Is PTEN p.Ile4Val (c.10A>G) pathogenic?

PTEN p.Ile4Val (c.10A>G) is classified Uncertain significance in PTEN (ClinVar, Expert panel, 5 submitters; last evaluated 2023-08-04). AlphaMissense: likely benign (0.0676); Absent from gnomAD v4.1; Associated with PTEN hamartoma tumor syndrome.

What condition is associated with PTEN p.Ile4Val (c.10A>G)?

PTEN p.Ile4Val (c.10A>G) is associated with PTEN hamartoma tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is PTEN p.Ile4Val (c.10A>G) in the general population?

PTEN p.Ile4Val (c.10A>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.Ile4Val (c.10A>G)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

PTEN p.Ile4Val

c.10A>G · rs1647701808 · VCV1704153

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0676 · 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

ClinGen expert panel — PTEN VCEP

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

PM2_Supporting PS2 PP2 BP4 BS3_Supporting

Curation rationale (ClinGen, verbatim)

NM_000314.8(PTEN):c.10A>G (p.Ile4Val) is currently classified as a variant of uncertain significance 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history (SCV002569820.2). PM2_Supporting: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. BS3_Supporting: Well-established functional studies show no deleterious effect: Phosphatase activity ≤ -1.11 (score = 1.00) per Mighell et al. 2018 (PMID: 29706350). BP4: REVEL score < 0.5 (score=0.294) Using the Bayesian point system (PMID: 29300386) for this variant with conflicting evidence: 1 pathogenic strong, 2 pathogenic supporting and 2 benign supporting codes get 4 + (1*2) +(- 1*2) points = total is 4 (VUS).

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

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -6.72	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 1.6, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	21.9	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.Ile4Val
Coding: c.10A>G
MANE Select: NM_000314
dbSNP: rs1647701808
Type: single nucleotide variant
Location: chr10:87864479 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB

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.Ile4Thr Uncertain significance ★★ ⚠ same residue
PTEN p.Ile4= Likely benign ★★ same residue
PTEN p.Ile4Ser Uncertain significance ★ same residue
PTEN p.Ile4fs Pathogenic ★ 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
PTEN c.165-1G>A 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-ile4val (accessed [today's date]).

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