NF1

Summary

NF1 (neurofibromin 1, HGNC:7765) is a protein-coding gene on chromosome 17q11.2, encoding Neurofibromin (P21359). Stimulates the GTPase activity of Ras. In precision oncology, NF1 Mutation confers sensitivity to Selumetinib in Plexiform Neurofibroma (CIViC Level A); 15 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 4763 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurofibromatosis type 1 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 29
• Clinical variants (ClinVar): 16,971 total — 4337 pathogenic, 624 likely-pathogenic
• Phenotypes (HPO): 251
• Precision-oncology evidence (CIViC): 16 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 33 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 14 downstream targets (CollecTRI)
• MANE Select transcript: NM_001042492

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7765
Approved symbol	NF1
Name	neurofibromin 1
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000196712
Ensembl biotype	protein_coding
OMIM	613113
Entrez	4763

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 13 protein_coding, 12 nonsense_mediated_decay, 10 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000356175, ENST00000358273, ENST00000422121, ENST00000431387, ENST00000456735, ENST00000466819, ENST00000468273, ENST00000471572, ENST00000479536, ENST00000479614, ENST00000487476, ENST00000488981, ENST00000489712, ENST00000490416, ENST00000493220, ENST00000495910, ENST00000498569, ENST00000577967, ENST00000579081, ENST00000581113, ENST00000581790, ENST00000582892, ENST00000584328, ENST00000684826, ENST00000684998, ENST00000686189, ENST00000687027, ENST00000687863, ENST00000688507, ENST00000689464, ENST00000691014, ENST00000691649, ENST00000692326, ENST00000693210, ENST00000693617, ENST00000696138, ENST00000696139, ENST00000696140, ENST00000696141

RefSeq mRNA: 3 — MANE Select: NM_001042492 NM_000267, NM_001042492, NM_001128147

CCDS: CCDS11264, CCDS42292, CCDS45645

Canonical transcript exons

ENST00000358273 — 58 exons

Exon	Start	End
ENSE00002342236	31252938	31253000
ENSE00002731556	31094977	31095369
ENSE00003483777	31159010	31159093
ENSE00003488561	31182508	31182665
ENSE00003517529	31181422	31181489
ENSE00003528366	31201411	31201485
ENSE00003550363	31201037	31201159
ENSE00003558799	31181710	31181785
ENSE00003559490	31155983	31156126
ENSE00003566524	31206240	31206371
ENSE00003629296	31169891	31169997
ENSE00003649334	31214451	31214585
ENSE00003693014	31163186	31163376
ENSE00003693905	31200422	31200595
ENSE00003897226	31374013	31377675
ENSE00003966122	31226435	31226684
ENSE00003966123	31337368	31337582
ENSE00003966124	31352257	31352414
ENSE00003966125	31358969	31359015
ENSE00003966126	31235611	31235772
ENSE00003966127	31349120	31349251
ENSE00003966128	31350183	31350318
ENSE00003966129	31336635	31336914
ENSE00003966130	31230260	31230382
ENSE00003966131	31358480	31358622
ENSE00003966132	31338025	31338139
ENSE00003966133	31259032	31259129
ENSE00003966134	31227523	31227606
ENSE00003966136	31265229	31265339
ENSE00003966140	31248984	31249119
ENSE00003966142	31233002	31233213
ENSE00003966143	31221850	31221929
ENSE00003966144	31360487	31360703
ENSE00003966145	31340505	31340645
ENSE00003966147	31227218	31227291
ENSE00003966148	31337819	31337880
ENSE00003966149	31338704	31338805
ENSE00003966151	31357269	31357369
ENSE00003966152	31260369	31260515
ENSE00003966153	31334838	31335031
ENSE00003966155	31223444	31223567
ENSE00003966156	31232700	31232881
ENSE00003966158	31261711	31261857
ENSE00003966160	31235918	31236021
ENSE00003966163	31330296	31330498
ENSE00003966164	31356460	31356582
ENSE00003966165	31325820	31326252
ENSE00003966166	31229025	31229465
ENSE00003966167	31229835	31229974
ENSE00003966168	31327499	31327839
ENSE00003966170	31356960	31357090
ENSE00003966172	31336333	31336473
ENSE00003966174	31343009	31343135
ENSE00003966175	31232073	31232189
ENSE00003966176	31219005	31219118
ENSE00003966178	31258344	31258502
ENSE00003966179	31230842	31230925
ENSE00003966180	31225095	31225250

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 94.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.3997 / max 715.5501, expressed in 1822 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160178	20.2185	1790
160176	17.7530	1802
160177	5.0892	1507
160187	0.6073	219
160182	0.3843	133
160186	0.1362	56
160179	0.1051	54
160193	0.0588	4
160180	0.0407	12
160192	0.0065	3

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
colonic epithelium	UBERON:0000397	94.30	gold quality
calcaneal tendon	UBERON:0003701	94.26	gold quality
adrenal tissue	UBERON:0018303	93.29	gold quality
secondary oocyte	CL:0000655	92.75	gold quality
ventricular zone	UBERON:0003053	92.40	gold quality
oocyte	CL:0000023	91.92	gold quality
buccal mucosa cell	CL:0002336	91.87	gold quality
sural nerve	UBERON:0015488	91.78	gold quality
ganglionic eminence	UBERON:0004023	91.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.32	gold quality
tendon	UBERON:0000043	91.26	gold quality
corpus callosum	UBERON:0002336	91.13	gold quality
cortical plate	UBERON:0005343	89.89	gold quality
corpus epididymis	UBERON:0004359	89.58	gold quality
CA1 field of hippocampus	UBERON:0003881	89.30	gold quality
stromal cell of endometrium	CL:0002255	89.17	gold quality
postcentral gyrus	UBERON:0002581	89.14	gold quality
tonsil	UBERON:0002372	89.04	gold quality
cauda epididymis	UBERON:0004360	88.96	gold quality
embryo	UBERON:0000922	88.95	gold quality
cerebellar hemisphere	UBERON:0002245	88.83	gold quality
choroid plexus epithelium	UBERON:0003911	88.82	gold quality
cerebellar cortex	UBERON:0002129	88.80	gold quality
caput epididymis	UBERON:0004358	88.77	gold quality
left testis	UBERON:0004533	88.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.40	gold quality
testis	UBERON:0000473	88.37	gold quality
right testis	UBERON:0004534	88.35	gold quality
orbitofrontal cortex	UBERON:0004167	88.31	gold quality
heart right ventricle	UBERON:0002080	88.29	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75688	yes	3217.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

14 targets.

