RIT1

Summary

RIT1 (Ras like without CAAX 1, HGNC:10023) is a protein-coding gene on chromosome 1q22, encoding GTP-binding protein Rit1 (Q92963). Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation. In precision oncology, RIT1 Mutation confers sensitivity to Selumetinib + Pictilisib in Lung Adenocarcinoma (CIViC Level D).

This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 6016 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 27
• Clinical variants (ClinVar): 413 total — 18 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 91
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006912

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10023
Approved symbol	RIT1
Name	Ras like without CAAX 1
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	RIBB, ROC1, MGC125864, MGC125865
Ensembl gene	ENSG00000143622
Ensembl biotype	protein_coding
OMIM	609591
Entrez	6016

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000368322, ENST00000368323, ENST00000461050, ENST00000462687, ENST00000539040, ENST00000609492, ENST00000650659, ENST00000651833, ENST00000651853, ENST00000704061, ENST00000859070, ENST00000912983, ENST00000912984

RefSeq mRNA: 3 — MANE Select: NM_006912 NM_001256820, NM_001256821, NM_006912

CCDS: CCDS1123, CCDS58036, CCDS58037

Canonical transcript exons

ENST00000368323 — 6 exons

Exon	Start	End
ENSE00001446871	155897808	155900618
ENSE00003462895	155904311	155904502
ENSE00003703203	155904731	155904804
ENSE00003703276	155910656	155910804
ENSE00003707431	155910450	155910506
ENSE00003841643	155911243	155911349

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 95.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.1995 / max 1024.8134, expressed in 1802 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14996	9.2309	1768
14995	8.7042	1680
14993	1.2609	335
14994	0.5869	231
14991	0.2738	110
14992	0.1428	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.68	gold quality
mononuclear cell	CL:0000842	95.10	gold quality
leukocyte	CL:0000738	94.83	gold quality
esophagus squamous epithelium	UBERON:0006920	93.29	gold quality
amniotic fluid	UBERON:0000173	93.27	gold quality
calcaneal tendon	UBERON:0003701	92.17	gold quality
stromal cell of endometrium	CL:0002255	92.16	gold quality
esophagus mucosa	UBERON:0002469	92.07	gold quality
lower esophagus mucosa	UBERON:0035834	92.00	gold quality
epithelium of esophagus	UBERON:0001976	91.49	gold quality
islet of Langerhans	UBERON:0000006	91.28	gold quality
blood	UBERON:0000178	91.26	gold quality
ventricular zone	UBERON:0003053	91.14	gold quality
adrenal tissue	UBERON:0018303	90.53	gold quality
vagina	UBERON:0000996	89.07	gold quality
esophagus	UBERON:0001043	88.87	gold quality
palpebral conjunctiva	UBERON:0001812	88.84	gold quality
granulocyte	CL:0000094	88.83	gold quality
ganglionic eminence	UBERON:0004023	88.67	gold quality
tendon	UBERON:0000043	88.65	gold quality
gall bladder	UBERON:0002110	88.65	gold quality
upper lobe of left lung	UBERON:0008952	88.65	gold quality
tendon of biceps brachii	UBERON:0008188	88.19	gold quality
descending thoracic aorta	UBERON:0002345	88.12	gold quality
colonic epithelium	UBERON:0000397	88.07	gold quality
right lung	UBERON:0002167	87.96	gold quality
upper lobe of lung	UBERON:0008948	87.96	gold quality
thoracic aorta	UBERON:0001515	87.94	gold quality
ascending aorta	UBERON:0001496	87.92	gold quality
bone marrow	UBERON:0002371	87.63	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

109 targeting RIT1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-345-3P	99.89	70.23	1421

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 36)

