NF1

Chr 17ADSomatic

neurofibromin 1

Also known as: NFNS, VRNF, WSS

NCBI Gene: 4763ENSG00000196712UniProt: P21359

This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Leukemia, juvenile myelomonocyticMIM #607785
ADSomatic
Neurofibromatosis-Noonan syndromeMIM #601321
AD
Neurofibromatosis, familial spinalMIM #162210
AD
Neurofibromatosis, type 1MIM #162200
AD
Watson syndromeMIM #193520
AD
Neurofibromatosis, type 1MIM #162200
AD
UniProtNeurofibromatosis 1
UniProtFamilial spinal neurofibromatosis
UniProtColorectal cancer
17416
ClinVar variants
0
Pathogenic / LP
0.90
pLI score· haploinsufficient
12
Active trials
Clinical Summary— NF1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
17416 total variants — no pathogenic classifications of 17416 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.29LOEUF
pLI 0.902
Z-score 8.73
OE 0.22 (0.16–0.29)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
6.54Z-score
OE missense 0.52 (0.49–0.55)
771 obs / 1479.1 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.22 (0.16–0.29)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.49–0.55)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 31 / 144.2Missense obs/exp: 771 / 1479.1Syn Z: 1.12

ClinVar Variant Classifications

17416 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

NF1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NF1-related neurofibromatosis

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkinCancerSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM
NEUROFIBROMIN 1; NF1
MIM #613113 · *

Leukemia, juvenile myelomonocytic

MIM #607785

Molecular basis of disorder known

Autosomal dominantSomatic mutation

Neurofibromatosis-Noonan syndrome

MIM #601321

Molecular basis of disorder known

Autosomal dominant

Neurofibromatosis, familial spinal

MIM #162210

Molecular basis of disorder known

Autosomal dominant

Neurofibromatosis, type 1

MIM #162200

Molecular basis of disorder known

Autosomal dominant

Watson syndrome

MIM #193520

Molecular basis of disorder known

Autosomal dominant

Neurofibromatosis, type 1

MIM #162200

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Pathogenic Germline Variants in 10,389 Adult Cancers.
Huang KL et al.·Cell
2018
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.
Sabbagh A et al.·Hum Mutat
2013
Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.
Giugliano T et al.·Genes (Basel)
2019
A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands.
van Minkelen R et al.·Clin Genet
2014Review
Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children.
Yao R et al.·Genes (Basel)
2019
Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I.
Riva M et al.·Genes Chromosomes Cancer
2022Cohort
Neurofibromatosis.
Korf BR·Handb Clin Neurol
2013Review
LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis.
Farncombe KM et al.·BMC Med Genomics
2022Review
Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants.
Kehrer-Sawatzki H et al.·Hum Genet
2022Review
Analysis of 200 unrelated individuals with a constitutional NF1 deep intronic pathogenic variant reveals that variants flanking the alternatively spliced NF1 exon 31 [23a] cause a classical neurofibromatosis type 1 phenotype while altering predominantly NF1 isoform type II.
Koczkowska M et al.·Hum Genet
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Personalized pharmacokinetic-pharmacodynamic guided therapy via an induced pluripotent stem cell-derived multi-organoid platform in NF1-mutant breast cancer.
Lim JH et al.·Signal Transduct Target Ther
2026🔓 Open Access
Differential Preclinical Efficacy of Combined CDK4/6 and MEK Inhibition in Low-Grade Serous Ovarian Carcinoma Based on KRAS/NF1 Mutational Status.
Bittner M et al.·Int J Mol Sci
2026
Proof-of-principle of NF1 gene therapy in plexiform neurofibroma xenograft mouse models.
Hewa Bostanthirige D et al.·Commun Biol
2026Functional
Phenotypic Spectrum of Neurofibromatosis Type 1 Patients in India and Low Prevalence of Microdeletions in NF1 Gene.
Kaur R et al.·Am J Med Genet A
2026Cohort
Report of Concomitant Intracranial Cysts in Unrelated Patients With Heterozygous Germline NF1 Pathogenic Variants.
Harahsheh EY et al.·Ann Intern Med Clin Cases
2026🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Invasive PreNatal Diagnosis in a Context of Family History of Single-gene Disorders, IncludingSickle Cell DiseaseCystic Fibrosis

Development of Non-Invasive Prenatal Diagnosis for Single Gene Disorders

RECRUITING
NCT06147414Assistance Publique - Hôpitaux de ParisStarted 2024-10-23
Blood sample
Fallopian Tube Endometrioid AdenocarcinomaFallopian Tube High Grade Serous AdenocarcinomaOvarian Endometrioid Adenocarcinoma

Testing the Addition of Ipatasertib to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) for Stage III or IV Epithelial Ovarian Cancer

ACTIVE NOT RECRUITING
NCT05276973Phase PHASE1National Cancer Institute (NCI)Started 2022-09-08
BiopsyCarboplatinIpatasertib
Costello SyndromeNoonan SyndromeCardiofaciocutaneous Syndrome

Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies

RECRUITING
NCT04888936National Cancer Institute (NCI)Started 2022-04-25
NF2 Deficiency

Gene Therapy for Neurofibromatosis Type 2 (NF2) with ST002

NOT YET RECRUITING
NCT06834438Phase NACancer Institute and Hospital, Chinese Academy of Medical SciencesStarted 2025-02-15
ST002
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING
NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23
OlaparibDasatinibNivolumab plus Ipilimumab
Malignant Peripheral Nerve Sheath Tumors

Multi-Institutional Registry for Malignant Peripheral Nerve Sheath Tumors

RECRUITING
NCT03141021Washington University School of MedicineStarted 2017-04-28
Pediatric Low-grade Glioma

Phase 1/2 Study of Mirdametinib + Vinblastine for Newly Diagnosed/Previously Untreated PLGG + Activation of MAPK

RECRUITING
NCT06666348Phase PHASE1, PHASE2St. Justine's HospitalStarted 2026-01-12
Mirdametinib
Melanoma

MElanoma Research Lymph Node Prediction Implementation National_001

ACTIVE NOT RECRUITING
NCT04759781SkylineDxStarted 2021-08-25
Acute Myeloid Leukemia

Testing the Combination of an Anti-Cancer Drug, Iadademstat, With Other Anti-Cancer Drugs (Venetoclax and Azacitidine) for Treating AML

RECRUITING
NCT06514261Phase PHASE1National Cancer Institute (NCI)Started 2024-12-18
AzacitidineBiospecimen CollectionBiospecimen Collection
Prader-Willi SyndromePWS-like SyndromeSilver Russel Syndrome

GROWing Up With Rare GENEtic Syndromes

RECRUITING
NCT04463316dr. Laura C. G. de Graaff-HerderStarted 2018-10-01
Retrospective file studies
Acinar Cell CarcinomaAdenoid Cystic CarcinomaAdrenal Cortical Carcinoma

Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

ACTIVE NOT RECRUITING
NCT02834013Phase PHASE2National Cancer Institute (NCI)Started 2017-01-30
Biospecimen CollectionComputed TomographyEchocardiography Test
Refractory CancerCNS TumorsCNS Tumor, Adult

A Study of Avutometinib for People With Solid Tumor Cancers

RECRUITING
NCT06104488Phase PHASE1Memorial Sloan Kettering Cancer CenterStarted 2023-10-20
Avutometinib

External Resources

Links to major genomics databases and tools