Target	Regulation
AFP	Repression
DDB1	Unknown
DDB2	Unknown
FOS	Activation
GNRH1	Unknown
HSD11B2	Unknown
MBP	Unknown
MSH2	Unknown
MYC	Activation
PLAT	Repression
PPP2R2D	Unknown
SFTPB	Unknown
SP3	Unknown
TP53	Activation

Upstream regulators (CollecTRI, top): AR, CEBPA, CEBPB, CEBPG, CREB1, CTCF, EGR1, ETS2, FOS, FOXA1, FOXD2, GFI1, HNF4A, IRF2, IRF8, JUN, JUNB, MYB, MYOD1, NKX2-5, NR5A1, POU6F2, RUNX1, SP1, SP3, SPI1, STAT5A, TBP, TBPL1, TFAP2A, TFAP4, TP53, TWIST1, TWIST2, YY1

miRNA regulators (miRDB)

233 targeting NF1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene (PMID:11704931)
• C–>U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme (PMID:11727199)
• mutation analysis of the NF1 gene in osteofibrous dysplasia (PMID:11727265)
• Combination of analyses of loss of heterozygosity, southern blotting and southern blot densitometry can be used as a powerful method to detect large deletions, especially when family record is not available or the patient is a sporadic case. (PMID:11748857)
• Heterozygous astrocytes have decreased attachment, delayed actin cytoskeleton re-organization during cell spreading, and increased motility. (PMID:11751683)
• Genotype analysis indicated families 7610 and 7473 bear deletions. (PMID:11754043)
• No correlation has been found between type, location or size of NF1 mutations and size or location of plexiform neurofibromas (PNFs), suggesting that many types of NF1 mutations may lead to development of PNFs. (PMID:11857752)
• This study demonstrated that NF1 mRNA belongs to a rare group of mRNAs that are not targeted to free polysomes or ribosomes of the rough endoplasmic reticulum. (PMID:11896214)
• linkage disequilibrium and founder effect analysis of the NF1 gene in French Canadians from the Quebec population (PMID:11934389)
• report novel aberrant NF1 splicing, which is not random and affects only specific parts of the transcript across its length (PMID:12073021)
• Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. (PMID:12077339)
• Various new NF1 splice variants was described. Furhter insight into the significance of some of these variants is provided by accurate quantification of variant transcript levels in different human tissues. (PMID:12095621)
• Differential NF1 patterns by interphase cytogenetics in malignant peripheral nerve sheath tumor and morphologically similar spindle cell neoplasms. (PMID:12152785)
• the motor protein kinesin-1 links this protein and merlin in a common cellular pathway of neurofibromatosis (PMID:12191989)
• NF1 tumor suppressor may function in the regulation of epidermal histogenesis via controlling the organization of the keratin cytoskeleton during the assembly of desmosomes and hemidesmosomes. (PMID:12199909)
• In the cells haploinsufficient for NF1 we found an altered signal-to-noise ratio detectable as increased variation in dendrite formation. (PMID:12368469)
• probably does not have a role as tumor suppressor in sporadic pilocytic astrocytomas (PMID:12387455)
• nf1 gene is a mutational target in a mismatch repair-deficient cell and its inactivation is an important step of the malignant progression of MMR-deficient cells (PMID:12522551)
• Eighteen novel mutations have been found in a neurofibromatosis 1 cohort. (PMID:12552569)
• NF1 microdeletion individuals have a substantially higher lifetime risk for the development of malignant peripheral nerve sheath tumors than individuals with NF1 who do not have an NF1 microdeletion (PMID:12660952)
• Neurofibromatosis-Noonan syndrome (NFNS) can in some cases result from different mutations in the NF1 gene. (PMID:12707950)
• mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation (PMID:12730209)
• mutations and clinical spectrum in patients with spinal neurofibromas (PMID:12746402)
• Recurrent mutations are more common than previously described, being present in 45% of the patients in whom the NF1 causative mutation has been identified. (PMID:12807981)
• novel NF1 point mutations, deletions, and frameshift mutations causing premature termination and aberrant splicing. (PMID:12872266)
• Mutations of the NF1 gene may occasionally play a role in the pathogenesis of uveal melanoma. (PMID:12963615)
• LOH at NF1 may be one of the genetic features seen in peripheral nerve sheath tumors from different locations and should be interpreted with caution (PMID:13679444)
• new information concerning the transcriptional regulation of the NF1 gene, and the most thorough attempt to date to map functionally relevant regions within the NF1 proximal promoter region (PMID:14647436)
• NF-1 is actively transported to the cell nucleus. (PMID:14988005)
• Neurofibromin 1 genetic alteration may play a part in the pathogenesis of neurofibromatosis type 1. (PMID:15096131)
• NF1 mutational spectrum in the Italian population reporting four-year experience with the direct analysis of the whole NF1 coding region in 110 unrelated subjects affected by NF1 (PMID:15146469)
• molecular evolution and genomic organization (PMID:15233998)
• ICSBP1 activates transcription of the gene encoding neurofibromin 1 (PMID:15371411)
• preliminary crystallographic characterization of a novel segment (homologous to the yeast Sec14p lipid exchange protein) from the neurofibromatosis type 1 protein (PMID:15583390)
• We described a patient with ectropion and the mutation R1748X in the NF1 gene (PMID:15627836)
• The differences between normal and NF1 keratinocytes were dependent on extracellular calcium concentration. (PMID:15735964)
• TBP affects the NF1 and c-fos promoters in a manner reciprocal to that of TLF, stimulating the c-fos promoter and inhibiting NF1 transcription (PMID:15767669)
• We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. (PMID:15944227)
• NF1 tumor suppressor gene is a direct transcriptional target of RUNX1 and the t(8;21) fusion protein, suggesting that suppression of NF1 expression contributes to the molecular pathogenesis of acute myeloid leukemia . (PMID:15988004)
• the NF1 gene is mutated in Chinese Han families with type 1 neurofibromatosis (PMID:16005615)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nf1b	ENSDARG00000004184
danio_rerio	nf1a	ENSDARG00000012982
mus_musculus	Nf1	ENSMUSG00000020716
rattus_norvegicus	Nf1	ENSRNOG00000013780
drosophila_melanogaster	Nf1	FBGN0015269

