Is PTEN p.His61Arg (c.182A>G) pathogenic?

PTEN p.His61Arg (c.182A>G) is classified Likely pathogenic in PTEN (ClinVar, Expert panel, 7 submitters; last evaluated 2023-12-01). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.His61Arg (c.182A>G)?

PTEN p.His61Arg (c.182A>G) is associated with PTEN hamartoma tumor syndrome, Cowden syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.His61Arg (c.182A>G) in the general population?

PTEN p.His61Arg (c.182A>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.His61Arg (c.182A>G)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

PTEN p.His61Arg

c.182A>G · rs398123316 · VCV189402

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9987 · 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 PS4_Supporting PS3_Moderate PP2 PP3

Curation rationale (ClinGen, verbatim)

PTEN c.182A>G (p.His61Arg) meets criteria to be classified as likely 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). PS3_M: Massively parallel functional assay interrogating phosphatase activity demonstrating a statistically significant difference from wild type (PMID: 29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID: 28526761). PM2_P: 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 = 0.981.

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

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic ✓ concordant with ClinVar
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -15.71	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 2.8, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	28.3	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.His61Arg
Coding: c.182A>G
MANE Select: NM_000314
dbSNP: rs398123316
Type: single nucleotide variant
Location: chr10:87925530 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 61: a β-strand; the phosphatase tensin-type domain; a UniProt-annotated variant site (found in a patient with congenital cardiac disease, macrocephaly, ventriculomegaly, skeletal defects, anal atresia, tracheoesophageal fistula, renal anomalies; likely pathogenic); a UniProt-annotated variant site (in cws1; loss of phosphatase activity towards ins(1,3,4,5)p4)

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 ovarian neoplasm

For PTEN hamartoma tumor syndrome (Orphanet):

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

Similar variants

PTEN p.His61Asp Likely pathogenic ★★★ same residue
PTEN p.His61= Benign/Likely benign ★★ same residue
PTEN p.His61Pro Likely pathogenic ★ same residue
PTEN p.His61Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.His61Gln Uncertain significance ★ ⚠ same residue
PTEN p.His61Tyr Likely pathogenic ★ same residue
PTEN c.1026+1G>A Pathogenic ★★★ same condition
PTEN c.1027-1852A>G Likely 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-his61arg (accessed [today's date]).

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