PTPN11

Chr 12AD

protein tyrosine phosphatase non-receptor type 11

Also known as: BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2

NCBI Gene: 5781 ENSG00000179295 UniProt: Q06124 OMIM: 176876

The protein is a tyrosine phosphatase that regulates cellular signaling pathways controlling cell growth, differentiation, and migration through its two Src homology-2 domains that bind phospho-tyrosine substrates. Mutations cause Noonan syndrome, LEOPARD syndrome, metachondromatosis, and juvenile myelomonocytic leukemia through autosomal dominant inheritance. The pathogenic mechanism involves disrupted cellular signaling due to altered phosphatase activity affecting multiple developmental and metabolic pathways.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

GOFmechanismADLOEUF 0.144 OMIM phenotypes

VCEP Guidelines: RASopathyReleased

View Specifications ClinGen Panel

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

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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

25 unique Pathogenic / Likely Pathogenic· 181 VUS of 400 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PTPN11

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

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

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

LoF OE0.03 (0.01–0.14)

0≤0.351.4

Missense OE0.52 (0.46–0.59)

0≤0.61.4

Synonymous OE0.91

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePTPN11-related Noonan syndrome with multiple lentiginesOTHERAD

definitivePTPN11-related Noonan syndromeGOFAD

0.4785th %ile

GOF

0.6541th %ile

LOF

0.60top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 36% of P/LP variants are LoF · LOEUF 0.14

GOFprediction above median · 1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNPTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effectsPMID:16377799

GOFThe association of this p.G60A PTPN11 mutation with neuroblastoma provides new evidence that gain of function PTPN11 mutations may play an important role in the pathogenesis of solid tumors associated with Noonan syndrome.PMID:18328949

LOFConstitutive deregulation of the Ras pathway either through activating mutations of PTPN11 or through haploinsufficiency of neurofibromin, which acts as a Ras-inactivating GTP-ase, is probably the common pathogenetic mechanism explaining the phenotypic overlap of NS and NF1. (c) 2006 Wiley-Liss, IncPMID:17103458

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic15

VUS181

Likely Benign170

Conflicting1

Pathogenic

Likely Pathogenic

181

VUS

170

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	3	2	0	10
Likely Pathogenic	4	11	0	0	15
VUS	1	161	16	3	181
Likely Benign	0	4	54	112	170
Benign	0	0	0	0	0
Conflicting	—				1
Total	10	179	72	115	377

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.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — PTPN11

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING

NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21

NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies

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®

RASopathy

Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)

RECRUITING

NCT06489067University of Bari Aldo MoroStarted 2024-01-15

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

FludarabineBusulfanMelphalan