Paralogs (10): RASAL2 (ENSG00000075391), RASAL3 (ENSG00000105122), RASA4 (ENSG00000105808), RASAL1 (ENSG00000111344), DAB2IP (ENSG00000136848), RASA1 (ENSG00000145715), RASA2 (ENSG00000155903), RASA4B (ENSG00000170667), RASA3 (ENSG00000185989), SYNGAP1 (ENSG00000197283)

Protein

Protein identifiers

Neurofibromin — P21359 (reviewed: P21359)

Alternative names: Neurofibromatosis-related protein NF-1

All UniProt accessions (22): A0A1W2PPA7, A0A1W2PS74, A0A8I5KSC3, A0A8I5KSM3, A0A8I5KV71, A0A8I5KWR6, A0A8I5KWT7, A0A8I5KYK6, A0A8Q3WL04, A0A8Q3WL11, A0A8Q3WL49, P21359, H0Y465, J3KRT8, J3KSB5, J3KSX8, J3QLS2, J3QQN8, J3QSG6, K7EID4, K7EJE7, K7ENT2

UniProt curated annotations — full annotation on UniProt →

Function. Stimulates the GTPase activity of Ras. NF1 shows greater affinity for Ras GAP, but lower specific activity. May be a regulator of Ras activity.

Subunit / interactions. Interacts with HTR6. Interacts with SPRED2.

Subcellular location. Nucleus. Nucleolus. Cell membrane.

Tissue specificity. Detected in brain, peripheral nerve, lung, colon and muscle.

Post-translational modifications. Ubiquitinated by RNF7/RBX2, leading to its degradation.

Disease relevance. Neurofibromatosis 1 (NF1) [MIM:162200] A disease characterized by patches of skin pigmentation (cafe-au-lait spots), Lisch nodules of the iris, tumors in the peripheral nervous system and fibromatous skin tumors. Individuals with the disorder have increased susceptibility to the development of benign and malignant tumors. The disease is caused by variants affecting the gene represented in this entry. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785] An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. The disease is caused by variants affecting the gene represented in this entry. Watson syndrome (WTSN) [MIM:193520] A syndrome characterized by the presence of pulmonary stenosis, cafe-au-lait spots, and intellectual disability. It is considered as an atypical form of neurofibromatosis. The disease is caused by variants affecting the gene represented in this entry. Familial spinal neurofibromatosis (FSNF) [MIM:162210] Considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors. The disease is caused by variants affecting the gene represented in this entry. Neurofibromatosis-Noonan syndrome (NFNS) [MIM:601321] Characterized by manifestations of both NF1 and Noonan syndrome (NS). NS is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. The disease is caused by variants affecting the gene represented in this entry. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The gene represented in this entry may be involved in disease pathogenesis.

Domain organisation. Binds phospholipids via its C-terminal CRAL-TRIO domain. Binds primarily glycerophospholipids with monounsaturated C18:1 and/or C16:1 fatty acid moieties and a phosphatidylethanolamine or phosphatidylcholine headgroup. Has lesser affinity for lipids containing phosphatidylserine and phosphatidylinositol.

Isoforms (6)

UniProt ID	Names	Canonical?
P21359-1	II	yes
P21359-2	I
P21359-3	3
P21359-4	4
P21359-5	5
P21359-6	6

RefSeq proteins (3): NP_000258, NP_001035957, NP_001121619 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001251	CRAL-TRIO_dom	Domain
IPR001936	RasGAP_dom	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR023152	RasGAP_CS	Conserved_site
IPR036865	CRAL-TRIO_dom_sf	Homologous_superfamily
IPR039360	Ras_GTPase	Family
IPR054071	PH_NF1	Domain

Pfam: PF00616, PF13716, PF21877

UniProt features (360 total): helix 148, sequence variant 111, turn 31, strand 30, modified residue 14, splice variant 8, mutagenesis site 5, sequence conflict 3, chain 2, domain 2, region of interest 2, initiator methionine 1, short sequence motif 1, compositionally biased region 1, site 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
6OB3	X-RAY DIFFRACTION	2.1
3PG7	X-RAY DIFFRACTION	2.19
2D4Q	X-RAY DIFFRACTION	2.3
1NF1	X-RAY DIFFRACTION	2.5
2E2X	X-RAY DIFFRACTION	2.5
3PEG	X-RAY DIFFRACTION	2.52
6V6F	X-RAY DIFFRACTION	2.54
3P7Z	X-RAY DIFFRACTION	2.65
6V65	X-RAY DIFFRACTION	2.76
6OB2	X-RAY DIFFRACTION	2.85
7PGP	ELECTRON MICROSCOPY	3.1
7PGU	ELECTRON MICROSCOPY	3.3
7PGS	ELECTRON MICROSCOPY	3.4
8EDO	ELECTRON MICROSCOPY	3.4
7PGQ	ELECTRON MICROSCOPY	3.5
7R03	ELECTRON MICROSCOPY	3.6
8E20	ELECTRON MICROSCOPY	3.6
8EDM	ELECTRON MICROSCOPY	3.6
7R04	ELECTRON MICROSCOPY	3.7
8EDL	ELECTRON MICROSCOPY	3.7
8EDN	ELECTRON MICROSCOPY	3.8
7PGR	ELECTRON MICROSCOPY	4
7MOC	ELECTRON MICROSCOPY	4.56
7PGT	ELECTRON MICROSCOPY	4.8
7MP5	ELECTRON MICROSCOPY	5.6
7MP6	ELECTRON MICROSCOPY	6.25

Predicted structure (AlphaFold)

No AlphaFold model available for P21359 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1276 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (14): 2, 864, 876, 2188, 2467, 2514, 2515, 2521, 2523, 2543, 2565, 2597, 2802, 2817

Mutagenesis-validated functional residues (5):

Position	Phenotype
1691	reduces phospholipid binding; when associated with a-1695; a-1769 and a-1771.
1695	reduces phospholipid binding; when associated with a-1691; a-1769 and a-1771.
1769	reduces phospholipid binding; when associated with a-1691; a-1695 and a-1771.
1771	reduces phospholipid binding; when associated with a-1691; a-169 and a-1769.
1771	reduces protein stability.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5658442	Regulation of RAS by GAPs
R-HSA-6802953	RAS signaling downstream of NF1 loss-of-function variants
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802957	Oncogenic MAPK signaling