• Rit plays a key role in human neuronal development and regeneration through activating both known and as yet undefined signaling pathways (PMID:12668729)
• Gene amplification is one of the main activating ways of RIT1 gene in hepatocellular carcinoma (HCC), and its amplification might be correlated with HCC carcinogenesis, while point mutation might be not. (PMID:14767908)
• Data suggest that Rit is involved in a novel pathway of neuronal development and regeneration by coupling specific trophic factor signals to sustained activation of the B-Raf/ERK and p38 MAP kinase cascades. (PMID:15632082)
• the studies establish Rit as a central regulator of a p38 MAPK-dependent signaling cascade that functions as a critical cellular survival mechanism in response to stress (PMID:21444726)
• the Rit-p38-MSK1/2 signaling pathway may have an important role in the stress-dependent regulation of CREB-dependent gene expression. (PMID:23038261)
• the present studies identify a critical role for the Rit-p38 MAPK signaling cascade in promoting hippocampal neuron survival following oxidative stress (PMID:23123784)
• ROC1 knockdown remarkably inhibited bladder cancer cell growth, arrested cells at the G2 phase of the cell cycle, and induced the p53-dependent cell senescence. (PMID:23667514)
• study demonstrates that RIT1 abnormalities, including activating mutations and locus amplifications, are novel lesions in a subgroup of patients with myeloid neoplasms, particularly frequent in chronic myelomonocytic leukemia (PMID:23765226)
• we highlight recent studies using transgenic and knockout animal models which have begun to elucidate the physiological roles for the Rit subfamily, including emerging roles in the regulation of neuronal morphology and cellular survival signaling (PMID:23770287)
• Five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. (PMID:23791108)
• Data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas. (PMID:24469055)
• four additional cases of Noonan syndrome with mutations in RIT1, were identified. (PMID:24939608)
• Because of the relatively high frequency of mutations in RIT1 among patients with NS and its occurrence in different populations, we suggest that it should be added to the list of genes included in panels for the molecular diagnosis of NS. (PMID:25124994)
• Mutations in RIT1 cause Noonan syndrome. Mutations in RIT1 affect RAS-MAPK/MEK-ERK signaling. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins. (PMID:25959749)
• We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable pathogenicity was detected. (PMID:26518681)
• elevated expression of RIT1 may contribute to the progression of endometrial cancer and thus may serve as a novel prognostic marker and a promising molecular target for the treatment of endometrial cancer. (PMID:26617739)
• A genotype-phenotype correlation analysis of available records indicated that germline RIT1 mutations cause a noonan syndrome phenotype characterized by a mild facial appearance. (PMID:26714497)
• Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies. (PMID:26757980)
• RIT1 is one of the major genes for NS. The RIT1-associated phenotype differs gradually from other NS subtypes, with a high prevalence of cardiovascular manifestations, especially hypertrophic cardiomyopathy. (PMID:27101134)
• Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum (PMID:27109146)
• Biochemical Classification of Disease-associated Mutants of RAS-like Protein Expressed in Many Tissues (RIT1). (PMID:27226556)
• Congenital left main coronary artery atresia in a Noonan syndrome is associated with RIT1 variant, leading to unrescued sudden death. (PMID:28347726)
• The functional assessment supported the pathogenicity of the RAF1 and RIT1 variants of unknown significance (VUSs), while the significance of two VUSs in A2ML1 remained unclear. (PMID:29402968)
• Data show that Ras-like without CAAX 1 protein (RIT1) binds the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. (PMID:29734338)
• RIT1 displays tumor-suppressing functions in ESCC. (PMID:30348939)
• Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1. (PMID:30872527)
• Mek inhibitor reverses hypertrophic cardiomyopathy in RIT1 mutated Noonan syndrome. (PMID:31355539)
• The molecular functions of RIT1 and its contribution to human disease. (PMID:32766847)
• The potential oncogenic role of the RAS-like GTP-binding gene RIT1 in glioblastoma. (PMID:32831193)
• The RIT1 C-terminus associates with lipid bilayers via charge complementarity. (PMID:33517146)
• Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1. (PMID:34184824)
• Integrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer. (PMID:34373451)
• Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1. (PMID:34846918)
• RIT1 Promotes Glioma Proliferation and Invasion via the AKT/ERK/NF-kB Signaling Pathway. (PMID:35290620)
• Cardiac features of Noonan syndrome in Japanese patients. (PMID:35475426)
• RIT1 regulates mitosis and promotes proliferation by interacting with SMC3 and PDS5 in hepatocellular carcinoma. (PMID:38017479)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rit1	ENSDARG00000069150
mus_musculus	Rit1	ENSMUSG00000028057
rattus_norvegicus	Rit1	ENSRNOG00000064584

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), RASL11B (ENSG00000128045), KRAS (ENSG00000133703), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

GTP-binding protein Rit1 — Q92963 (reviewed: Q92963)

Alternative names: Ras-like protein expressed in many tissues, Ras-like without CAAX protein 1

All UniProt accessions (6): Q92963, A0A494C0S1, A0A494C0U3, A0A994J480, V9GY29, V9GYC3

UniProt curated annotations — full annotation on UniProt →

Function. Plays a crucial role in coupling NGF stimulation to the activation of both EPHB2 and MAPK14 signaling pathways and in NGF-dependent neuronal differentiation. Involved in ELK1 transactivation through the Ras-MAPK signaling cascade that mediates a wide variety of cellular functions, including cell proliferation, survival, and differentiation.

