RNASE3

Summary

RNASE3 (ribonuclease A family member 3, HGNC:10046) is a protein-coding gene on chromosome 14q11.2, encoding Eosinophil cationic protein (P12724). Cytotoxin and helminthotoxin with low-efficiency ribonuclease activity. In precision oncology, RAF1 Amplification confers sensitivity to Paclitaxel + Carboplatin + Sorafenib in Skin Melanoma (CIViC Level B); 3 further curated variant–drug associations are listed below.

The protein encoded by this gene belongs to the pancreatic ribonuclease family, a subset of the ribonuclease A superfamily. The protein exhibits antimicrobial activity against pathogenic bacteria

Source: NCBI Gene 6037 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 26 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 1,436 total — 13 pathogenic, 27 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 12 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 163
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.11 (intermediate), LOEUF 1.94 (unconstrained)
• MANE Select transcript: NM_002935

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10046
Approved symbol	RNASE3
Name	ribonuclease A family member 3
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	ECP, RAF1
Ensembl gene	ENSG00000169397
Ensembl biotype	protein_coding
OMIM	131398
Entrez	6037

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

MANE Select: ENST00000304639

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000304639, ENST00001091252, ENST00001091253, ENST00001134612

RefSeq mRNA: 1 — MANE Select: NM_002935 NM_002935

CCDS: CCDS9560

Canonical transcript exons

ENST00000304639 — 2 exons

Exon	Start	End
ENSE00001124180	20891682	20892348
ENSE00001137146	20891385	20891451

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 99.40.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2602 / max 176.2572, expressed in 30 samples.

Highest expression (Bgee): trabecular bone tissue, bone marrow, bone marrow cell, male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RNASE3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

12 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.8e-18	+0.23	14:20891649:C:A
Skin Sun Exposed Lower leg	eqtl	4.7e-15	+0.42	14:20971816:T:G
Adipose Visceral Omentum	eqtl	5.9e-06	+0.26	14:20891649:C:A
Adipose Subcutaneous	eqtl	1.6e-04	+0.24	14:20891649:C:A
Artery Tibial	eqtl	1.6e-04	-0.24	14:20964472:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.3e-03	+0.28	14:20945412:C:A
Small Intestine Terminal Ileum	eqtl	1.1e-02	-0.59	14:20384611:G:T
Breast Mammary Tissue	eqtl	1.2e-02	+0.26	14:20892970:T:A
Spleen	eqtl	1.5e-02	+0.22	14:20965208:A:C
Artery Aorta	eqtl	1.5e-02	+0.23	14:20891649:C:A
Brain Substantia nigra	eqtl	3.0e-02	-1.47	14:19930087:T:C
Brain Spinal cord cervical c-1	eqtl	3.8e-02	-0.74	14:20798901:CATTT:C

