PTPN11

Chr 12

protein tyrosine phosphatase non-receptor type 11

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

NCBI Gene: 5781ENSG00000179295UniProt: Q06124

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

GeneReviewsResearchGenerating clinical summary…
GOFmechanismLOEUF 0.14
VCEP Guidelines: RASopathyReleased
View SpecificationsClinGen 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
200 unique Pathogenic / Likely Pathogenic· 527 VUS of 1343 total submissions
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Clinical Trials
5 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 ↗
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?
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 OE?0.03 (0.01–0.14)
0≤0.351.4
Missense OE?0.52 (0.46–0.59)
0≤0.61.4
Synonymous OE?0.91
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

This gene — mechanism propensity

DN
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 · 24% of P/LP variants are LoF · LOEUF 0.14 · ClinGen HI: Sufficient evidence for dosage pathogenicity
GOFprediction above median · 1 literature citation · 72% of P/LP are missense
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, effects1
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.2
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, Inc3

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

References

  1. 1.PMID 16377799 ↗
  2. 2.PMID 18328949 ↗
  3. 3.PMID 17103458 ↗

ClinVar Variant Classifications

1343 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic105
Likely Pathogenic95
VUS527
Likely Benign460
Benign62
Conflicting70
105
Pathogenic
95
Likely Pathogenic
527
VUS
460
Likely Benign
62
Benign
70
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
33
66
6
0
105
Likely Pathogenic
14
78
2
1
95
VUS
4
433
85
5
527
Likely Benign
0
8
176
276
460
Benign
0
5
52
5
62
Conflicting
—70
Total515903212871,319

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap PTPN11 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

PTPN11 · protein map & ClinVar variants

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

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