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: 5781 ENSG00000179295 UniProt: Q06124

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 ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtLEOPARD syndrome 1

UniProtNoonan syndrome 1

UniProtLeukemia, juvenile myelomonocytic

UniProtMetachondromatosis

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · Noonan syndrome · AD · ClinGen 2018
Definitive · Noonan syndrome with multiple lentigines · AD · ClinGen 2018
Definitive · Noonan syndrome 1 · AD · Ambry Genetics
Definitive · LEOPARD syndrome 1 · AD · G2P
Disputed · Costello syndrome · AD · ClinGen 2018 — evidence questions this relationship
Disputed · cardiofaciocutaneous syndrome · AD · ClinGen 2018 — evidence questions this relationship

+1 more curated pair

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

269

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.14

LOEUF· LoF intol.

GOF*

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in PTPN11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

465 rare PASS variants

Rare truncating (LoF)

1 in 1,100

21 rare PASS variants

Rare synonymous (reference)

1 in 170

253 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PTPN11. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 210	1 in 6,700
South Asian	~43k	1 in 140	1 in 960
Remaining (unassigned)	~30k	1 in 85	none seen
European (Finnish)	~27k	1 in 920	1 in 1,000
Admixed American	~22k	1 in 110	none seen
African / African American	~21k	1 in 170	≈ 1 in 9,200
East Asian	~20k	1 in 160	none seen
Ashkenazi Jewish	~13k	1 in 1,100	1 in 1,700
Middle Eastern	~2,884	1 in 180	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