Subunit / interactions. Interacts with AFDN, the C-terminal domain of RALGDS and RLF, but not with RIN1 and PIK3CA. RLF binds exclusively to the active GTP-bound form. Strongly interacts with BRAF, but only weakly with RAF1. BARF and RAF1 association is dependent upon the GTP-bound state. Interacts with RGL3.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in many tissues.

Disease relevance. Noonan syndrome 8 (NS8) [MIM:615355] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Alternates between an inactive form bound to GDP and an active form bound to GTP.

Miscellaneous. Stimulation of the NGF and EGF receptor signaling pathways results in rapid and prolonged activation. Shows rapid uncatalyzed guanine nucleotide dissociation rates, which are much faster than those of most Ras subfamily members.

Similarity. Belongs to the small GTPase superfamily. Ras family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92963-1	1	yes
Q92963-2	2
Q92963-3	3

RefSeq proteins (3): NP_001243749, NP_001243750, NP_008843* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (35 total): sequence variant 9, strand 7, helix 7, mutagenesis site 4, binding site 3, splice variant 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9MF1	X-RAY DIFFRACTION	2.2
4KLZ	X-RAY DIFFRACTION	2.3
9MEY	X-RAY DIFFRACTION	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92963-F1	87.78	0.73

Functional residue map

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

Ligand- & substrate-binding residues (3): 28–35; 75–79; 134–137

Mutagenesis-validated functional residues (4):

Position	Phenotype
35	dominant negative. loss of interaction with afdn, rlf and ralgds.
53	loss of interaction with afdn, rlf and ralgds; when associated with l-79.
55	loss of interaction with afdn, but not with rlf and ralgds; when associated with l-79.
79	constitutively active. dramatic reduction of the rate of gtp hydrolysis. loss of interaction with afdn, rlf and ralgds;

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-187706	Signalling to p38 via RIT and RIN

MSigDB gene sets: 420 (showing top): AP1_01, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, KAAB_FAILED_HEART_ATRIUM_DN, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, CAGCTG_AP4_Q5, RODRIGUES_NTN1_TARGETS_DN, AP1_Q4_01, BRN2_01, OCT1_03, BACH2_01, WTGAAAT_UNKNOWN, TCF11_01, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, TGANTCA_AP1_C

GO Biological Process (2): signal transduction (GO:0007165), Ras protein signal transduction (GO:0007265)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), calmodulin binding (GO:0005516), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): plasma membrane (GO:0005886), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signalling to ERKs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
guanyl ribonucleotide binding	2
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
protein binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

2017 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIT1	RGL3	Q3MIN7	476
RIT1	NAIF1	Q69YI7	471
RIT1	KSR2	Q6VAB6	451
RIT1	USF1	P22415	368
RIT1	LZTR1	Q8N653	365
RIT1	OR5H1	A6NKK0	359
RIT1	RBM46	Q8TBY0	355
RIT1	SPDYC	Q5MJ68	338
RIT1	A2ML1	A8K2U0	337
RIT1	CTDSP2	O14595	337
RIT1	SHOC2	Q9UQ13	319
RIT1	ZNF687	Q8N1G0	310
RIT1	BCL2L12	Q9HB09	306
RIT1	PLPPR1	Q8TBJ4	301
RIT1	NPAT	Q14207	295

IntAct

43 interactions, top by confidence:

