NTRK3

Chr 15

neurotrophic receptor tyrosine kinase 3

Also known as: GP145-TrkC, TRKC, gp145(trkC)

NCBI Gene: 4916 ENSG00000140538 UniProt: Q16288 OMIM: 191316

The protein is a receptor tyrosine kinase that binds neurotrophin-3 and activates signaling pathways controlling cell survival and differentiation in nervous system and heart development. Mutations cause neurodevelopmental disorders with intellectual disability and may be associated with certain cancers including medulloblastomas. This gene is highly constrained against loss-of-function mutations (pLI 0.998), indicating that complete loss of function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Disputed · congenital heart disease · AD · ClinGen 2024

evidence questions this relationship

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

192

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.26

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.26LOEUF

pLI 0.998

Z-score 5.18

OE 0.12 (0.06–0.26)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.83Z-score

OE missense 0.77 (0.70–0.83)

375 obs / 489.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.26)

0≤0.351.4

Missense OE?0.77 (0.70–0.83)

0≤0.61.4

Synonymous OE?1.20

0≤1.21.6

LoF obs/exp: 5 / 40.7Missense obs/exp: 375 / 489.2Syn Z: -2.15

Background carrier burden — how many people carry a rare variant somewhere in NTRK3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 52

1,177 rare PASS variants

Rare truncating (LoF)

1 in 2,300

69 rare PASS variants

Rare synonymous (reference)

1 in 68

570 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NTRK3. 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 62	1 in 3,200
South Asian	~43k	1 in 51	1 in 1,500
Remaining (unassigned)	~30k	1 in 63	1 in 1,000
European (Finnish)	~27k	1 in 200	1 in 2,100
Admixed American	~22k	1 in 84	1 in 3,300
African / African American	~21k	1 in 45	1 in 2,500
East Asian	~20k	1 in 63	1 in 970
Ashkenazi Jewish	~13k	1 in 190	none seen
Middle Eastern	~2,884	1 in 73	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): 14 of 18 coding exons well covered in gnomAD exomes; exon 18 poorly covered; exons 6, 11, 13 marginal. Genomes: 16 of 18 (exons 3, 14 below).? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NTRK3 · 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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Solid TumorsCNS Tumors

Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

ACTIVE NOT RECRUITING

NCT02650401Phase PHASE1, PHASE2Hoffmann-La RocheStarted 2016-05-03

Entrectinib

Oncogene-addicted Non Small Cell Lung CancerEGFR MutationALK Fusion-positive Solid or CNS Tumors

Integrated Genomics in Oncogene-driven NSCLC With Acquired Resistance

ENROLLING BY INVITATION

NCT07122882Chang Gung Memorial HospitalStarted 2025-09-01

Breast CancerCholangiocarcinomaColorectal Cancer

Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions)

ACTIVE NOT RECRUITING

NCT02568267Phase PHASE2Hoffmann-La RocheStarted 2015-11-19

Entrectinib

Solid Tumors Harboring NTRK Fusion

A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children

ACTIVE NOT RECRUITING

NCT02637687Phase PHASE1, PHASE2BayerStarted 2015-12-16

Larotrectinib (Vitrakvi, BAY2757556)

Clinical Literature

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Landmark / reviewRecent case evidence

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