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
138483	0.2602	30

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.40	gold quality
bone marrow	UBERON:0002371	98.07	gold quality
bone marrow cell	CL:0002092	96.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.26	gold quality
mononuclear cell	CL:0000842	86.64	gold quality
monocyte	CL:0000576	86.63	gold quality
leukocyte	CL:0000738	85.75	gold quality
blood	UBERON:0000178	78.64	gold quality
granulocyte	CL:0000094	74.86	gold quality
spleen	UBERON:0002106	71.69	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.37	gold quality
sperm	CL:0000019	67.81	gold quality
male germ cell	CL:0000015	66.47	gold quality
right lung	UBERON:0002167	64.70	gold quality
Brodmann (1909) area 10	UBERON:0013541	63.31	gold quality
upper arm skin	UBERON:0004263	62.75	gold quality
upper lobe of left lung	UBERON:0008952	60.71	gold quality
pancreatic ductal cell	CL:0002079	60.41	silver quality
tongue squamous epithelium	UBERON:0006919	60.01	gold quality
upper lobe of lung	UBERON:0008948	58.72	gold quality
saphenous vein	UBERON:0007318	58.40	gold quality
gluteal muscle	UBERON:0002000	57.98	gold quality
body of tongue	UBERON:0011876	57.88	gold quality
triceps brachii	UBERON:0001509	57.82	gold quality
amniotic fluid	UBERON:0000173	57.76	silver quality
dorsal root ganglion	UBERON:0000044	57.50	gold quality
thymus	UBERON:0002370	57.50	silver quality
trigeminal ganglion	UBERON:0001675	56.99	gold quality
tibia	UBERON:0000979	56.82	silver quality
lateral globus pallidus	UBERON:0002476	56.79	gold quality
tongue	UBERON:0001723	56.74	gold quality
cerebellar vermis	UBERON:0004720	56.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	56.37	gold quality
spinal cord	UBERON:0002240	56.33	gold quality
inferior vagus X ganglion	UBERON:0005363	56.31	gold quality
pericardium	UBERON:0002407	56.19	gold quality
urethra	UBERON:0000057	56.08	gold quality
right adrenal gland cortex	UBERON:0035827	55.93	gold quality
substantia nigra pars compacta	UBERON:0001965	55.90	gold quality
nipple	UBERON:0002030	55.82	gold quality
trachea	UBERON:0003126	55.79	gold quality
synovial joint	UBERON:0002217	55.77	gold quality
right adrenal gland	UBERON:0001233	55.56	gold quality
superior surface of tongue	UBERON:0007371	55.54	gold quality
penis	UBERON:0000989	55.53	gold quality
subthalamic nucleus	UBERON:0001906	55.53	gold quality
pons	UBERON:0000988	55.49	gold quality
dorsal plus ventral thalamus	UBERON:0001897	55.47	gold quality
ventral tegmental area	UBERON:0002691	55.40	gold quality
layer of synovial tissue	UBERON:0007616	55.34	gold quality
cardia of stomach	UBERON:0001162	55.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	55.25	gold quality
deltoid	UBERON:0001476	55.21	gold quality
descending thoracic aorta	UBERON:0002345	55.07	gold quality
renal medulla	UBERON:0000362	54.96	gold quality
pylorus	UBERON:0001166	54.91	gold quality
pharyngeal mucosa	UBERON:0000355	54.90	gold quality
lateral nuclear group of thalamus	UBERON:0002736	54.89	gold quality
right coronary artery	UBERON:0001625	54.56	gold quality
medulla oblongata	UBERON:0001896	54.33	gold quality
left adrenal gland	UBERON:0001234	54.10	gold quality
vena cava	UBERON:0004087	53.89	gold quality
adrenal cortex	UBERON:0001235	53.88	gold quality
buccal mucosa cell	CL:0002336	53.48	gold quality
midbrain	UBERON:0001891	53.14	gold quality
left adrenal gland cortex	UBERON:0035825	53.13	gold quality
substantia nigra	UBERON:0002038	53.04	gold quality
superior vestibular nucleus	UBERON:0007227	52.81	gold quality
pleura	UBERON:0000977	52.76	gold quality
adrenal gland	UBERON:0002369	52.63	gold quality
lung	UBERON:0002048	52.50	gold quality
tibialis anterior	UBERON:0001385	52.28	silver quality
mucosa of stomach	UBERON:0001199	52.26	gold quality
mammalian vulva	UBERON:0000997	52.24	gold quality
lymph node	UBERON:0000029	52.12	gold quality
cranial nerve II	UBERON:0000941	52.06	silver quality
parietal pleura	UBERON:0002400	52.06	gold quality
quadriceps femoris	UBERON:0001377	51.72	gold quality
visceral pleura	UBERON:0002401	51.55	gold quality
epithelial cell of pancreas	CL:0000083	51.27	gold quality
Brodmann (1909) area 46	UBERON:0006483	50.95	gold quality
vastus lateralis	UBERON:0001379	50.62	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
left testis	UBERON:0004533	50.10	gold quality
rectum	UBERON:0001052	50.06	gold quality
caecum	UBERON:0001153	49.37	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
orbitofrontal cortex	UBERON:0004167	49.22	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
testis	UBERON:0000473	48.98	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
right testis	UBERON:0004534	48.52	gold quality
muscle tissue	UBERON:0002385	48.50	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-89232	yes	690.93
E-CURD-112	yes	31.88
E-MTAB-9067	yes	22.78
E-CURD-122	yes	10.58
E-ANND-3	yes	6.67
E-MTAB-9801	yes	5.29

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 129 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	856.4	medium
Skeletal muscle	tissue	163.1	not detected
Tongue	tissue	102.5
Heart muscle	tissue	85.3	low
Liver	tissue	59.3	low
Parathyroid gland	tissue	54.3	not detected
Caudate putamen	tissue	42.4
Frontal cortex	tissue	42.3
Kidney	tissue	42.2	high
Pancreas	tissue	42.1	high
Thymus	tissue	41.8
Skin 1	tissue	39.5	low
Esophagus	tissue	38.6	low
Ovary	tissue	36.8	not detected
Tonsil	tissue	36.7	medium
Smooth muscle	tissue	36.4	not detected
Thyroid gland	tissue	36.3	not detected
Small intestine	tissue	34.1	not detected
Urinary bladder	tissue	33.9	medium
Rectum	tissue	33.6	medium
Bone marrow	tissue	33.0	not detected
Colon	tissue	32.1	medium
Epididymis	tissue	32.1	medium
Stomach 1	tissue	31.9	medium
Prostate	tissue	31.9	medium
Fallopian tube	tissue	31.5	medium
Duodenum	tissue	31.3	high
Choroid plexus	tissue	31.2
Placenta	tissue	31.0	medium
Seminal vesicle	tissue	30.3	not detected
Cerebellum	tissue	29.9	low
Cervix	tissue	29.3	low
Lung	tissue	28.6	medium
Endometrium 1	tissue	28.4	not detected
Superior colliculi	tissue	28.3
Lymph node	tissue	28.1	medium
Hippocampus	tissue	26.9	not detected
Breast	tissue	26.7	medium
Spinal cord	tissue	26.7
Salivary gland	tissue	26.5	medium
Nucleus accumbens	tissue	26.3
Spleen	tissue	25.7	not detected
Gallbladder	tissue	25.6	medium
Appendix	tissue	25.5	low
Corpus callosum	tissue	25.0
Medulla oblongata	tissue	24.7
Retina	tissue	24.4
Midbrain	tissue	24.3
Adipose tissue	tissue	24.2	not detected
Thalamus	tissue	24.2
Substantia nigra	tissue	24.2
Olfactory bulb	tissue	24.1
Hippocampal formation	tissue	22.7
Cerebral cortex	tissue	22.6	low
Pons	tissue	22.6
Somatosensory cortex	tissue	22.6
Locus coeruleus	tissue	22.2
Periaqueductal gray	tissue	21.7
Occipital cortex	tissue	21.5
Motor cortex	tissue	21.3