MSigDB gene sets: 1066 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_GLUTAMATE_SECRETION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, MORF_FLT1, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_ACID_SECRETION, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_COGNITION, GOBP_BEHAVIOR, YAGI_AML_WITH_INV_16_TRANSLOCATION

GO Biological Process (113): MAPK cascade (GO:0000165), angiogenesis (GO:0001525), osteoblast differentiation (GO:0001649), metanephros development (GO:0001656), response to hypoxia (GO:0001666), liver development (GO:0001889), endothelial cell proliferation (GO:0001935), negative regulation of endothelial cell proliferation (GO:0001937), positive regulation of endothelial cell proliferation (GO:0001938), regulation of cell-matrix adhesion (GO:0001952), negative regulation of cell-matrix adhesion (GO:0001953), negative regulation of leukocyte migration (GO:0002686), protein import into nucleus (GO:0006606), cell communication (GO:0007154), Ras protein signal transduction (GO:0007265), neuroblast proliferation (GO:0007405), negative regulation of neuroblast proliferation (GO:0007406), brain development (GO:0007420), peripheral nervous system development (GO:0007422), heart development (GO:0007507), skeletal muscle tissue development (GO:0007519), visual learning (GO:0008542), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), regulation of gene expression (GO:0010468), negative regulation of Schwann cell proliferation (GO:0010626), Schwann cell proliferation (GO:0014010), Schwann cell development (GO:0014044), negative regulation of angiogenesis (GO:0016525), Rac protein signal transduction (GO:0016601), spinal cord development (GO:0021510), amygdala development (GO:0021764), forebrain astrocyte development (GO:0021897), neural tube development (GO:0021915), cerebral cortex development (GO:0021987), myelination in peripheral nervous system (GO:0022011), actin cytoskeleton organization (GO:0030036), extracellular matrix organization (GO:0030198), collagen fibril organization (GO:0030199), osteoclast differentiation (GO:0030316), adrenal gland development (GO:0030325)

GO Molecular Function (5): GTPase activator activity (GO:0005096), phosphatidylethanolamine binding (GO:0008429), phosphatidylcholine binding (GO:0031210), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), presynapse (GO:0098793), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
RAF/MAP kinase cascade	1
Oncogenic MAPK signaling	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
endothelial cell proliferation	2
regulation of endothelial cell proliferation	2
cell-matrix adhesion	2
animal organ development	2
phospholipid binding	2
binding	2
nuclear lumen	2
neuron projection	2
synapse	2
intracellular signaling cassette	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
ossification	1
cell differentiation	1
kidney development	1
response to stress	1
response to decreased oxygen levels	1
gland development	1
hepaticobiliary system development	1
epithelial cell proliferation	1
negative regulation of epithelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
regulation of cell-substrate adhesion	1
regulation of cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
negative regulation of immune system process	1
regulation of leukocyte migration	1
negative regulation of cell migration	1
leukocyte migration	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cellular process	1
small GTPase-mediated signal transduction	1
generation of neurons	1
neural precursor cell proliferation	1
neuroblast proliferation	1
negative regulation of neurogenesis	1

Protein interactions and networks

STRING

5050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NF1	NF2	P35240	971
NF1	SPRED1	Q7Z699	946
NF1	KRAS	P01116	926
NF1	BRAF	P15056	895
NF1	NRAS	P01111	886
NF1	TMEM127	O75204	882
NF1	TP53	P04637	880
NF1	SMAD4	Q13485	865
NF1	BRCA1	P38398	864
NF1	RET	P07949	839
NF1	PTEN	P60484	839
NF1	PTPN11	Q06124	837
NF1	SDHD	O14521	835
NF1	SDHB	P21912	823
NF1	PDGFRA	P16234	803

IntAct

192 interactions, top by confidence:

A	B	Type	Score
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
HRAS	NF1	psi-mi:“MI:0915”(physical association)	0.600
HRAS	NF1	psi-mi:“MI:0914”(association)	0.600
SPRED1	NF1	psi-mi:“MI:0915”(physical association)	0.570
NF1	SPRED1	psi-mi:“MI:0915”(physical association)	0.570
SPRED1	NF1	psi-mi:“MI:0914”(association)	0.570
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
CA14	EXOC5	psi-mi:“MI:0914”(association)	0.530
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
NF1	APP	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (298): FAF2 (Affinity Capture-MS), NF1 (Affinity Capture-Western), FAF2 (Affinity Capture-Western), FAF2 (Reconstituted Complex), NF1 (Biochemical Activity), NF1 (Affinity Capture-RNA), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS), NF1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4ITC5, A1L1F4, A4L9P7, E9Q8I9, F1MKX4, F1QFR9, F1R2X6, F8VPU6, O94915, P21359, P42345, P42346, P51593, P97526, Q04690, Q14997, Q29RF7, Q2HJG5, Q498H0, Q4KLU7, Q4QXM3, Q4VA53, Q5F3U9, Q5F3V3, Q5R6J0, Q5SSW2, Q5TBA9, Q5U241, Q5VYK3, Q6A026, Q6DDM4, Q6GP04, Q6NRP2, Q6P4S8, Q6PDI5, Q6TRW4, Q7PX35, Q7TMY8, Q7Z3U7, Q7Z6Z7

Diamond homologs: P21359, P35608, P58069, P97526, Q04690, Q63713, F6SEU4, P18963, P19158, P41823, P42680, P48423, Q14644, Q15283, Q28013, Q54Y08, Q5M7N9, Q5T7P8, Q60790, Q62746, Q86YV0, Q96PV0, Q99N80, Q9QUH6, Q9QYJ2, P09851, P20936, P50904, Q3UHC7, Q5VWQ8, Q6P730, Q8MLZ5, Q9UJF2, C9J798, O43374, P35991, P51813, Q03526, Q06187, Q08881

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY10
NF1	up-regulates	ADCY2
NF1	up-regulates	ADCY3
NF1	up-regulates	ADCY4
NF1	up-regulates	ADCY5
NF1	up-regulates	ADCY6
NF1	up-regulates	ADCY7
NF1	up-regulates	ADCY8
NF1	up-regulates	ADCY9
NF1	“down-regulates activity”	HRAS	“gtpase-activating protein”
NF1	“down-regulates quantity by repression”	AFP	“transcriptional regulation”
TWIST2	“down-regulates quantity by repression”	NF1	“transcriptional regulation”
TWIST1	“down-regulates quantity by repression”	NF1	“transcriptional regulation”
NF1	“down-regulates activity”	HRAS
NF1	up-regulates	Adenylate_cyclase
RNF7	“down-regulates activity”	NF1	ubiquitination
SPRED1	“up-regulates quantity”	NF1	binding
NF1	“down-regulates activity”	KRAS	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	8	49.1×	3e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	9	48.8×	3e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	43.3×	7e-10
Activation of BH3-only proteins	8	32.0×	9e-09
Signaling by FLT3 ITD and TKD mutants	5	30.7×	2e-05
RHO GTPases activate PKNs	8	20.5×	3e-07
FLT3 Signaling	7	19.5×	3e-06
FOXO-mediated transcription	7	19.0×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
T cell costimulation	7	15.3×	3e-04
protein targeting	7	15.0×	3e-04
ephrin receptor signaling pathway	6	12.1×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 33 cancer types — ACC, ALL, AML, ANGS, BLCA, BRCA, CCRCC, CHOL, CLLSLL, COADREAD, GB, GBM…(+21 more).

