Is PTPN1 p.Pro89Ser (c.265C>T) pathogenic?

PTPN1 p.Pro89Ser (c.265C>T) is classified Uncertain significance in PTPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.353); Very rare (popmax 8.48e-05%, nfe).

How common is PTPN1 p.Pro89Ser (c.265C>T) in the general population?

PTPN1 p.Pro89Ser (c.265C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PTPN1 p.Pro89Ser (c.265C>T)?

AlphaMissense predicts ambiguous (score 0.353) — an in-silico prediction, not a clinical call.

PTPN1 p.Pro89Ser

c.265C>T · VCV3940380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.353 · ACMG-weighted

gnomAD v4.1

Rare

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

Computational evidence

Protein change
AlphaMissense	0.353	ambiguous
REVEL	0.577	indeterminate
SaProt	LLR -11.29	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 69 kb · p 5.6e-16 · regional, not allelic
Overall
CADD	26.8	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) · 1/1,179,898 alleles

Overall 6.2e-05% 1/1,613,978 alleles · very rare exomes 1/1,461,710 · genomes 0/152,268 · 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: PTPN1
Protein: p.Pro89Ser
Coding: c.265C>T
MANE Select: NM_002827
Type: single nucleotide variant
Location: chr20:50568389 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.70 · 433 PDB
Residue 89: the tyrosine-protein phosphatase domain; a turn

Full PTPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PTPN1 p.Cys414= Benign ★★ same type
PTPN1 p.Thr164= Benign ★★ same type
PTPN1 p.Gly209Arg Pathogenic ★ same type
PTPN1 p.Ala189Gly Uncertain significance ★ ⚠ same type
PTPN1 p.Ala416Thr Uncertain significance ★ ⚠ same type
PTPN1 p.Arg238Lys Uncertain significance ★ ⚠ same type
PTPN1 p.Arg380Gly Uncertain significance ★ ⚠ same type
PTPN1 p.Asp265His Uncertain significance ★ ⚠ same type

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/ptpn1-p-pro89ser (accessed [today's date]).

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