Brain sub-regions (HPA Brain Atlas): detected in 374; highest nTPM — Blood vessel (36.9), Cerebellar cortex (31.3), Posterior thalamic nucleus (30.5), Flocculonodular lobe (30.1), Area postrema (29.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, NFATC2

miRNA regulators (miRDB)

Targeting RNASE3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

25 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-3936	97.64	64.47	732
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-6858-5P	96.05	64.59	1020
HSA-MIR-4765	93.11	66.17	737

Functional genomics

gnomAD constraint: pLI 0.11, LOEUF 1.94, missense Z 0.574 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000304639 — one region, missense o/e 0.94. ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• EDN and ECP are paralogs in human and Old World monkeys. (PMID:11959927)
• Measurement of ECP polymorphism is a significant indicator for the disease activity in asthmatic patient. (PMID:12524255)
• serum levels elevated in asthmatic patients during acute attack (PMID:12530121)
• results suggest a differential release of ECP by the serum eosinophil, depending on the disease status and asthma exacerbation severity (PMID:12974194)
• Presence of ECP in human milk is associated with development of cow milk allergy and atopic dermatitis in the breast-fed infant, but has no direct association with the maternal atopy. (PMID:14630983)
• ECP contributes to surfactant dysfunction in asthma, which in turn could lead to airway obstruction. (PMID:15007353)
• The presence of Torque tenovirus (TTV) and TTV load correlate with concentrations of serum eosinophil cationic protein in children with acute respiratory disease (PMID:15295703)
• conformational transitions at the level of sidechain interactions (PMID:15317478)
• serum ECP asthma patients, during and after a mild pollen season (PMID:15928844)
• The involvement of some cationic and aromatic surface exposed residues of eosinophil cationic protein in the inhibition of proliferation of mammalian cell lines was assessed. (PMID:16010966)
• Among mite-allergic patients T-bet expression was down-regulated, which had no relation to ECP concentration and allergic symptoms. (PMID:16874959)
• These results demonstrate that eosinophils degranulate in vivo at the host-parasite interface, and that the released ECP reaches concentrations that could be harmful for the parasite, Echinococcus granulosus. (PMID:16879306)
• ECP is present in the middle ear effusion of otitis media of effusion. There was a positive correlation between ECP level and IgE level. (PMID:16883790)
• The high thermal stability of ECP may contribute to its resistance to degradation when the protein is secreted to the extracellular medium during the immune response. (PMID:17088327)
• Tryptophan solvent exposure and the depth of the protein insertion in the lipid bilayer were monitored by the degree of protein fluorescence quenching by KI and brominated phospholipids, respectively. (PMID:17223693)
• study concludes that ECP is present in several molecular forms with varying biological activities; some of this functional heterogeneity is based on the genetic polymorphism of the ECP gene and some on post-translational modifications (PMID:17250693)
• the A-G-G haplotype in the RNASE3 gene influences the development of asthma, in particular, an allergic form of asthma (PMID:17362255)
• In the asthma group, there was no correlation between methacholine end-point concentration and the eosinophil counts or serum ECP levels. In contrast, AMP end-point concentration correlated with the eosinophil counts and with serum ECP levels. (PMID:17573858)
• ECP stimulates TGF-beta(1)-release by human lung fibroblasts, suggesting a potential mechanism for eosinophils in the fibrotic response. (PMID:17587163)
• neutrophils from allergic patients were able to produce ECP by an IgE-dependent mechanism. (PMID:17675527)
• Both genetic and post-translational causes of the molecular heterogeneity of the eosinophil cationic protein, was detected. (PMID:17726151)
• ECP might be used as a disease activity marker in Churg-Strauss syndrome (PMID:17804567)
• Determined faecal and serum ECP levels add background information concerning reference levels at paediatric age for further studies indifferent clinical settings. (PMID:17852809)
• Eosinophil cationic protein may serve as a possible contributor to the pathophysiology of exercise-induced bronchoconstriction in asthmatic children. (PMID:17885861)
• Transcriptional regulation of human eosinophil RNases by an evolutionary- conserved sequence motif in primate genome. (PMID:17927842)
• cell surface-bound heparan sulfate proteoglycans serve as the major receptor for ECP internalization (PMID:17944807)
• The cytotoxic effect of ECP is attained through a mechanism different from that of other cytotoxic RNases and may be related with the ECP accumulation associated with the inflammatory processes, in which eosinophils are present. (PMID:18087674)
• ECP can bind with high affinity to the bacteria-wall components, a first-encounter step which is key to its antimicrobial mechanism of action. (PMID:18293932)
• Results describe the release of eosinophil cationic protein from intact tissue biopsies from patients with nasal polyps. (PMID:18345486)
• the tight interaction between ECP and heparin acts as the primary step for ECP endocytosis (PMID:18593710)
• higher expression levels in adenoid tissue of children with house dust mite allergies (PMID:18657051)
• These results may indicate the absence of a correlation between clinical status and quality of life and levels of eosinophilic cationic protein in tissues with allergic inflammation. (PMID:18716399)
• No variation in genes eosinophil cationic protein for Atopic dermatitis pathogenesis in this German cohort. (PMID:19014520)
• The expression level of ECP mRNA was up-regulated in nasal polyps. (PMID:19086659)
• Serum eosinophil cationic protein and eosinophil peroxidase in patients with seasonal rhinitis demonstrated a high predictive ability for later development of asthma. (PMID:19133919)
• Data show that conformational diversity of ECP is observed for the loop segments 17-22, 65-68, and 92-95 and most exposed sidechains. (PMID:19189375)
• ECP stimulates migration of human lung fibroblasts (PMID:19284504)
• Using phospholipid vesicles as membrane models, RNase 3 triggers first the vesicle aggregation, while RNase 7 induces leakage well before the aggregation step. (PMID:19366593)
• Bactericidal and membrane disruption activities of the eosinophil cationic protein are located in N-terminal. (PMID:19450231)
• decreased levels following alpine mountain climate therapy in patients with allergic diseases and chronic obstructive pulmonary disease (PMID:19476022)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rnase2a	ENSMUSG00000047222
mus_musculus	Ear14	ENSMUSG00000050766
mus_musculus	Rnase2b	ENSMUSG00000059606
mus_musculus	Ear6	ENSMUSG00000062148
mus_musculus	Ear2	ENSMUSG00000072596
mus_musculus	Ear1	ENSMUSG00000072601
mus_musculus	Ear10	ENSMUSG00000090166
rattus_norvegicus	Rnase2	ENSRNOG00000032133
rattus_norvegicus	Ear1	ENSRNOG00000062969
rattus_norvegicus	Rnase3	ENSRNOG00000063957
rattus_norvegicus	Ear1l1	ENSRNOG00000070444
rattus_norvegicus	Rnase17	ENSRNOG00000077288
rattus_norvegicus	LOC100361866	ENSRNOG00000085776

