NTRK1

Chr 1AR

neurotrophic receptor tyrosine kinase 1

Also known as: MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA

NCBI Gene: 4914 ENSG00000198400 UniProt: P04629 OMIM: 191315

The protein is a receptor tyrosine kinase that binds nerve growth factor (NGF) and regulates the development, differentiation, and survival of sympathetic and sensory neurons through multiple signaling pathways including MAPK and PI3K-AKT cascades. Mutations cause congenital insensitivity to pain with anhidrosis, a severe autosomal recessive disorder characterized by inability to feel pain, absent sweating, self-injurious behavior, and cognitive disability that manifests from birth. The gene is extremely intolerant to loss-of-function variants (pLI near 1.0), indicating that biallelic mutations are required for disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Insensitivity to pain, congenital, with anhidrosisMIM #256800

UniProtCongenital insensitivity to pain with anhidrosis

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary sensory and autonomic neuropathy type 4 · AR · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

240

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.66

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — NTRK1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 3.19

OE 0.43 (0.29–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.03Z-score

OE missense 0.87 (0.80–0.94)

419 obs / 482.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.29–0.66)

0≤0.351.4

Missense OE?0.87 (0.80–0.94)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 16 / 37.0Missense obs/exp: 419 / 482.6Syn Z: 0.04

Background carrier burden — how many people carry a rare variant somewhere in NTRK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

1,085 rare PASS variants

Rare truncating (LoF)

1 in 1,000

157 rare PASS variants

Rare synonymous (reference)

1 in 71

521 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NTRK1. 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 58	1 in 1,800
South Asian	~43k	1 in 40	1 in 680
Remaining (unassigned)	~30k	1 in 32	1 in 680
European (Finnish)	~27k	1 in 97	1 in 2,300
Admixed American	~22k	1 in 36	1 in 1,200
African / African American	~21k	1 in 42	1 in 1,500
East Asian	~20k	1 in 38	1 in 440
Ashkenazi Jewish	~13k	1 in 110	none seen
Middle Eastern	~2,884	1 in 29	≈ 1 in 1,400

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 17 coding exons well covered in gnomAD exomes and genomes.? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NTRK1 · 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

📖

GeneReview available — NTRK1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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)

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

NTRK1/2/3 Fusion Gene Detection

NTRK 1,2,3 Rearrangements in Patients With Solid Tumors

ACTIVE NOT RECRUITING

NCT06780384Federico CappuzzoStarted 2020-02-05

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

High Grade GliomaCNS Tumor

Entrectinib as a Single Agent in Upfront Therapy for Children <3 Years of Age With NTRK1/2/3 or ROS1-FUSED CNS Tumors

RECRUITING

NCT06528691Phase PHASE2St. Jude Children's Research HospitalStarted 2026-05-01

EntrectinibCyclophosphamideEtoposide

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

Locally Advanced Solid TumorsMetastatic Solid Tumors

A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements

RECRUITING

NCT03093116Phase PHASE1, PHASE2Turning Point Therapeutics, Inc.Started 2017-03-07

Oral repotrectinib (TPX-0005)

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

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