MRAS

Summary

MRAS (muscle RAS oncogene homolog, HGNC:7227) is a protein-coding gene on chromosome 3q22.3, encoding Ras-related protein M-Ras (O14807). Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival.

This gene encodes a member of the Ras family of small GTPases. These membrane-associated proteins function as signal transducers in multiple processes including cell growth and differentiation, and dysregulation of Ras signaling has been associated with many types of cancer. The encoded protein may play a role in the tumor necrosis factor-alpha and MAP kinase signaling pathways. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 22808 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome 11 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 36
• Clinical variants (ClinVar): 268 total — 5 likely-pathogenic
• Phenotypes (HPO): 84
• MANE Select transcript: NM_001085049

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7227
Approved symbol	MRAS
Name	muscle RAS oncogene homolog
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Aliases	M-RAs, R-RAS3, RRAS3
Ensembl gene	ENSG00000158186
Ensembl biotype	protein_coding
OMIM	608435
Entrez	22808

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000289104, ENST00000423968, ENST00000461114, ENST00000464896, ENST00000474559, ENST00000475711, ENST00000477784, ENST00000478647, ENST00000494949, ENST00000614350, ENST00000621127, ENST00000867251, ENST00000949756, ENST00000949757, ENST00000949758, ENST00000949759, ENST00000949760, ENST00000949761, ENST00000949762, ENST00000949763, ENST00000949764

RefSeq mRNA: 6 — MANE Select: NM_001085049 NM_001085049, NM_001252090, NM_001252091, NM_001252092, NM_001252093, NM_012219

CCDS: CCDS3100, CCDS58855

Canonical transcript exons

ENST00000423968 — 6 exons

Exon	Start	End
ENSE00001037571	138398469	138398568
ENSE00001037576	138400534	138400613
ENSE00001327781	138402170	138405533
ENSE00001355734	138372866	138373076
ENSE00001834866	138348579	138348767
ENSE00003626282	138397324	138397477

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 97.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3450 / max 250.9812, expressed in 1466 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38786	4.5984	702
38789	2.4574	996
38788	2.2611	1003
38792	2.2466	1100
38790	1.8112	862
38784	0.4824	216
38793	0.3617	178
38791	0.2931	156
202946	0.2549	137
38782	0.2486	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	97.71	gold quality
medial globus pallidus	UBERON:0002477	97.47	gold quality
nucleus accumbens	UBERON:0001882	97.29	gold quality
globus pallidus	UBERON:0001875	97.22	gold quality
right atrium auricular region	UBERON:0006631	97.03	gold quality
peripheral nervous system	UBERON:0000010	96.97	gold quality
tibial nerve	UBERON:0001323	96.97	gold quality
heart left ventricle	UBERON:0002084	96.60	gold quality
cardiac atrium	UBERON:0002081	96.58	gold quality
cardiac ventricle	UBERON:0002082	96.57	gold quality
adrenal tissue	UBERON:0018303	96.17	gold quality
heart	UBERON:0000948	96.16	gold quality
trigeminal ganglion	UBERON:0001675	96.06	gold quality
right frontal lobe	UBERON:0002810	96.06	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.89	gold quality
middle temporal gyrus	UBERON:0002771	95.85	gold quality
amygdala	UBERON:0001876	95.84	gold quality
heart right ventricle	UBERON:0002080	95.83	gold quality
apex of heart	UBERON:0002098	95.75	gold quality
caudate nucleus	UBERON:0001873	95.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.36	gold quality
ventral tegmental area	UBERON:0002691	95.25	gold quality
substantia nigra pars compacta	UBERON:0001965	95.14	gold quality
superior vestibular nucleus	UBERON:0007227	95.12	gold quality
left adrenal gland cortex	UBERON:0035825	95.10	gold quality
right adrenal gland	UBERON:0001233	95.07	gold quality
temporal lobe	UBERON:0001871	95.05	gold quality
adrenal cortex	UBERON:0001235	95.01	gold quality
right adrenal gland cortex	UBERON:0035827	95.00	gold quality
putamen	UBERON:0001874	94.94	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.62
E-CURD-112	yes	3.87
E-GEOD-99795	no	25.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

151 targeting MRAS, 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-4673	100.00	66.64	1490
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-1297	99.91	73.41	3162

Literature-anchored findings (GeneRIF, showing 20)

• implicated in a novel pathway of neuronal differentiation by coupling specific trophic factors to the MAPK cascade through the activation of B-Raf (PMID:12138204)
• These findings proved a crucial role of the cross-talk between two Ras-family GTPases M-Ras and Rap1, mediated by RA-GEF-2, in adhesion signaling. (PMID:17538012)
• Identification of one new CAD risk locus on 3q22.3 in MRAS, and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43. (PMID:19198612)
• Both MRAS and SHOC2 play a key role in polarized migration. (PMID:24211266)
• The MRAS gene loci might have a minor effect in conferring susceptibility to coronary artery disease in the Chinese population. (PMID:25800439)
• The association of the MARS rs6782181 polymorphism and serum lipid levels is different between the Mulao and Han populations, or between males and females in the both ethnic groups. (PMID:25973078)
• Results discovered for the first time that MRAS is recurrently mutated, indicating that MRAS mutations could drive tumorigenesis of Type IV gastric neoplasm. (PMID:27891760)
• acute coronary syndrome in Czechs (30.4% vs 29.4% carriers of the minor T allele of MRAS[recessive model], p = 0.54; OR 1.05; 95% CI 0.89-1.24 for males and 32.1% vs 29.7% carriers of the minor T allele, p = 0.28; OR 1.12; 95% CI 0.91-1.37 for females) (PMID:29264877)
• In human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene. (PMID:30431558)
• Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. (PMID:31108500)
• We confirmed that the MRAS gene represents a causative gene for RASopathy. (PMID:31173466)
• In Chinese Han population, no association of MRAS single nucleotide polymorphisms with Ischemic Stroke risk was observed, while G allele of rs40593 was associated with increased risk of cerebral infarction. rs40593, rs751357, rs6782181 were associated with increased total cholesterol levels. (PMID:31770223)
• Correlation between MRAS gene polymorphism and atherosclerosis. (PMID:32495899)
• Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant. (PMID:34080768)
• Structural basis for SHOC2 modulation of RAS signalling. (PMID:35768504)
• Structure of the MRAS-SHOC2-PP1C phosphatase complex. (PMID:35830882)
• Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. (PMID:35831509)
• Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. (PMID:36175670)
• Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS. (PMID:37277529)
• Crystal structure of the GDP-bound human M-RAS protein in two crystal forms. (PMID:39196705)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mrasb	ENSDARG00000062865
danio_rerio	mrasa	ENSDARG00000075285
mus_musculus	Mras	ENSMUSG00000032470
rattus_norvegicus	Mras	ENSRNOG00000014060
caenorhabditis_elegans		WBGENE00004311

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), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), 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

Ras-related protein M-Ras — O14807 (reviewed: O14807)

Alternative names: Ras-related protein R-Ras3

All UniProt accessions (4): O14807, C9J601, C9J8Q6, Q6FGP0

UniProt curated annotations — full annotation on UniProt →

Function. Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival. Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates the MAPK pathway activation. The formation of the SMP complex only occurs when MRAS is GTP-bound. MRAS has low intrinsic GTPase activity and may require additional factors for activation. The SMP complex specifically dephosphorylates the inhibitory phosphorylation at ‘Ser-259’ of RAF1 kinase, ‘Ser-365’ of BRAF kinase and ‘Ser-214’ of ARAF kinase, stimulating their kinase activities.

Subunit / interactions. Component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex consisting of SHOC2, GTP-bound M-Ras/MRAS and the catalytic subunit of protein phosphatase 1 (either PPP1CA, PPP1CB or PPP1CC). Interacts (active GTP-bound form) with both SHOC2 and PP1c (all isoforms) to form a tertiary complex; SHOC2 and PP1c preferably bind M-Ras/MRAS, but they also bind K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS. Interacts with RGL3. Interacts (active GTP-bound form preferentially) with RGS14.

Subcellular location. Cell membrane.

Tissue specificity. Expression highly restricted to the brain and heart.

Disease relevance. Noonan syndrome 11 (NS11) [MIM:618499] 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. NS11 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 magnesium ion per subunit.

Induction. By IL9/interleukin-9, but not by IL2/interleukin-2 or IL4/interleukin-4.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O14807-1	1	yes
O14807-2	2

RefSeq proteins (6): NP_001078518, NP_001239019, NP_001239020, NP_001239021, NP_001239022, NP_036351 (=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 (57 total): binding site 24, helix 9, mutagenesis site 8, strand 7, sequence variant 3, chain 1, propeptide 1, short sequence motif 1, modified residue 1, lipid moiety-binding region 1, splice variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
9O0P	X-RAY DIFFRACTION	1.5
9O0Q	X-RAY DIFFRACTION	1.9
7TXH	X-RAY DIFFRACTION	1.95
9C1A	X-RAY DIFFRACTION	1.96
9B4R	X-RAY DIFFRACTION	2.1
7TVF	X-RAY DIFFRACTION	2.17
9C1B	X-RAY DIFFRACTION	2.27
9B4T	X-RAY DIFFRACTION	2.75
9MEZ	X-RAY DIFFRACTION	2.8
7UPI	ELECTRON MICROSCOPY	2.89
7SD0	ELECTRON MICROSCOPY	2.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14807-F1	86.61	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 (24): 27; 28; 38; 39; 40; 42; 44; 45; 45; 67; 70; 126 …

Post-translational modifications (2): 205, 205

Mutagenesis-validated functional residues (8):

Position	Phenotype
22	promotes gtp binding.
41	impairs smp complex formation.
53	impairs smp complex formation.
71	promotes smp complex formation. promotes gtp binding.
74	impairs smp complex formation.
131–133	impairs smp complex formation when mutated to corresponding residues in hras.
131–133	impairs smp complex formation when mutated to corresponding residues in kras.
132	impairs smp complex formation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5673000	RAF activation
R-HSA-9726840	SHOC2 M1731 mutant abolishes MRAS complex function
R-HSA-9726842	Gain-of-function MRAS complexes activate RAF signaling

MSigDB gene sets: 415 (showing top): GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, KEGG_MAPK_SIGNALING_PATHWAY, AAGCCAT_MIR135A_MIR135B, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, KEGG_TIGHT_JUNCTION, BLALOCK_ALZHEIMERS_DISEASE_UP, BILD_E2F3_ONCOGENIC_SIGNATURE, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, VANTVEER_BREAST_CANCER_ESR1_DN, chr3q22, OCT1_B, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION

GO Biological Process (4): Ras protein signal transduction (GO:0007265), actin cytoskeleton organization (GO:0030036), cellular response to leukemia inhibitory factor (GO:1990830), signal transduction (GO:0007165)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), GTP-dependent protein binding (GO:0030742), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): protein phosphatase type 1 complex (GO:0000164), plasma membrane (GO:0005886), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by MRAS-complex mutants	2
RAF/MAP kinase cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
guanyl ribonucleotide binding	2
cellular anatomical structure	2
small GTPase-mediated signal transduction	1
cytoskeleton organization	1
actin filament-based process	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
protein serine/threonine phosphatase complex	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

2351 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRAS	SHOC2	Q9UQ13	984
MRAS	RAPGEF6	Q8TEU7	843
MRAS	RAPGEF5	Q92565	780
MRAS	RAPGEF2	Q9Y4G8	744
MRAS	RAF1	P04049	714
MRAS	RALGDS	Q12967	706
MRAS	PPP1CB	P37140	704
MRAS	PPP1CC	P36873	682
MRAS	SOS1	Q07889	673
MRAS	PLXNB1	O43157	667
MRAS	RASA1	P20936	614
MRAS	AFDN	P55196	589
MRAS	RASSF5	Q8WWW0	547
MRAS	IQGAP1	P46940	531
MRAS	MIA3	Q5JRA6	510

IntAct

20 interactions, top by confidence:

A	B	Type	Score
AFDN	MRAS	psi-mi:“MI:0915”(physical association)	0.510
MRAS	AFDN	psi-mi:“MI:0915”(physical association)	0.510
RAF1	MRAS	psi-mi:“MI:0407”(direct interaction)	0.440
MRAS	PKLR	psi-mi:“MI:0915”(physical association)	0.400
PPP1CA	MRAS	psi-mi:“MI:0915”(physical association)	0.400
PPP1CB	MRAS	psi-mi:“MI:0915”(physical association)	0.400
SHOC2	MRAS	psi-mi:“MI:0915”(physical association)	0.400
	MRAS	psi-mi:“MI:0915”(physical association)	0.400
MRAS	ELOC	psi-mi:“MI:0915”(physical association)	0.370
Rassf5	MRAS	psi-mi:“MI:0915”(physical association)	0.370
RAP1GDS1	MRAS	psi-mi:“MI:0914”(association)	0.350
PLXNB1	MRAS	psi-mi:“MI:0914”(association)	0.350
HRAS	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): MRAS (Reconstituted Complex), MRAS (Affinity Capture-Western), SHOC2 (Affinity Capture-Western), MRAS (Affinity Capture-Western), PKLR (Affinity Capture-MS), RALGDS (Two-hybrid), LZTR1 (Biochemical Activity), LZTR1 (Affinity Capture-Western), MRAS (Reconstituted Complex), MRAS (Reconstituted Complex), MRAS (Reconstituted Complex), MRAS (Affinity Capture-Western), BRAF (Affinity Capture-Western), RAPGEF5 (Affinity Capture-Western), RAPGEF5 (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

3 interactions.

A	Effect	B	Mechanism
FNTA	“up-regulates activity”	MRAS
FNTB	“up-regulates activity”	MRAS
SHOC2	up-regulates	MRAS	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	5
Uncertain significance	122
Likely benign	112
Benign	11

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2686009	NM_001085049.3(MRAS):c.359C>T (p.Pro120Leu)	Likely pathogenic
560681	NM_001085049.3(MRAS):c.67G>C (p.Gly23Arg)	Likely pathogenic
635781	NM_001085049.3(MRAS):c.68G>T (p.Gly23Val)	Likely pathogenic
635782	NM_001085049.3(MRAS):c.203C>T (p.Thr68Ile)	Likely pathogenic
635783	NM_001085049.3(MRAS):c.212A>G (p.Gln71Arg)	Likely pathogenic

SpliceAI

1265 predictions. Top by Δscore:

Variant	Effect	Δscore
3:138397322:A:AG	acceptor_gain	1.0000
3:138397323:G:GG	acceptor_gain	1.0000
3:138397323:GTTCT:G	acceptor_gain	1.0000
3:138398464:CCCA:C	acceptor_loss	1.0000
3:138398466:CAGG:C	acceptor_loss	1.0000
3:138398467:A:T	acceptor_loss	1.0000
3:138398467:AG:A	acceptor_gain	1.0000
3:138398468:GG:G	acceptor_gain	1.0000
3:138398468:GGGA:G	acceptor_gain	1.0000
3:138398523:G:GT	donor_gain	1.0000
3:138398535:G:GT	donor_gain	1.0000
3:138398543:G:GT	donor_gain	1.0000
3:138398544:A:T	donor_gain	1.0000
3:138398567:AT:A	donor_gain	1.0000
3:138398569:G:GG	donor_gain	1.0000
3:138402166:A:G	acceptor_gain	1.0000
3:138348321:CCCGG:C	donor_gain	0.9900
3:138348324:GG:G	donor_gain	0.9900
3:138348325:GG:G	donor_gain	0.9900
3:138348325:GGTA:G	donor_loss	0.9900
3:138348326:GTAA:G	donor_loss	0.9900
3:138348327:TAAG:T	donor_loss	0.9900
3:138372848:C:G	acceptor_gain	0.9900
3:138372850:T:G	acceptor_gain	0.9900
3:138373074:ACGGT:A	donor_loss	0.9900
3:138373075:CGG:C	donor_loss	0.9900
3:138373077:G:A	donor_loss	0.9900
3:138373077:G:GG	donor_gain	0.9900
3:138373078:T:A	donor_loss	0.9900
3:138374551:A:AG	acceptor_gain	0.9900

AlphaMissense

1398 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:138372941:G:A	G20R	1.000
3:138372941:G:C	G20R	1.000
3:138372941:G:T	G20W	1.000
3:138372942:G:A	G20E	1.000
3:138372942:G:T	G20V	1.000
3:138372956:G:C	G25R	1.000
3:138372956:G:T	G25C	1.000
3:138372957:G:A	G25D	1.000
3:138372957:G:T	G25V	1.000
3:138372959:A:C	K26Q	1.000
3:138372960:A:T	K26I	1.000
3:138372961:A:C	K26N	1.000
3:138372961:A:T	K26N	1.000
3:138372969:T:C	L29P	1.000
3:138372995:T:C	F38L	1.000
3:138372997:T:A	F38L	1.000
3:138372997:T:G	F38L	1.000
3:138373020:T:A	I46N	1.000
3:138397327:T:C	L66P	1.000
3:138397329:G:A	D67N	1.000
3:138397329:G:C	D67H	1.000
3:138397329:G:T	D67Y	1.000
3:138397330:A:C	D67A	1.000
3:138397330:A:G	D67G	1.000
3:138397330:A:T	D67V	1.000
3:138397331:C:A	D67E	1.000
3:138397331:C:G	D67E	1.000
3:138397336:C:A	A69D	1.000
3:138397338:G:A	G70R	1.000
3:138397338:G:C	G70R	1.000

dbSNP variants (sampled 300 via entrez): RS1000009406 (3:138391040 G>T), RS1000031948 (3:138369736 G>C), RS1000065097 (3:138379034 T>C), RS1000083950 (3:138369438 T>A), RS1000101212 (3:138354036 A>G,T), RS1000271604 (3:138393481 G>C), RS1000278605 (3:138361038 T>A), RS1000327621 (3:138349785 A>G), RS1000336724 (3:138363567 G>A,T), RS1000346465 (3:138350090 C>G), RS1000380803 (3:138352497 AT>A,ATTT), RS1000383788 (3:138399512 C>G), RS1000464645 (3:138377334 C>T), RS1000483751 (3:138398904 G>A), RS1000512826 (3:138401086 C>G)

Disease associations

OMIM: gene MIM:608435 | disease phenotypes: MIM:618499

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome 11	Definitive	Autosomal dominant
Noonan syndrome	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Noonan syndrome	Moderate	AD

Mondo (3): Noonan syndrome 11 (MONDO:0032786), RASopathy (MONDO:0021060), Noonan syndrome (MONDO:0018997)

Orphanet (2): Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), RASopathy (Orphanet:536391)

HPO phenotypes

84 total (30 of 84 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:0000276	Long face
HP:0000307	Pointed chin
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:0000414	Bulbous nose
HP:0000465	Webbed 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:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000938	Osteopenia

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000338_1	Coronary heart disease	7.000000e-13
GCST000998_22	Coronary heart disease	3.000000e-08
GCST002289_18	Coronary artery disease	1.000000e-07
GCST002337_30	Amyotrophic lateral sclerosis (sporadic)	3.000000e-06
GCST002783_180	Body mass index	7.000000e-06
GCST002783_44	Body mass index	3.000000e-07
GCST004557_161	Body mass index	3.000000e-08
GCST004557_265	Body mass index	3.000000e-06
GCST004557_45	Body mass index	6.000000e-09
GCST004557_87	Body mass index	3.000000e-06
GCST004558_211	Body mass index (joint analysis main effects and physical activity interaction)	5.000000e-06
GCST004558_229	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-09
GCST004558_60	Body mass index (joint analysis main effects and physical activity interaction)	3.000000e-06
GCST004558_80	Body mass index (joint analysis main effects and physical activity interaction)	4.000000e-08
GCST004559_158	Body mass index in physically active individuals	8.000000e-06
GCST004787_26	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	9.000000e-12
GCST005194_39	Coronary artery disease	5.000000e-16
GCST005195_125	Coronary artery disease	2.000000e-17
GCST005196_111	Coronary artery disease	3.000000e-18
GCST006988_85	Blond vs. brown/black hair color	3.000000e-08
GCST007094_135	Diastolic blood pressure	5.000000e-09
GCST007099_60	Systolic blood pressure	4.000000e-07
GCST007576_249	Chronotype	5.000000e-12
GCST010479_65	Coronary artery disease	1.000000e-09
GCST010774_22	Essential hypertension (time to event)	9.000000e-09
GCST010866_11	Coronary artery disease	1.000000e-20
GCST010989_232	Body size at age 10	6.000000e-14
GCST011365_67	Myocardial infarction	4.000000e-10
GCST011494_9	Daytime nap	3.000000e-07
GCST90020024_1271	A body shape index	2.000000e-17