Paralogs (12): RNASE1 (ENSG00000129538), RNASE7 (ENSG00000165799), RNASE2 (ENSG00000169385), RNASE6 (ENSG00000169413), RNASE8 (ENSG00000173431), RNASE11 (ENSG00000173464), RNASE10 (ENSG00000182545), RNASE9 (ENSG00000188655), RNASE13 (ENSG00000206150), ANG (ENSG00000214274), RNASE12 (ENSG00000258436), RNASE4 (ENSG00000258818)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1890465) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 15 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased neutrophil cell number	1
enlarged heart	1
small thymus	1
decreased body weight	1
decreased body size	1
postnatal growth retardation	1
lung inflammation	1
infertility	1
abnormal respiratory system physiology	1
abnormal neutrophil differentiation	1
abnormal neutrophil physiology	1
decreased macrophage cell number	1
impaired neutrophil recruitment	1
enlarged gallbladder	1
decreased granulocyte monocyte progenitor cell number	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gorilla gorilla gorilla	P47782	99.4%	Diamond
Pan troglodytes	P47785	99.4%	Diamond
Macaca nemestrina	Q8SPY5	99.4%	Diamond
Papio hamadryas	Q8SPY7	99.4%	Diamond
Pongo pygmaeus	O46526	98.7%	Diamond
Macaca mulatta	O46533	98.7%	Diamond
Macaca fascicularis	P47783	98.1%	Diamond
Chlorocebus aethiops	O46534	98.0%	Diamond
Miopithecus talapoin	Q8SPZ7	97.4%	Diamond
Aotus trivirgatus	O46528	96.0%	Diamond
Saguinus oedipus	O46530	96.0%	Diamond
Nomascus leucogenys	Q8SPY8	95.0%	Diamond
Saimiri sciureus	O46529	94.0%	Diamond
Sus scrofa	P15466	91.2%	Diamond
Saguinus labiatus	Q8SPY3	91.1%	Diamond
Callithrix jacchus	Q8SPY2	88.6%	Diamond
Bos taurus	P08904	72.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
RNASE1	protein-coding	6035
RNASE2	protein-coding	6036
RNASE6	protein-coding	6039
EDDM3B	protein-coding	64184
EDDM3A	protein-coding	10876

Protein

Protein identifiers

Eosinophil cationic protein — P12724 (reviewed: P12724)

Alternative names: Ribonuclease 3

All UniProt accessions (1): P12724

UniProt curated annotations — full annotation on UniProt →

Function. Cytotoxin and helminthotoxin with low-efficiency ribonuclease activity. Possesses a wide variety of biological activities. Exhibits antibacterial activity, including cytoplasmic membrane depolarization of preferentially Gram-negative, but also Gram-positive strains. Promotes E.coli outer membrane detachment, alteration of the overall cell shape and partial loss of cell content.

Subunit / interactions. Interacts with bacterial lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In vitro interacts with and insert into lipid bilayers composed of dioleoyl phosphatidylcholine and dioleoyl phosphatidylglycerol. In vitro, tends to form amyloid-like aggregates at pH 3, but not at pH 5, nor 7.

Subcellular location. Secreted.

Similarity. Belongs to the pancreatic ribonuclease family.

RefSeq proteins (1): NP_002926* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001427	RNaseA	Family
IPR023411	RNaseA_AS	Active_site
IPR023412	RNaseA_domain	Domain
IPR036816	RNaseA-like_dom_sf	Homologous_superfamily

Pfam: PF00074

UniProt features (37 total): strand 9, helix 6, disulfide bond 4, glycosylation site 3, sequence variant 3, turn 2, active site 2, site 2, signal peptide 1, chain 1, mutagenesis site 1, region of interest 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

11 structures by resolution:

PDB	Title	Method	Resolution (Å)
4X08	Structure of H128N/ECP mutant in complex with sulphate anions at 1.34 Angstroms.	X-RAY DIFFRACTION	1.34
4OWZ	Structure of ECP/H15A mutant.	X-RAY DIFFRACTION	1.47
4OXB	Structure of ECP with sulphate anions at 1.50 Angstroms	X-RAY DIFFRACTION	1.5
4OXF	Structure of ECP in complex with citrate ions at 1.50 Angstroms	X-RAY DIFFRACTION	1.5
4A2O	STRUCTURE OF THE HUMAN EOSINOPHIL CATIONIC PROTEIN IN COMPLEX WITH SULFATE ANIONS	X-RAY DIFFRACTION	1.69
4A2Y	STRUCTURE OF THE HUMAN EOSINOPHIL CATIONIC PROTEIN IN COMPLEX WITH CITRATE ANIONS	X-RAY DIFFRACTION	1.7
1DYT	X-ray crystal structure of ECP (RNase 3) at 1.75 A	X-RAY DIFFRACTION	1.75
1H1H	Crystal Structure of Eosinophil Cationic Protein in Complex with 2’,5’-ADP at 2.0 A …	X-RAY DIFFRACTION	2
1QMT	Recombinant Human Eosinophil Cationic Protein	X-RAY DIFFRACTION	2.4
2KB5	Solution NMR Structure of Eosinophil Cationic Protein/RNase 3	SOLUTION NMR
2LVZ	Solution structure of a Eosinophil Cationic Protein-trisaccharide heparin mimetic complex	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12724-F1	90.69	0.81

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, TKL Ser/Thr protein kinases, Predicted intracellular proteins, RAS pathway related proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; plasma membrane

Antibody reliability (HPA): IH approved · IF supported

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 (4)

Position	Role
42	proton acceptor
155	proton donor
60	may be involved in lps-binding
62	may be involved in lps- and lta-binding

Ligand- & substrate-binding residues (1)

Position	Role
65–69	substrate

Post-translational modifications (1)

Type	Positions
3’-nitrotyrosine	60

Disulfide bonds (4)

Type	Positions
Disulfide bond	50–110, 64–123, 82–138, 89–98

Glycosylation sites (3)

Type	Positions
N-linked (glcnac…) asparagine	92, 119, 84

Mutagenesis-validated functional residues (1)

Position	Phenotype
40	loss of in vitro formation of amyloid-like aggregates.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-6803157	Antimicrobial peptides	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—

MSigDB gene sets: 1052 (showing top): PID_BCR_5PATHWAY, PID_SHP2_PATHWAY, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOMF_ENDONUCLEASE_ACTIVITY, BIOCARTA_FMLP_PATHWAY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GRUETZMANN_PANCREATIC_CANCER_DN

GO Biological Process (10): innate immune response in mucosa (GO:0002227), RNA catabolic process (GO:0006401), chemotaxis (GO:0006935), antibacterial humoral response (GO:0019731), induction of bacterial agglutination (GO:0043152), innate immune response (GO:0045087), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), defense response to bacterium (GO:0042742)

GO Molecular Function (6): lipopolysaccharide binding (GO:0001530), nucleic acid binding (GO:0003676), endonuclease activity (GO:0004519), RNA nuclease activity (GO:0004540), hydrolase activity (GO:0016787), nuclease activity (GO:0004518)

GO Cellular Component (2): extracellular region (GO:0005576), azurophil granule lumen (GO:0035578)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Innate Immune System	2
Immune System	1

GO top-level categories

24 GO namespaces:

Category	Terms
defense response to bacterium	3
antimicrobial humoral response	2
nuclease activity	2
mucosal immune response	1
innate immune response	1
RNA metabolic process	1
nucleic acid catabolic process	1
response to chemical	1
taxis	1
antibacterial humoral response	1
immune response	1
defense response to symbiont	1
defense response	1
response to bacterium	1
lipid binding	1
carbohydrate derivative binding	1
binding	1
catalytic activity, acting on RNA	1
catalytic activity	1
catalytic activity, acting on a nucleic acid	1
cellular anatomical structure	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
antibacterial humoral response	BP	direct assay
antimicrobial humoral immune response mediated by antimicrobial peptide	BP	direct assay
defense response to Gram-negative bacterium	BP	direct assay
defense response to Gram-positive bacterium	BP	direct assay
induction of bacterial agglutination	BP	direct assay
innate immune response	BP	direct assay
innate immune response in mucosa	BP	direct assay
lipopolysaccharide binding	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 802 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASE3	EPX	P11678	970
RNASE3	ANG	P03950	860
RNASE3	IL5	P05113	827
RNASE3	CCL11	P50877	678
RNASE3	PRG2	P13727	675
RNASE3	RNASET2	O00584	648
RNASE3	MPO	P05164	635
RNASE3	IL13	P35225	607
RNASE3	IL4	P05112	606
RNASE3	RNASE2	P10153	604
RNASE3	RNASEL	Q05823	580
RNASE3	CLC	Q05315	574
RNASE3	IL5RA	Q01344	570
RNASE3	CCL26	Q9Y258	570
RNASE3	CCL24	O00175	547
RNASE3	ELANE	P08246	547

IntAct

Human interaction partners of RNASE3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
GGPS1	association	0.640	2
RNASEH1	association	0.350	1

BioGRID (23 interactions; top human partners by supporting records): ACTA2 (Affinity Capture-MS; 2 records), ACTB (Affinity Capture-MS; 2 records), ACTBL2 (Affinity Capture-MS; 2 records), BLK (Affinity Capture-MS; 2 records), EFR3B (Affinity Capture-MS; 2 records), GGPS1 (Affinity Capture-MS; 2 records), GTPBP2 (Affinity Capture-MS; 2 records), POTEI (Affinity Capture-MS; 2 records), RNH1 (Affinity Capture-MS; 2 records), UBAC1 (Affinity Capture-MS; 2 records), GNAZ (Affinity Capture-MS), RAD21 (Affinity Capture-Western), RNF123 (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
EPX	“up-regulates activity”	RNASE3	“post translational modification”

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — BLCA.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for RNASE3: 1,436 ClinVar records (40 pathogenic / likely pathogenic); 43 ClinGen expert-panel interpretations; 3 CIViC cancer variants; 1 PharmGKB clinical annotation; 26 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,436 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	27
Uncertain significance	684
Likely benign	501
Benign	73

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 40 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
13957	NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)	Pathogenic	reviewed by expert panel	48
13958	NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)	Pathogenic	reviewed by expert panel	16
13960	NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)	Pathogenic	reviewed by expert panel	13
40601	NM_002880.4(RAF1):c.775T>A (p.Ser259Thr)	Pathogenic	reviewed by expert panel	10
40613	NM_002880.4(RAF1):c.1082G>C (p.Gly361Ala)	Pathogenic	reviewed by expert panel	9
21342	NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)	Pathogenic	reviewed by expert panel	7
44633	NM_002880.4(RAF1):c.776C>A (p.Ser259Tyr)	Pathogenic	reviewed by expert panel	7
504514	NM_002880.4(RAF1):c.775T>G (p.Ser259Ala)	Pathogenic	reviewed by expert panel	5
40599	NM_002880.4(RAF1):c.768G>T (p.Arg256Ser)	Likely pathogenic	reviewed by expert panel	7
40607	NM_002880.4(RAF1):c.788T>G (p.Val263Gly)	Likely pathogenic	reviewed by expert panel	7
40600	NM_002880.4(RAF1):c.769T>C (p.Ser257Pro)	Likely pathogenic	reviewed by expert panel	4
40603	NM_002880.4(RAF1):c.776C>T (p.Ser259Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
426303	NM_002880.4(RAF1):c.778A>C (p.Thr260Pro)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2883997	NM_002880.4(RAF1):c.786T>G (p.Asn262Lys)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
13959	NM_002880.4(RAF1):c.1472C>G (p.Thr491Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3

Per-variant reference — Sugi Variant

Explore RNASE3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

ClinGen expert-panel interpretations (43)

Expert ACMG interpretations from RASopathy VCEP for Noonan syndrome; RASopathy — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	9
Likely Pathogenic	2
Uncertain Significance	4
Likely Benign	10
Benign	18

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 1,646):

Position(s)	Effect	Δscore	Sites
3:12584659	acceptor_loss	1.0000
3:12584665	acceptor_gain	1.0000
3:12584845–12584846	donor_loss	1.0000	5
3:12584983	acceptor_loss	1.0000	2
3:12585120–12585121	donor_loss	1.0000	4
3:12590793	donor_loss	1.0000	2
3:12590796–12590797	donor_loss	1.0000	6
3:12590835	donor_gain	1.0000
3:12604134–12604135	donor_loss	1.0000	5
3:12604290–12604291	acceptor_loss	1.0000	6

AlphaMissense

296 missense substitutions predicted likely pathogenic (of 1,047 scored), across 70 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M54	9	0.796	0.953
F38	8	0.911	0.986
F70	8	0.902	0.989
N68	8	0.872	0.939
S101	8	0.858	0.969
H42	8	0.847	0.911
D157	8	0.840	0.882
D145	8	0.803	0.881
C110	7	0.923	0.975
C82	7	0.921	0.962
C138	7	0.921	0.965
C98	7	0.913	0.965
C123	7	0.912	0.961
C89	7	0.906	0.965
C50	7	0.886	0.945
C64	7	0.882	0.956
F75	7	0.881	0.990
N58	7	0.860	0.933
H99	7	0.837	0.962
H155	7	0.814	0.903

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.76e-05
Glioblastoma Multiforme (validation)	favorable	3.08e-05
Kidney Chromophobe (TCGA)	unfavorable	0.000406

Disease associations

OMIM: gene MIM:131398 | disease phenotypes: MIM:611553, MIM:611554, MIM:615916, MIM:163950, MIM:151100, MIM:192600, MIM:609942

GenCC curated gene-disease

8 curated gene-disease records:

Disease	Classification	Inheritance	Records
Noonan syndrome 5	Definitive	Autosomal dominant	5
Noonan syndrome	Definitive	Autosomal dominant	2
dilated cardiomyopathy 1NN	Strong	Autosomal dominant	3
LEOPARD syndrome 2	Strong	Autosomal dominant	3
Noonan syndrome with multiple lentigines	Supportive	Autosomal dominant	2
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant
cardiofaciocutaneous syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity

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

4 validity classifications:

Disease	Classification	Inheritance
Costello syndrome	Disputed	AD
Noonan syndrome	Definitive	AD
cardiofaciocutaneous syndrome	Disputed	AD
Noonan syndrome with multiple lentigines	Limited	AD

Mondo (13): Noonan syndrome 5 (MONDO:0012690), LEOPARD syndrome 2 (MONDO:0012691), dilated cardiomyopathy 1NN (MONDO:0014396), Noonan syndrome (MONDO:0018997), RASopathy (MONDO:0021060), Noonan syndrome with multiple lentigines (MONDO:0007893), Noonan syndrome 1 (MONDO:0008104), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), hypertrophic cardiomyopathy 1 (MONDO:0008647), Noonan syndrome 3 (MONDO:0012371), Costello syndrome (MONDO:0009026), cardiofaciocutaneous syndrome (MONDO:0015280), (MONDO:0015470)

Orphanet (5): Familial isolated dilated cardiomyopathy (Orphanet:154), Noonan syndrome with multiple lentigines (Orphanet:500), RASopathy (Orphanet:536391), Noonan syndrome (Orphanet:648), Noonan syndrome and Noonan-related syndrome (Orphanet:98733)

HPO phenotypes

showing 60 of 163 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000078	Abnormality of the genital system
HP:0000144	Decreased fertility
HP:0000154	Wide mouth
HP:0000179	Thick lower lip vermilion
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000271	Abnormality of the face
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
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:0000431	Wide nasal bridge
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:0000708	Atypical behavior
HP:0000766	Abnormal sternum morphology
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0000912	Sprengel anomaly
HP:0000938	Osteopenia
HP:0000957	Cafe-au-lait spot
HP:0000958	Dry skin
HP:0000969	Edema
HP:0000970	Anhidrosis
HP:0000974	Hyperextensible skin
HP:0000978	Bruising susceptibility
HP:0000989	Pruritus
HP:0000995	Melanocytic nevus
HP:0000998	Hypertrichosis
HP:0001000	Abnormal skin pigmentation
HP:0001003	Multiple lentigines
HP:0001004	Lymphedema
HP:0001053	Hypopigmented skin patches
HP:0001058	Poor wound healing
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability

GWAS associations

26 associations:

Study	Trait	p-value
GCST004235_35	Total cholesterol levels	1e-18
GCST90020027_1113	Waist-hip index	3e-17
GCST90020027_1111	Waist-hip index	5e-17
GCST90020025_1695	Waist-to-hip ratio adjusted for BMI	8e-17
GCST90020025_1697	Waist-to-hip ratio adjusted for BMI	1e-16
GCST006585_1972	Blood protein levels	1e-14
GCST90020027_1114	Waist-hip index	2e-14
GCST90020029_933	Waist circumference adjusted for body mass index	2e-14
GCST90020025_1698	Waist-to-hip ratio adjusted for BMI	4e-14
GCST90020024_151	A body shape index	7e-14
GCST90020026_629	Hip index	2e-12
GCST90020025_1692	Waist-to-hip ratio adjusted for BMI	2e-11
GCST010796_3090	Electrocardiogram morphology (amplitude at temporal datapoints)	4e-11
GCST010796_3092	Electrocardiogram morphology (amplitude at temporal datapoints)	8e-11
GCST010242_242	HDL cholesterol levels	2e-10
GCST002221_10	Cholesterol, total	2e-9
GCST010042_114	Asthma	2e-9
GCST010796_3091	Electrocardiogram morphology (amplitude at temporal datapoints)	3e-9
GCST000760_20	Cholesterol, total	4e-9
GCST005962_54	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	9e-9
GCST90020029_934	Waist circumference adjusted for body mass index	1e-8
GCST005956_65	Waist-to-hip ratio adjusted for BMI	1e-7
GCST000960_17	Cardiac hypertrophy	7e-7
GCST005958_3	Waist-to-hip ratio adjusted for BMI (age >50)	2e-6
GCST010151_15	Carotid intima media thickness x smoking interaction	8e-6
GCST005957_13	Waist-to-hip ratio adjusted for BMI (age <50)	9e-6

EFO canonical traits (from GWAS)

10 canonical traits:

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0002503	cardiac hypertrophy
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006527	smoking status measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004327	electrocardiography
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors

8 disease descriptors:

Descriptor	Name	Tree numbers
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
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.)*
C537117	LEOPARD syndrome, 2 *(supp.)*
C548083	Noonan Syndrome 5 *(supp.)*
C537846	Noonan like syndrome *(supp.)*
C537847	Noonan syndrome 3 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication, from 4 curated evidence items; also 1 functional, 1 oncogenic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

4 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
RAF1 Amplification	Paclitaxel + Carboplatin + Sorafenib	Skin Melanoma	Sensitivity/Response	CIViC B	EID1496
RAF1 Amplification	B-Raf/VEGFR-2 Inhibitor RAF265 + Trametinib	Bladder Carcinoma	Sensitivity/Response	CIViC D	EID11767
RAF1 Amplification	Sorafenib	Hepatocellular Carcinoma	Sensitivity/Response	CIViC D	EID9113
RAF1 R391W	Vemurafenib	Melanoma	Resistance	CIViC D	EID4824

CIViC curated variants (3)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

R391W (missense variant), S257L, Amplification (transcript amplification).