A	B	Type	Score
YAF2	E2F6	psi-mi:“MI:0914”(association)	0.640
RIT1	PAK1	psi-mi:“MI:0915”(physical association)	0.620
PAK1	RIT1	psi-mi:“MI:0915”(physical association)	0.620
RIT1	PAK1	psi-mi:“MI:0407”(direct interaction)	0.620
RIT1	CDC42	psi-mi:“MI:0915”(physical association)	0.620
RIT1	RAC1	psi-mi:“MI:0915”(physical association)	0.620
PAK1	RIT1	psi-mi:“MI:0403”(colocalization)	0.620
RIT1	CDC42	psi-mi:“MI:0407”(direct interaction)	0.620
RIT1	RAC1	psi-mi:“MI:0407”(direct interaction)	0.620
CDC42	RIT1	psi-mi:“MI:0403”(colocalization)	0.620
RIT1	RAC1	psi-mi:“MI:0403”(colocalization)	0.620
RGL3	RIT1	psi-mi:“MI:0915”(physical association)	0.560
TMEM182	LGALS3	psi-mi:“MI:0914”(association)	0.560
RIT1	MAD2L1BP	psi-mi:“MI:0914”(association)	0.530
RIT1	RLF	psi-mi:“MI:0915”(physical association)	0.510
RIT1	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.440
RIT1	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
RIT1	GRB2	psi-mi:“MI:0915”(physical association)	0.400
RIT1	DLST	psi-mi:“MI:0915”(physical association)	0.400
RIT1		psi-mi:“MI:0915”(physical association)	0.400
RIT1	RGL1	psi-mi:“MI:0915”(physical association)	0.400
RIT1	ACTL6B	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1238): LZTR1 (Affinity Capture-MS), CAMKV (Affinity Capture-MS), RIT2 (Affinity Capture-MS), MAD2L1BP (Affinity Capture-MS), RALGDS (Two-hybrid), RIT1 (Reconstituted Complex), LZTR1 (Affinity Capture-MS), LZTR1 (Affinity Capture-Western), LZTR1 (Reconstituted Complex), PTN (Two-hybrid), LRIF1 (Two-hybrid), RGL3 (Two-hybrid), RIT1 (Proximity Label-MS), MLLT4 (Two-hybrid), RLF (Reconstituted Complex)

ESM2 similar proteins: A8NU18, D3Z8L7, G4MZY8, G4N1S3, O08989, O14807, O42785, O93856, P01114, P04388, P08647, P0CQ42, P0CQ43, P10114, P10301, P10833, P22126, P22278, P22279, P22280, P28775, P32252, P32253, P32254, P34726, P38976, P51539, P61225, P61226, P61227, P62070, P62071, P70425, P70426, P87018, P97538, Q01387, Q05058, Q06AU2, Q08DI5

Diamond homologs: A1DZY4, A6QP66, A8NU18, C4YKT4, O08989, O14807, O35929, O88667, O93856, O94363, P01119, P03967, P08645, P08647, P0CY32, P10114, P10536, P11233, P11234, P15064, P17609, P22124, P22126, P22278, P22279, P22280, P28775, P32254, P36860, P36863, P48555, P59279, P61105, P61225, P61226, P61227, P62070, P62071, P63320, P63321

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RLF	“up-regulates activity”	RIT1	binding
RALGDS	“up-regulates activity”	RIT1	binding
AFDN	“up-regulates activity”	RIT1	binding
RIT1	“up-regulates activity”	BRAF	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
RAF/MAP kinase cascade	5	12.7×	1e-03
Signaling by Receptor Tyrosine Kinases	5	10.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	5	12.6×	4e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	5
Uncertain significance	196
Likely benign	137
Benign	15

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1065464	NM_006912.6(RIT1):c.280G>T (p.Glu94Ter)	Pathogenic
1695891	NM_006912.6(RIT1):c.67A>G (p.Lys23Glu)	Pathogenic
183401	NM_006912.6(RIT1):c.104G>C (p.Ser35Thr)	Pathogenic
183406	NM_006912.6(RIT1):c.244T>A (p.Phe82Ile)	Pathogenic
183407	NM_006912.6(RIT1):c.244T>C (p.Phe82Leu)	Pathogenic
183408	NM_006912.6(RIT1):c.244T>G (p.Phe82Val)	Pathogenic
183409	NM_006912.6(RIT1):c.247A>C (p.Thr83Pro)	Pathogenic
183411	NM_006912.6(RIT1):c.265T>C (p.Tyr89His)	Pathogenic
2431215	NM_006912.6(RIT1):c.111G>C (p.Met37Ile)	Pathogenic
265328	NM_006912.6(RIT1):c.270G>T (p.Met90Ile)	Pathogenic
3349333	NM_006912.6(RIT1):c.69A>T (p.Lys23Asn)	Pathogenic
370035	NM_006912.6(RIT1):c.246T>A (p.Phe82Leu)	Pathogenic
372863	NM_006912.6(RIT1):c.245T>G (p.Phe82Cys)	Pathogenic
561621	NM_006912.6(RIT1):c.229G>T (p.Ala77Ser)	Pathogenic
561681	NM_006912.6(RIT1):c.268A>G (p.Met90Val)	Pathogenic
581105	NM_006912.6(RIT1):c.69A>C (p.Lys23Asn)	Pathogenic
60509	NM_006912.6(RIT1):c.284G>C (p.Gly95Ala)	Pathogenic
694696	NM_006912.6(RIT1):c.245T>C (p.Phe82Ser)	Pathogenic
2447640	NM_006912.6(RIT1):c.259G>A (p.Asp87Asn)	Likely pathogenic
3633617	NM_006912.6(RIT1):c.260A>C (p.Asp87Ala)	Likely pathogenic
976308	NM_006912.6(RIT1):c.268A>C (p.Met90Leu)	Likely pathogenic
981601	NM_006912.6(RIT1):c.113C>A (p.Thr38Asn)	Likely pathogenic
981604	NM_006912.6(RIT1):c.235C>G (p.Gln79Glu)	Likely pathogenic

