.224A>G)?

AlphaMissense predicts likely benign (score 0.1814) — an in-silico prediction, not a clinical call.

PTEN p.His75Arg

c.224A>G · rs2493711896 · VCV1788388

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1814 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

PTEN hamartoma tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.1814	likely benign
REVEL	0.589	indeterminate
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.His75Arg
Coding: c.224A>G
MANE Select: NM_000314
dbSNP: rs2493711896
Type: single nucleotide variant
Location: chr10:87931060 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 75: the phosphatase 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

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.His75Leu Uncertain significance ★ ⚠ same residue
PTEN p.His75Tyr Uncertain significance ★ ⚠ same residue
PTEN p.His75_Tyr76insTer Pathogenic/Likely pathogenic ★★ same residue
PTEN p.His75fs Pathogenic ★ same residue
PTEN p.His75Pro 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-his75arg (accessed [today's date]).

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