PTPN11

Chr 12

protein tyrosine phosphatase non-receptor type 11

NCBI Gene: 5781 ENSG00000179295 UniProt: Q06124

Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus (PubMed:10655584, PubMed:14739280, PubMed:18559669, PubMed:18829466, PubMed:26742426, PubMed:28074573, PubMed:32184441). Positively regulates MAPK signal transduction pathway (PubMed:28074573). Dephosphorylates GAB1, ARHGAP35 and EGFR (PubMed:28074573). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulation of its RhoA binding activity (PubMed:18559669). Dephosphorylates CDC73 (PubMed:26742426). Dephosphorylates SOX9 on tyrosine residues, leading to inactivate SOX9 and promote ossification (By similarity). Dephosphorylates tyrosine-phosphorylated NEDD9/CAS-L (PubMed:19275884). Acts as an effector of PDCD1-mediated inhibition of T-cell response: recruited by phosphorylated PDCD1, mediating dephosphorylation of key T-cell receptor (TCR) proximal signaling molecules, leading to TCR signaling inhibition (PubMed:32184441)

Primary Disease Associations & Inheritance

UniProtLEOPARD syndrome 1

UniProtNoonan syndrome 1

UniProtLeukemia, juvenile myelomonocytic

UniProtMetachondromatosis

576

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— PTPN11

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Gene-Disease Validity (ClinGen)

Noonan syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

36 Pathogenic / Likely Pathogenic· 263 VUS of 576 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.14LOEUF

pLI 1.000

Z-score 5.34

OE 0.03 (0.01–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

3.13Z-score

OE missense 0.52 (0.46–0.59)

171 obs / 331.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.14)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.46–0.59)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.91

0≤1.21.6

LoF obs/exp: 1 / 35.2Missense obs/exp: 171 / 331.3Syn Z: 0.82

ClinVar Variant Classifications

576 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19

Likely Pathogenic17

VUS263

Likely Benign235

Benign22

Conflicting20

Pathogenic

Likely Pathogenic

263

VUS

235

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	4	9	0	19
Likely Pathogenic	2	9	6	0	17
VUS	2	225	34	2	263
Likely Benign	0	1	85	149	235
Benign	0	0	20	2	22
Conflicting	—				20
Total	10	239	154	153	576

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PTPN11 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PTPN11-related Noonan syndrome with multiple lentigines

definitive

ADUndeterminedAltered Gene Product Structure

Dev. DisordersSkinCardiac

G2P ↗

missense variantinframe deletioninframe insertion

PTPN11-related Noonan syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkinCardiac

G2P ↗

missense variantinframe deletion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

External Resources

Links to major genomics databases and tools

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GeneReview available — PTPN11

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Literature

Landmark / reviewRecent case evidence

Key Publications

Landmark & review papers · by relevance

PubMed

Pathogenic Germline Variants in 10,389 Adult Cancers.

Huang KL et al.·Cell

2018

Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.

Zhao J et al.·Nat Med

2019

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment.

Linglart L et al.·Am J Med Genet C Semin Med Genet

2020Review

Non-coding recurrent mutations in chronic lymphocytic leukaemia.

Puente XS et al.·Nature

2015

The genetic landscape of high-risk neuroblastoma.

Pugh TJ et al.·Nat Genet

2013

Molecular diagnose of a large hearing loss population from China by targeted genome sequencing.

Wu J et al.·J Hum Genet

2022

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations.

Athota JP et al.·BMC Med Genet

2020

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Tartaglia M et al.·Am J Hum Genet

2002

Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.

Zhu G et al.·Cell

2020

Germline and somatic genetic landscape of pediatric myelodysplastic syndromes.

Kotmayer L et al.·Haematologica

2025Review

Top 10 resultsSearch PubMed ↗

Recent Gene-Specific Literature

Gene in title · MEDLINE · newest first

Europe PMC

Clinical phenotypes and cochlear implant outcomes in patients with PTPN11-associated noonan spectrum disorders: Insights from a genetically screened cohort.

Chen Z et al.·Eur Arch Otorhinolaryngol

2026Cohort

Characterization of the clonal hierarchy and immunophenotype of PTPN11 mutations in acute myeloid leukemia.

Fobare S et al.·JCI Insight

2026🔓 Open Access

Targeting MCL-1 and MAPK overcomes venetoclax resistance in FLT3-ITD-positive AML cells harbouring activating PTPN11 (SHP-2) mutations.

Fleischmann M et al.·Br J Haematol

2026

Investigating the prognostic potential of PTPN11 gene in papillary thyroid carcinoma: A comprehensive study of bulk and single cell transcriptome.

Wang H et al.·Medicine (Baltimore)

2025🔓 Open Access

Clinical and Genetic Characterization of Noonan Syndrome in a Romanian Cohort from Transylvania: Details on PTPN11 c.922A>G Variant and Phenotypic Spectrum.

Nazarie FV et al.·Diagnostics (Basel)

2025🔓 Open AccessCohort

Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Chronic Myeloid Leukemia, Chronic PhaseWithdrawal;Drug

Efficacy and Safety of TKIs' Withdrawal After a Two-step Dose Reduction in Patients with Chronic Myeloid Leukemia

ACTIVE NOT RECRUITING

NCT04147533Phase PHASE2Masaryk UniversityStarted 2020-06-16

Imatinib withdrawalDasatinibNilotinib

IGF1 Deficiency

Global Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).

RECRUITING

NCT00903110Esteve Pharmaceuticals, S.A.Started 2008-12-09

Increlex®

Acute Myeloid Leukemia

Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML

RECRUITING

NCT06514261Phase PHASE1National Cancer Institute (NCI)Started 2024-12-18

AzacitidineBiospecimen CollectionBiospecimen Collection

Hematologic MalignancyAcute LeukemiaRemission

MT2021-08T Cell Receptor Alpha/Beta Depletion PBSC Transplantation for Heme Malignancies

RECRUITING

NCT05735717Phase PHASE2Masonic Cancer Center, University of MinnesotaStarted 2023-05-11