SpliceAI

856 predictions. Top by Δscore:

Variant	Effect	Δscore
1:155900618:CCTT:C	acceptor_gain	1.0000
1:155900619:C:CC	acceptor_gain	1.0000
1:155900620:T:C	acceptor_gain	1.0000
1:155900621:T:C	acceptor_gain	1.0000
1:155900621:T:TC	acceptor_gain	1.0000
1:155900628:CAAAA:C	acceptor_gain	1.0000
1:155900632:A:AC	acceptor_gain	1.0000
1:155900632:A:C	acceptor_gain	1.0000
1:155900634:G:C	acceptor_gain	1.0000
1:155904305:CCTCA:C	donor_loss	1.0000
1:155904306:CTCA:C	donor_loss	1.0000
1:155904307:TCA:T	donor_loss	1.0000
1:155904308:CA:C	donor_loss	1.0000
1:155904309:A:T	donor_loss	1.0000
1:155904310:C:G	donor_loss	1.0000
1:155904310:CCTGT:C	donor_gain	1.0000
1:155904319:G:C	donor_gain	1.0000
1:155904499:CTGC:C	acceptor_gain	1.0000
1:155904503:C:CC	acceptor_gain	1.0000
1:155904802:CTT:C	acceptor_gain	1.0000
1:155910444:GCTTA:G	donor_loss	1.0000
1:155910445:CTTA:C	donor_loss	1.0000
1:155910446:TTAC:T	donor_loss	1.0000
1:155910447:TACCA:T	donor_loss	1.0000
1:155910448:A:AC	donor_gain	1.0000
1:155910448:ACCAA:A	donor_loss	1.0000
1:155910449:C:CA	donor_loss	1.0000
1:155910449:C:CC	donor_gain	1.0000
1:155910502:CATGG:C	acceptor_gain	1.0000
1:155910507:C:CC	acceptor_gain	1.0000

AlphaMissense

1438 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:155900557:G:A	S164F	1.000
1:155904335:C:A	K135N	1.000
1:155904335:C:G	K135N	1.000
1:155904439:A:G	S101P	1.000
1:155904452:A:C	F96L	1.000
1:155904452:A:T	F96L	1.000
1:155904454:A:G	F96L	1.000
1:155904456:C:T	G95E	1.000
1:155904457:C:A	G95W	1.000
1:155904457:C:G	G95R	1.000
1:155904457:C:T	G95R	1.000
1:155904494:A:C	F82L	1.000
1:155904494:A:T	F82L	1.000
1:155904496:A:G	F82L	1.000
1:155904736:C:G	G78R	1.000
1:155904736:C:T	G78R	1.000
1:155904743:A:C	D75E	1.000
1:155904743:A:T	D75E	1.000
1:155904744:T:A	D75V	1.000
1:155904744:T:C	D75G	1.000
1:155904744:T:G	D75A	1.000
1:155904745:C:G	D75H	1.000
1:155910664:C:T	G33E	1.000
1:155900509:C:G	R180P	0.999
1:155900515:A:G	L178P	0.999
1:155900523:G:C	F175L	0.999
1:155900523:G:T	F175L	0.999
1:155900524:A:G	F175S	0.999
1:155900525:A:G	F175L	0.999
1:155900554:G:T	A165D	0.999

dbSNP variants (sampled 300 via entrez): RS1000065339 (1:155904934 C>T), RS1000165319 (1:155907918 G>A), RS1000198460 (1:155908177 C>G,T), RS1000604723 (1:155898557 A>G), RS1000635813 (1:155898869 C>A), RS1000754900 (1:155900849 G>A), RS1000982612 (1:155906807 G>A,C), RS1001035556 (1:155912201 G>A,T), RS1001107143 (1:155912422 C>T), RS1001147156 (1:155903101 T>C,G), RS1001498020 (1:155908680 A>C), RS1001572966 (1:155908352 G>A), RS1001732105 (1:155901569 C>T), RS1001861429 (1:155899422 T>A,C,G), RS1001926285 (1:155901248 C>A)

