NF2

Chr 22AD

NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor

Also known as: ACN, BANF, SCH, SWNV, merlin-1

NCBI Gene: 4771 ENSG00000186575 UniProt: P35240 OMIM: 607379

The protein regulates contact-dependent inhibition of cell proliferation and functions in cell-cell adhesion and transmembrane signaling by linking cytoskeletal components with cell membrane proteins. Mutations cause neurofibromatosis type II, an autosomal dominant disorder characterized by nervous system and skin tumors and ocular abnormalities, as well as schwannomatosis and meningiomas. The pathogenic mechanism involves disruption of the protein's tumor suppressor function, leading to loss of growth control and subsequent tumorigenesis.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that is similar to some members of the ERM (ezrin, radixin, moesin) family of proteins that link cytoskeletal components with proteins in the cell membrane. The encoded protein is involved in regulation of contact-dependent inhibition of cell proliferation and functions in cell-cell adhesion and transmembrane signaling. The encoded protein has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics, and proteins involved in regulating ion transport. Disruption of this protein's function has been implicated in tumorigenesis and metastasis. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular abnormalities. [provided by RefSeq, May 2022]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.093 OMIM phenotypes

VCEP Guidelines: NeurofibromatosesIn Progress

ClinGen Panel

Clinical Summary— NF2

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Gene-Disease Validity (ClinGen)

NF2-related schwannomatosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

48 unique Pathogenic / Likely Pathogenic· 244 VUS of 398 total submissions

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Clinical Trials

10 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 5.44

OE 0.00 (0.00–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.29Z-score

OE missense 0.64 (0.57–0.72)

208 obs / 323.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.09)

0≤0.351.4

Missense OE?0.64 (0.57–0.72)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 0 / 34.5Missense obs/exp: 208 / 323.8Syn Z: 0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNF2-related schwannomatosisLOFAD

This gene — mechanism propensity

0.4884th %ile

GOF

0.5366th %ile

LOF

0.60top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 83% of P/LP variants are LoF · LOEUF 0.09 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFRole of NF2 haploinsufficiency in NF2-associated polyneuropathy.1

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.PMID 17655741 ↗

ClinVar Variant Classifications

398 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40

Likely Pathogenic8

VUS244

Likely Benign65

Benign1

Conflicting19

Pathogenic

Likely Pathogenic

244

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	0	6	0	40
Likely Pathogenic	6	0	1	1	8
VUS	2	178	62	2	244
Likely Benign	0	0	23	42	65
Benign	0	0	1	0	1
Conflicting	—				19
Total	42	178	93	45	377

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

View in ClinVar →

1 pathogenic / likely-pathogenic (of 2) ClinVar copy-number / structural variants overlap NF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

NF2 · 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

Refractory CancerCNS TumorsCNS Tumor, Adult

A Study of Avutometinib for People With Solid Tumor Cancers

ACTIVE NOT RECRUITING

NCT06104488Phase PHASE1Memorial Sloan Kettering Cancer CenterStarted 2023-10-20

Avutometinib

Mesothelioma

New Preclinical and Clinical Approaches to Mesothelioma

RECRUITING

NCT06536179Marco Emilio BianchiStarted 2024-07-25

Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING

NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21

NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies

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

Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING

NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17

AdavosertibAfatinibAfatinib Dimaleate

Melanoma

MElanoma Research Lymph Node Prediction Implementation National_001

ACTIVE NOT RECRUITING

NCT04759781SkylineDxStarted 2021-08-25

Acute LeukemiaAdenomatous PolyposisAdrenocortical Carcinoma

Familial Investigations of Childhood Cancer Predisposition

RECRUITING

NCT03050268St. Jude Children's Research HospitalStarted 2017-04-06

Advanced Solid TumorNSCLC (Non-small Cell Lung Cancer)Renal Cancer