Clinical variants and AI predictions

ClinVar

16971 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4337
Likely pathogenic	624
Uncertain significance	5864
Likely benign	3910
Benign	165

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1003143	NM_001042492.3(NF1):c.6886_6903del (p.Ile2296_Leu2301del)	Pathogenic
1004008	NM_001042492.3(NF1):c.3539T>G (p.Met1180Arg)	Pathogenic
1012199	NM_001042492.3(NF1):c.598A>T (p.Lys200Ter)	Pathogenic
1013132	NM_001042492.3(NF1):c.978dup (p.Leu327fs)	Pathogenic
1013391	GRCh37/hg19 17q11.2(chr17:29679275-29679432)x1	Pathogenic
1037719	NM_001042492.3(NF1):c.2324A>C (p.Glu775Ala)	Pathogenic
1042357	NM_001042492.3(NF1):c.3496G>T (p.Gly1166Cys)	Pathogenic
1042977	NM_001042492.3(NF1):c.725T>G (p.Met242Arg)	Pathogenic
1044895	NM_001042492.3(NF1):c.4931A>C (p.Asp1644Ala)	Pathogenic
1048673	NM_001042492.3(NF1):c.7171del (p.Val2391fs)	Pathogenic
1048674	NM_001042492.3(NF1):c.7739-3_7743delCAGAAACT	Pathogenic
1048676	NM_001042492.3(NF1):c.6488del (p.Leu2163fs)	Pathogenic
1048677	NM_001042492.3(NF1):c.1714dup (p.Glu572fs)	Pathogenic
1048679	NM_001042492.3(NF1):c.1702_1703dup (p.Thr569fs)	Pathogenic
1048680	NM_001042492.3(NF1):c.3114-1G>C	Pathogenic
1048682	NM_001042492.3(NF1):c.2034_2035insC (p.Ile679fs)	Pathogenic
1048683	NM_001042492.3(NF1):c.1920del (p.Ser641fs)	Pathogenic
1048684	NM_001042492.3(NF1):c.3641dup (p.Met1214fs)	Pathogenic
1048685	NM_001042492.3(NF1):c.2248dup (p.Thr750fs)	Pathogenic
1048686	NM_001042492.3(NF1):c.4327del (p.Ser1443fs)	Pathogenic
1048687	NM_001042492.3(NF1):c.546dup (p.Ile183fs)	Pathogenic
1048688	NM_001042492.3(NF1):c.3641_3645del (p.Met1214fs)	Pathogenic
1048689	NM_001042492.3(NF1):c.4578-9T>A	Pathogenic
1048690	NM_001042492.3(NF1):c.3574G>T (p.Glu1192Ter)	Pathogenic
1048691	NM_001042492.3(NF1):c.160del (p.Val54fs)	Pathogenic
1048694	NM_001042492.3(NF1):c.2847_2850+1del	Pathogenic
1048695	NM_001042492.3(NF1):c.1691_1692insC (p.Ala565fs)	Pathogenic
1048696	NM_001042492.3(NF1):c.3104del (p.Met1035fs)	Pathogenic
1048698	NM_001042492.3(NF1):c.5040T>A (p.Tyr1680Ter)	Pathogenic
1048700	NM_001042492.3(NF1):c.6732del (p.Gln2245fs)	Pathogenic

SpliceAI

11279 predictions. Top by Δscore:

Variant	Effect	Δscore
17:31095367:CAGG:C	donor_loss	1.0000
17:31095370:G:GA	donor_loss	1.0000
17:31155981:A:AG	acceptor_gain	1.0000
17:31155982:G:GG	acceptor_gain	1.0000
17:31155982:GC:G	acceptor_gain	1.0000
17:31155982:GCT:G	acceptor_gain	1.0000
17:31155982:GCTT:G	acceptor_gain	1.0000
17:31155982:GCTTC:G	acceptor_gain	1.0000
17:31156044:A:T	donor_gain	1.0000
17:31156122:ATATG:A	donor_gain	1.0000
17:31156123:TATG:T	donor_gain	1.0000
17:31156123:TATGG:T	donor_loss	1.0000
17:31156124:ATGG:A	donor_loss	1.0000
17:31156125:TG:T	donor_gain	1.0000
17:31156125:TGGTG:T	donor_loss	1.0000
17:31156126:GG:G	donor_gain	1.0000
17:31156126:GGT:G	donor_loss	1.0000
17:31156127:G:A	donor_loss	1.0000
17:31156127:G:GG	donor_gain	1.0000
17:31156128:T:A	donor_loss	1.0000
17:31159009:GA:G	acceptor_gain	1.0000
17:31163181:TTTAG:T	acceptor_loss	1.0000
17:31163184:A:AG	acceptor_gain	1.0000
17:31163185:G:GG	acceptor_gain	1.0000
17:31163185:GC:G	acceptor_gain	1.0000
17:31163372:ACCAG:A	donor_loss	1.0000
17:31163373:CCAG:C	donor_loss	1.0000
17:31163374:CAG:C	donor_loss	1.0000
17:31163375:AG:A	donor_loss	1.0000
17:31163376:GGT:G	donor_loss	1.0000