Disease associations

OMIM: gene MIM:609591 | disease phenotypes: MIM:615355, MIM:236750, MIM:163950, MIM:602501, MIM:115150, MIM:118400

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome	Definitive	Autosomal dominant
Noonan syndrome 8	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Noonan syndrome	Definitive	AD

Mondo (10): Noonan syndrome 8 (MONDO:0014143), non-immune hydrops fetalis (MONDO:0009369), Noonan syndrome (MONDO:0018997), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), RASopathy (MONDO:0021060), congenital heart disease (MONDO:0005453), Noonan syndrome 1 (MONDO:0008104), megalencephaly-capillary malformation-polymicrogyria syndrome (MONDO:0011240), cardiofaciocutaneous syndrome (MONDO:0015280), cherubism (MONDO:0007315)

Orphanet (7): Noonan syndrome (Orphanet:648), Non-immune hydrops fetalis (Orphanet:363999), RASopathy (Orphanet:536391), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Megalencephaly-capillary malformation-polymicrogyria syndrome (Orphanet:60040), Cardiofaciocutaneous syndrome (Orphanet:1340), Cherubism (Orphanet:184)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000078	Abnormality of the genital system
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000391	Thickened helices
HP:0000407	Sensorineural hearing impairment
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000635	Blue irides
HP:0000639	Nystagmus
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000938	Osteopenia
HP:0000953	Hyperpigmentation of the skin

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST000245_12	Conduct disorder (maternal expressed emotions interaction)	7.000000e-06
GCST001725_35	Inflammatory bowel disease	6.000000e-11
GCST004131_70	Inflammatory bowel disease	6.000000e-08
GCST004132_44	Crohn’s disease	2.000000e-07
GCST004904_249	Body mass index	1.000000e-09
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST008362_92	Birth weight	8.000000e-12
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10
GCST010700_5	Cortical thickness (MOSTest)	8.000000e-17
GCST010701_66	Cortical surface area (MOSTest)	1.000000e-09
GCST010702_43	Subcortical volume (MOSTest)	3.000000e-10
GCST010703_253	Brain morphology (MOSTest)	4.000000e-14
GCST011946_11	White matter hyperintensity volume	7.000000e-06
GCST011947_12	White matter hyperintensity volume	7.000000e-07
GCST011949_29	White matter hyperintensity volume (adjusted for hypertension)	3.000000e-06
GCST011950_36	White matter hyperintensity volume (adjusted for hypertension)	3.000000e-07
GCST011952_23	White matter hyperintensity volume x hypertension interaction (2df)	4.000000e-06
GCST011953_20	White matter hyperintensity volume x hypertension interaction (2df)	5.000000e-07
GCST90002387_233	Immature fraction of reticulocytes	1.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008342	parental emotion expression measurmement
EFO:0004340	body mass index
EFO:0004341	body fat distribution
EFO:0004344	birth weight
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D002636	Cherubism	C05.116.099.708.375.199; C05.500.174; C07.320.173; C16.131.621.207.540.170; C16.320.170
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
C535579	Cardiofaciocutaneous syndrome (supp.)
C536142	Megalencephaly cutis marmorata telangiectatica congenita (supp.)
C537846	Noonan like syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
RIT1 Mutation	Selumetinib + Pictilisib	Lung Adenocarcinoma	Sensitivity/Response	CIViC D	EID742

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, affects cotreatment	8
Benzo(a)pyrene	increases methylation, increases expression	6
Tobacco Smoke Pollution	increases expression, affects expression	4
Cyclosporine	decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Tretinoin	increases expression, decreases expression	3
sulforaphane	increases expression	2
cobaltous chloride	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression, decreases expression	2
Cadmium Chloride	increases expression	2
dicrotophos	decreases expression	1
N(6)-(delta(2)-isopentenyl)adenine	increases expression	1
chloroacetaldehyde	increases expression	1
methylmercuric chloride	decreases expression, increases expression	1
triphenyl phosphate	affects expression	1
methylparaben	decreases expression	1
sodium arsenite	increases expression	1
4-phenylenediamine	increases expression	1
nickel sulfate	increases expression	1
cupric oxide	increases expression	1
gadodiamide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
NSC 689534	affects binding, increases expression	1
Bortezomib	increases expression	1
Rosiglitazone	increases expression	1
Cidofovir	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1530	NCI-H2110	Cancer cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease