Is PTPRO p.Ile365Phe (c.1093A>T) pathogenic?

PTPRO p.Ile365Phe (c.1093A>T) is classified Uncertain significance in PTPRO (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.2027); Very rare (popmax 0.00167%, amr); Associated with PTPRO-related disorder.

What condition is associated with PTPRO p.Ile365Phe (c.1093A>T)?

PTPRO p.Ile365Phe (c.1093A>T) is associated with PTPRO-related disorder (ClinVar).

How common is PTPRO p.Ile365Phe (c.1093A>T) in the general population?

PTPRO p.Ile365Phe (c.1093A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PTPRO p.Ile365Phe (c.1093A>T)?

AlphaMissense predicts likely benign (score 0.2027) — an in-silico prediction, not a clinical call.

PTPRO p.Ile365Phe

c.1093A>T · rs772562526 · VCV3047187

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTPRO-related disorder

Computational evidence

Protein change
AlphaMissense	0.2027	likely benign
REVEL	0.128	moderately benign-leaning
SaProt	LLR -6.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP -2.9, phastCons 0.01
Regional constraint	o/e 0.93	unconstrained · MANE · 258 kb · p 0.015 · regional, not allelic
Overall
CADD	22.5	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

Grpmax group 0.00167% Admixed American · 1/60,026 alleles

Overall 6.21e-05% 1/1,610,774 alleles · very rare exomes 1/1,458,442 · genomes 0/152,332 · 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: PTPRO
Protein: p.Ile365Phe
Coding: c.1093A>T
MANE Select: NM_030667
dbSNP: rs772562526
Type: single nucleotide variant
Location: chr12:15502051 (GRCh38)
Gene constraint: LOEUF 0.513 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 77.55 · 2 PDB
Residue 365: the fibronectin type-iii 4 domain

Full PTPRO gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PTPRO-related disorder

Similar variants

PTPRO c.76-67403G>A Uncertain significance ★ same condition
PTPRO p.Ala731Thr Uncertain significance ⚠ same condition
PTPRO c.1891+6G>T Likely benign same condition
PTPRO c.1891+8A>T Likely benign same condition
PTPRO c.2438-10A>C Likely benign same condition
PTPRO c.2748-10T>C Likely benign same condition
PTPRO c.3255+7C>T Likely benign same condition
PTPRO c.3546+9A>G Likely benign 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/ptpro-p-ile365phe (accessed [today's date]).

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