AlphaMissense

18784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:31095334:T:A	W9R	1.000
17:31095334:T:C	W9R	1.000
17:31095336:G:C	W9C	1.000
17:31095336:G:T	W9C	1.000
17:31155984:T:C	L21P	1.000
17:31156050:T:C	L43P	1.000
17:31156083:T:A	V54D	1.000
17:31156095:T:C	L58P	1.000
17:31159062:T:A	I86K	1.000
17:31159074:T:C	L90P	1.000
17:31163331:T:C	L145P	1.000
17:31163333:A:C	S146R	1.000
17:31163335:C:A	S146R	1.000
17:31163335:C:G	S146R	1.000
17:31181722:T:A	W223R	1.000
17:31181722:T:C	W223R	1.000
17:31182576:T:A	W267R	1.000
17:31182576:T:C	W267R	1.000
17:31182595:T:C	L273P	1.000
17:31200492:C:A	A320D	1.000
17:31200513:T:C	L327P	1.000
17:31200591:T:C	L353P	1.000
17:31214554:T:C	L499P	1.000
17:31219063:T:C	L529P	1.000
17:31221854:T:C	L549P	1.000
17:31221863:T:C	L552P	1.000
17:31221889:T:A	W561R	1.000
17:31221889:T:C	W561R	1.000
17:31221890:G:C	W561S	1.000
17:31221891:G:C	W561C	1.000

dbSNP variants (sampled 300 via entrez): RS1000002010 (17:31112683 A>G), RS1000030925 (17:31332869 G>A), RS1000050152 (17:31181875 T>C), RS1000059111 (17:31155106 T>C), RS1000071690 (17:31232497 T>C), RS1000103404 (17:31322694 T>C), RS1000105599 (17:31377928 A>C), RS1000127818 (17:31132393 A>T), RS1000135422 (17:31153319 G>A,T), RS1000137106 (17:31140139 A>G), RS1000138572 (17:31276154 A>G), RS1000159998 (17:31103931 G>A), RS1000180654 (17:31132689 G>A,C), RS1000191996 (17:31290144 T>A), RS1000192774 (17:31291561 G>C,T)

Disease associations

OMIM: gene MIM:613113 | disease phenotypes: MIM:162200, MIM:607785, MIM:162210, MIM:193520, MIM:601321, MIM:109800, MIM:167000, MIM:613659, MIM:168000, MIM:114030, MIM:613675, MIM:114480, MIM:615959, MIM:612219, MIM:191100, MIM:151380, MIM:153640, MIM:155100, MIM:600208, MIM:605249, MIM:171300, MIM:192600, MIM:615986, MIM:604370, MIM:148300, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
neurofibromatosis type 1	Definitive	Autosomal dominant
neurofibromatosis-Noonan syndrome	Strong	Autosomal dominant
Moyamoya disease	Moderate	Autosomal dominant
hereditary pheochromocytoma-paraganglioma	Supportive	Autosomal dominant
familial ovarian cancer	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neurofibromatosis type 1	Definitive	AD
familial ovarian cancer	No Known Disease Relationship	AD

Mondo (54): neurofibromatosis type 1 (MONDO:0018975), juvenile myelomonocytic leukemia (MONDO:0011908), hereditary neoplastic syndrome (MONDO:0015356), neurofibromatosis, familial spinal (MONDO:0008078), Watson syndrome (MONDO:0008672), neurofibromatosis-Noonan syndrome (MONDO:0011035), urinary bladder cancer (MONDO:0001187), ovarian cancer (MONDO:0008170), gastric cancer (MONDO:0001056), mosaic neurofibromatosis type 1 (MONDO:0859763), neurofibroma (MONDO:0016755), hereditary pheochromocytoma-paraganglioma (MONDO:0017366), cafe au lait spots, multiple (MONDO:0007245), intellectual disability (MONDO:0001071), chromosome 17q11.2 deletion syndrome, 1.4Mb (MONDO:0013357)

Orphanet (51): Neurofibromatosis type 1 (Orphanet:636), Inherited cancer-predisposing syndrome (Orphanet:140162), Juvenile myelomonocytic leukemia (Orphanet:86834), Neurofibromatosis-Noonan syndrome (Orphanet:638), Rare ovarian cancer (Orphanet:213500), Mosaic neurofibromatosis type 1 (Orphanet:634461), Neurofibroma (Orphanet:252183), Hereditary pheochromocytoma-paraganglioma (Orphanet:29072), Familial isolated café-au-lait macules (Orphanet:2678), 17q11.2 microduplication syndrome (Orphanet:139474), 17q11 microdeletion syndrome (Orphanet:97685), Middle aortic syndrome (Orphanet:1456), Hereditary breast cancer (Orphanet:227535), Autosomal recessive centronuclear myopathy (Orphanet:169186), Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion (Orphanet:363700)

HPO phenotypes

251 total (30 of 251 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000053	Macroorchidism
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000126	Hydronephrosis
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000246	Sinusitis
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000271	Abnormality of the face
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000405	Conductive hearing impairment
HP:0000411	Protruding ear
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000475	Broad neck

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST004066_131	Hip circumference	2.000000e-08
GCST006088_1	Familial squamous cell lung carcinoma	1.000000e-06
GCST006088_2	Familial squamous cell lung carcinoma	1.000000e-06
GCST006464_23	Endometrial cancer	4.000000e-08
GCST006465_1	Endometrial cancer (endometrioid histology)	1.000000e-07
GCST006948_2	Feeling nervous	3.000000e-08
GCST007324_55	Adventurousness	6.000000e-19
GCST007325_62	General risk tolerance (MTAG)	2.000000e-19
GCST008156_15	Hip circumference adjusted for BMI	2.000000e-07
GCST008522_19	Bitter alcoholic beverage consumption	2.000000e-07
GCST009145_8	Total cholesterol levels	7.000000e-14
GCST009379_179	Type 2 diabetes	4.000000e-08
GCST010118_62	Type 2 diabetes	4.000000e-11
GCST010135_18	Oily fish consumption	3.000000e-10
GCST010140_10	Pork consumption	3.000000e-10
GCST010204_215	Low density lipoprotein cholesterol levels	3.000000e-14
GCST010243_43	Apolipoprotein B levels	1.000000e-17
GCST010245_108	LDL cholesterol levels	1.000000e-14
GCST010703_342	Brain morphology (MOSTest)	4.000000e-10
GCST010989_20	Body size at age 10	2.000000e-08
GCST012227_338	Hip circumference adjusted for BMI	3.000000e-15
GCST90000025_582	Appendicular lean mass	2.000000e-25
GCST90002393_516	Monocyte count	9.000000e-19
GCST90002394_520	Monocyte percentage of white cells	9.000000e-12
GCST90002400_208	Plateletcrit	4.000000e-12
GCST90002402_447	Platelet count	1.000000e-19
GCST90011899_95	Aspartate aminotransferase levels	1.000000e-13
GCST90014033_70	Haemorrhoidal disease	7.000000e-10
GCST90020028_1369	Hip circumference adjusted for BMI	1.000000e-10