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0008002	physical activity measurement
EFO:0003924	hair color
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0008328	chronotype measurement
EFO:0004918	age at diagnosis
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007828	daytime rest measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation, decreases expression	5
sodium arsenite	decreases reaction, increases activity, increases phosphorylation, decreases expression, increases expression	4
Particulate Matter	increases abundance, increases expression	3
Estradiol	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Asbestos, Crocidolite	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sulindac sulfide	increases expression	1
saikosaponin D	decreases expression	1
vanadyl sulfate	increases degradation, increases phosphorylation, decreases reaction, increases activity, affects binding (+1 more)	1
15-acetyldeoxynivalenol	increases expression	1
4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline	decreases reaction, increases activity	1
PCB 180	affects expression	1
torcetrapib	increases expression	1
(+)-JQ1 compound	decreases expression	1
Febuxostat	increases expression	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects expression	1
Vehicle Emissions	increases expression	1
Carbamazepine	affects expression	1
Chelating Agents	affects binding, decreases expression	1
Cisplatin	increases expression	1
Copper	affects binding, decreases expression	1
Diclofenac	affects expression	1
Diethylstilbestrol	increases expression	1
Fluorouracil	affects expression	1
Ketoconazole	increases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B1XJ	Abcam HeLa MRAS KO	Cancer cell line	Female
CVCL_D0QM	UMGi014-C-17	Induced pluripotent stem cell	Male
CVCL_D7VA	Ubigene A-549 MRAS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
NCT00960128	Not specified	COMPLETED	Observational Prospective Study on Patients Treated With Norditropin®
NCT02486731	Not specified	COMPLETED	Hormonal Sensitivity in Patients With Noonan and LEOPARD Syndromes
NCT03435627	Not specified	COMPLETED	Post Marketing Surveillance on Long-term Use With Norditropin® (Short Stature Due to Noonan Syndrome)
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05202210	Not specified	RECRUITING	Constitution of a Biological Collection to Study the Pathophysiology in Noonan Syndrome
NCT05308927	Not specified	ENROLLING_BY_INVITATION	French Registry of Children Treated With Norditropin® for Short Stature Associated With Noonan Syndrome
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT05761314	Not specified	RECRUITING	Solid Tumors in RASopathies
NCT06267807	Not specified	COMPLETED	Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders
NCT06331117	Not specified	UNKNOWN	Effect of RAS/MAPK Pathway Hyperactivation on Growth’ and Bone’ Profile of the RASopathies
NCT06355622	Not specified	UNKNOWN	Prevalence and Characterization of Pain in RASopathies
NCT06550635	Not specified	COMPLETED	Joint and Hematologic Disorders of Noonan Syndrome: French Descriptive Cross-sectional Study
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07259135	Not specified	NOT_YET_RECRUITING	Link Between Abnormal Bleeding and Coagulation Disorders in Noonan Syndromes
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT07464821	Not specified	RECRUITING	National Multicentre Study on Lipid Profile in Noonan Syndrome and Related Disorders: Trends by Age, Gender and Genotype
NCT06489067	Not specified	RECRUITING	Study of the Thyroid Function and Echostructural Morphology in Patients Affected With Rasopathies (ECORAS2023)
NCT06776380	Not specified	RECRUITING	Pubertal Development in Patients with RASopathies
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT07344480	Not specified	RECRUITING	Retrospective Natural History Study of RASopathy-associated Cardiomyopathy (RAS-CM)