EFO canonical traits (17, from GWAS)

EFO ID	Trait name
EFO:0006953	family history of lung cancer
EFO:0009597	feeling nervous measurement
EFO:0008579	risk-taking behaviour
EFO:0008039	BMI-adjusted hip circumference
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0004574	total cholesterol measurement
EFO:0008111	diet measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004346	neuroimaging measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004980	appendicular lean mass
EFO:0005091	monocyte count
EFO:0007989	monocyte percentage of leukocytes
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (35)

Descriptor	Name	Tree numbers
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003397	Craniopharyngioma	C04.557.465.625.200; C04.557.580.625.200
D000080443	Diffuse Intrinsic Pontine Glioma	C04.557.465.625.600.380.185; C04.557.470.670.380.185; C04.557.580.625.600.380.185; C04.588.614.250.195.411.100.500; C10.228.140.211.500.100.500; C10.551.240.250.400.200.500
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007640	Keratoconus	C11.204.627
D007948	Leukemia, Monocytic, Acute	C04.557.337.539.275.484; C15.378.508.539.275.484
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525
D008209	Lymphedema	C15.604.496
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009072	Moyamoya Disease	C10.228.140.300.200.600; C10.228.140.300.510.200.737; C14.907.137.615; C14.907.253.123.620; C14.907.253.560.200.737
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D020752	Neurocutaneous Syndromes	C10.562; C16.131.077.350.712; C16.131.831.350.712; C16.320.850.250.712; C17.800.804.350.712; C17.800.827.250.712
D009455	Neurofibroma	C04.557.580.600.580; C10.551.775.500.750; C10.668.829.725.500.600
D018318	Neurofibroma, Plexiform	C04.557.580.600.580.585; C10.551.775.500.750.500; C10.668.829.725.500.600.500
D017253	Neurofibromatoses	C04.557.580.600.580.590; C04.700.631; C10.562.600; C10.574.500.549; C16.320.400.560; C16.320.700.633
D009456	Neurofibromatosis 1	C04.557.580.600.580.590.650; C04.700.631.650; C10.562.600.500; C10.574.500.549.400; C10.668.829.675; C16.320.400.560.400; C16.320.700.633.650
D020339	Optic Nerve Glioma	C04.557.465.625.600.380.795; C04.557.470.670.380.795; C04.557.580.625.600.380.795; C04.588.614.300.600.600; C04.588.614.596.240.240.500; C10.292.225.800.500; C10.292.700.500.500; C10.551.360.500.500; C10.551.775.250.500.500; C11.640.544.500
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D010673	Pheochromocytoma	C04.557.465.625.650.700.725; C04.557.580.625.650.700.725
D012175	Retinoblastoma	C04.557.465.625.600.725; C04.557.470.670.725; C04.557.580.625.600.725; C04.588.364.818.760; C11.270.862; C11.319.475.760; C11.768.717.760
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
D012512	Sarcoma, Ewing	C04.557.450.565.575.650.800; C04.557.450.795.620.800
D013285	Strabismus	C10.292.562.887; C11.590.810
D014402	Tuberous Sclerosis	C04.445.810; C04.651.800; C04.700.700; C10.500.507.400.750; C10.562.850; C10.574.500.865; C16.131.666.507.400.750; C16.320.400.880; C16.320.700.700
C565918	Bardet-Biedl Syndrome 9 (supp.)
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 16 predictive associations from 19 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
NF1 Mutation	Selumetinib	Plexiform Neurofibroma	Sensitivity/Response	CIViC A	EID11176 +2
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Inactivating Mutation	Selumetinib	Cancer	Sensitivity/Response	CIViC B	EID11696
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Mutation	Selumetinib	Cancer	Sensitivity/Response	CIViC B	EID11681
NF1 Loss	Everolimus + Bevacizumab	Malignant Peripheral Nerve Sheath Tumor	Sensitivity/Response	CIViC B	EID7727
NF1 Mutation	Tipifarnib	Neurofibroma	Sensitivity/Response	CIViC B	EID7426
NF1 Mutation	Selumetinib	Childhood Low-grade Glioma	Sensitivity/Response	CIViC B	EID7487
NF1 Mutation OR GNA11 Q209L	Trametinib	Cancer	Sensitivity/Response	CIViC B	EID12027
NF1 Mutation	Vemurafenib	Skin Melanoma	Resistance	CIViC C	EID1470 +1
NF1 Loss	Cetuximab + Afatinib	Melanoma	Sensitivity/Response	CIViC D	EID12435
NF1 Loss	JQ1 Compound	Malignant Peripheral Nerve Sheath Tumor	Sensitivity/Response	CIViC D	EID1743
NF1 Loss	Binimetinib	Neuroblastoma	Sensitivity/Response	CIViC D	EID1956
NF1 Mutation	Mirdametinib + Sirolimus	Skin Melanoma	Sensitivity/Response	CIViC D	EID1469
NF1 Mutation	VTX-11e + AZ628	Skin Melanoma	Sensitivity/Response	CIViC D	EID1471
NF1 Mutation	Trametinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID6054
BRAF V600E AND NF1 Loss	Vemurafenib	Melanoma	Resistance	CIViC D	EID90
NF1 Loss	Dabrafenib	Melanoma	Resistance	CIViC D	EID1957

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

75 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	7
bisphenol A	increases expression, affects cotreatment, decreases expression, decreases methylation	5
methylmercuric chloride	decreases expression, affects cotreatment	3
trichostatin A	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	decreases expression, decreases methylation, affects cotreatment, increases abundance, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	increases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression, increases methylation	2
Cadmium Chloride	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
2,4,6-tribromophenol	decreases expression	1
naringenin	affects cotreatment, increases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
decabromobiphenyl ether	decreases expression	1
tributyltin	increases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	affects response to substance	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1

Cellosaurus cell lines

310 cell lines: 265 cancer cell line, 15 induced pluripotent stem cell, 12 embryonic stem cell, 12 telomerase immortalized cell line, 3 transformed cell line, 3 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0022	U-87MG ATCC	Cancer cell line	Male
CVCL_0D36	NZM072	Cancer cell line	Sex unspecified
CVCL_0D40	NZM077	Cancer cell line	Sex unspecified
CVCL_0D47	NZM087	Cancer cell line	Male
CVCL_1150	CTV-1	Cancer cell line	Male
CVCL_1166	D-566MG	Cancer cell line	Male
CVCL_1219	FTC-133	Cancer cell line	Male
CVCL_1232	GI-ME-N	Cancer cell line	Female
CVCL_1441	SJNB-10	Cancer cell line	Male
CVCL_1484	NCI-H1651	Cancer cell line	Male

Clinical trials (associated diseases)

228 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00169611	PHASE4	COMPLETED	NF1-Attention: Study of Children With Neurofibromatosis Type 1 Treated by Methylphenidate
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT04205578	PHASE3	UNKNOWN	NBP in Patients With Moyamoya Disease of High Risk for Ischemic Cerebrovascular Events
NCT02471339	PHASE3	COMPLETED	Acceptance and Commitment Training for Adolescents and Young Adults With Neurofibromatosis Type 1, Plexiform Neurofibromas, and Chronic Pain
NCT03871257	PHASE3	ACTIVE_NOT_RECRUITING	A Study of the Drugs Selumetinib Versus Carboplatin/Vincristine in Patients With Neurofibromatosis and Low-Grade Glioma
NCT04461886	PHASE3	TERMINATED	A Long-term Study of NPC-12G Gel in Neurofibromatosis Type I
NCT04924608	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Selumetinib in Adults With NF1 Who Have Symptomatic, Inoperable Plexiform Neurofibromas
NCT05913037	PHASE3	ACTIVE_NOT_RECRUITING	FCN-159 in Adult Patients With Symptomatic, Inoperable Neurofibromatosis Type 1-Related Plexiform Neurofibromas
NCT00021541	PHASE2	COMPLETED	R115777 to Treat Children With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
NCT00030264	PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Neurofibromatosis and Progressive Plexiform Neurofibromas
NCT00076102	PHASE2	COMPLETED	Pirfenidone in Children and Young Adults With Neurofibromatosis Type I and Progressive Plexiform Neurofibromas
NCT00304083	PHASE2	COMPLETED	Combination Chemotherapy in Treating Patients With Stage III or Stage IV Malignant Peripheral Nerve Sheath Tumors
NCT00326872	PHASE2	TERMINATED	AZD2171 in Treating Patients With Neurofibromatosis Type 1 and Plexiform Neurofibroma and/or Neurofibroma Near the Spine
NCT00589784	PHASE2	COMPLETED	Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma
NCT00634270	PHASE2	COMPLETED	A Phase II Study of the mTOR Inhibitor Sirolimus in Neurofibromatosis Type 1 Related Plexiform Neurofibromas
NCT00754780	PHASE2	COMPLETED	Clinical Trial of Pirfenidone in Adult Patients With Neurofibromatosis 1
NCT00846430	PHASE2	COMPLETED	Medical Treatment of High-Risk Neurofibromas
NCT00853580	PHASE2	COMPLETED	A Randomized Placebo-Controlled Study of Lovastatin in Children With Neurofibromatosis Type 1
NCT01125046	PHASE2	COMPLETED	Bevacizumab in Treating Patients With Recurrent or Progressive Meningiomas
NCT01402817	PHASE2	TERMINATED	Study of Sutent®/Sunitinib (SU11248) in Subjects With NF-1 Plexiform Neurofibromas
NCT01412892	PHASE2	COMPLETED	Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas
NCT01553149	PHASE2	COMPLETED	Low-Dose or High-Dose Lenalidomide in Treating Younger Patients With Recurrent, Refractory, or Progressive Pilocytic Astrocytoma or Optic Pathway Glioma
NCT01673009	PHASE2	COMPLETED	Phase II Study of Gleevec/Imatinib Mesylate (STI-571, NCS 716051) in Neurofibromatosis (NF1) Patients With Plexiform Neurofibromas
NCT01968590	PHASE2	TERMINATED	Vitamin D Supplementation for Adults With Neurofibromatosis Type 1 (NF1)
NCT02096471	PHASE2	COMPLETED	MEK Inhibitor PD-0325901 Trial in Adolescents and Adults With NF1
NCT02101736	PHASE2	COMPLETED	Cabozantinib for Plexiform Neurofibromas (PN) in Subjects With NF1 in Children and Adults
NCT02332902	PHASE2	COMPLETED	Everolimus for Treatment of Disfiguring Cutaneous Lesions in Neurofibromatosis1 CRAD001CUS232T
NCT02407405	PHASE2	ACTIVE_NOT_RECRUITING	MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas
NCT02728388	PHASE2	RECRUITING	Photodynamic Therapy for Benign Dermal Neurofibromas- Phase II
NCT02839720	PHASE2	COMPLETED	Selumetinib in Treating Patients With Neurofibromatosis Type 1 and Cutaneous Neurofibroma
NCT02964884	PHASE2	ACTIVE_NOT_RECRUITING	Interventions for Reading Disabilities in NF1
NCT03090971	PHASE2	COMPLETED	Use of Topical Liquid Diclofenac Following Laser Microporation of Cutaneous Neurofibromas in Patients With NF1
NCT03109301	PHASE2	WITHDRAWN	Mitogen Activated Protein Kinase Kinase (MEK1/2) Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in People With Neurofibromatosis Type 1 (NF1) Mutated Gastrointestinal Stromal Tumors (GIST)
NCT03190915	PHASE2	ACTIVE_NOT_RECRUITING	Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia
NCT03231306	PHASE2	COMPLETED	Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas
NCT03433183	PHASE2	COMPLETED	SARC031: MEK Inhibitor Selumetinib (AZD6244) in Combination With the mTOR Inhibitor Sirolimus for Patients With Malignant Peripheral Nerve Sheath Tumors
NCT03741101	PHASE2	UNKNOWN	Treatment of NF1-related Plexiform Neurofibroma With Trametinib
NCT03962543	PHASE2	ACTIVE_NOT_RECRUITING	MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas
NCT04435665	PHASE2	COMPLETED	NFX-179 Topical Gel Treatment in Adults With Neurofibromatosis 1 (NF1) and Cutaneous Neurofibromas (cNF)
NCT04481035	PHASE2	COMPLETED	Antioxidant Therapy With N-acetylcysteine for Learning and Motor Behavior in Children With Neurofibromatosis Type 1