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs11710163	Efficacy	3	carboplatin;cisplatin;docetaxel;gemcitabine;paclitaxel	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11710163	RAF1	3	3.50	1	carboplatin;cisplatin;docetaxel;gemcitabine;paclitaxel

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs11710163	carboplatin, cisplatin, docetaxel, gemcitabine, paclitaxel	Efficacy	Genotype AG is associated with increased overall survival due to carboplatin, cisplatin, docetaxel, gemcitabine or paclitaxel in people with Carcinoma, Non-Small-Cell Lung as compared to genotype AA.	PMID:21636554

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Beclomethasone	increases expression, decreases expression, affects cotreatment, affects reaction	6
Salmeterol Xinafoate	decreases expression, affects cotreatment, affects reaction, increases expression	2
perfluorooctanoic acid	affects expression	1
zafirlukast	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
montelukast	decreases expression	1
CP 31398	decreases expression	1
perfluorohexanesulfonic acid	increases expression	1
Formoterol Fumarate	decreases expression	1
Allergens	affects reaction, affects cotreatment, increases expression	1
Vehicle Emissions	increases expression	1
Cadmium	decreases expression, increases abundance	1
Dust	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Budesonide	decreases expression	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 323 trials:

NCT	Phase	Status	Title
NCT03048084	Phase 4	RECRUITING	Seizure Treatment in Glioma
NCT06625047	Phase 4	COMPLETED	Comparing Telehealth and In-person Assessments in Glioma Patients Receiving Oral Chemotherapy
NCT07486713	Phase 4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT00452725	Phase 3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	Phase 3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	Phase 3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	Phase 3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	Phase 3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	Phase 3	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
NCT00045968	Phase 3	UNKNOWN	Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer
NCT00256425	Phase 3	UNKNOWN	Cognitive Rehabilitation of Glioma Patients
NCT01479686	Phase 3	COMPLETED	iMRI Guided Resection in Cerebral Glioma Surgery
NCT01502280	Phase 3	COMPLETED	Fluorescence-guided Surgery for Low- and High-grade Gliomas
NCT01655927	Phase 3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT02363075	Phase 3	UNKNOWN	Dexamfetamine Sulphate in Patients With Glioma Suffering From Severe Asthenia
NCT03149575	Phase 3	TERMINATED	VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM
NCT03722355	Phase 3	COMPLETED	Hyperfractionated RT With BCNU Versus Conventional RT With BCNU for Supratentorial Malignant Glioma
NCT04164901	Phase 3	ACTIVE_NOT_RECRUITING	Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)
NCT05303519	Phase 3	RECRUITING	SIGMA (Safusidenib in IDH1 Mutant Glioma Maintenance)
NCT05512403	Phase 3	RECRUITING	Evaluation of Diagnostic Performances of 18F-FDOPA PET KInetics
NCT05580562	Phase 3	RECRUITING	ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
NCT06330337	Phase 3	RECRUITING	Effect of Electroacupuncture Combined With Paclitaxel Clinical Efficacy of Patients With Recurrence of High-grade Glioma
NCT06496971	Phase 3	RECRUITING	A Prospective Pivotal Study to Evaluate the Efficacy and Safety of Avastin® Bevacizumab (BEV) With or Without Microbubble-mediated Focused Ultrasound (FUS-MB) Using NaviFUS System in Recurrent Glioblastoma Multiforme Patients
NCT06750458	Phase 3	NOT_YET_RECRUITING	Dapagliflozin Versus Dexamethasone Role in Pre-operative Management of Non- Diabetic Brain Tumor Patients
NCT07698457	Phase 3	NOT_YET_RECRUITING	Clinical Benefit of 18F-FET in Glioma.
NCT00351221	Phase 2	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	Phase 2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	Phase 2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00047879	Phase 2	COMPLETED	Phase II Trial of Peginterferon Alpha-2b and Thalidomide in Adults With Recurrent Gliomas
NCT00107003	Phase 2	COMPLETED	GW572016 to Treat Recurrent Malignant Brain Tumors
NCT00108069	Phase 2	COMPLETED	Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors
NCT00147160	Phase 2	COMPLETED	Phase II Cisplatin + Temozolomide in Malignant Glial Tumours in Children and Adolescents
NCT00165360	Phase 2	COMPLETED	Prolonged Daily Temozolomide for Low-Grade Glioma
NCT00200161	Phase 2	COMPLETED	Temozolomide & RT Followed by Dose Dense vs Temozolomide & Retinoic Acid in Pts w/Glioblastoma
NCT00213278	Phase 2	COMPLETED	Phase 2 Study of Vinblastine in Children With Recurrent or Refractory Low Grade Glioma
NCT00350727	Phase 2	COMPLETED	Pazopanib In Combination With Lapatinib In Adult Patients With Relapsed Malignant Glioma
NCT00360828	Phase 2	TERMINATED	Phase II Study of Irinotecan HCI for Recurrent Anaplastic Astrocytomas, Mixed Malignant Gliomas, and Oligodendrogliomas
NCT00389090	Phase 2	TERMINATED	A Phase II Study of Temozolomide and O6-Benzylguanine (O6-BG) in Patients With Temozolomide-Resistant Anaplastic Glioma
NCT00392171	Phase 2	COMPLETED	The Effects of Continuous 28-day (28/28) Temozolomide Chemotherapy in Subjects With Recurrent Malignant Glioma Who Have Failed the Conventional 5-day (5/28) Treatment (P04601)
NCT00404495	Phase 2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.
NCT00409214	Phase 2	COMPLETED	Phase IIa Safety and Light Dose-escalation Study in Patients With Primary or Recurrent/High-grade Glioma Using the Litx™ System to Confirm the Zone of Tumor Destruction During the Intraoperative Treatment of Glioma
NCT00412542	Phase 2	COMPLETED	Thalidomide and Temozolomide or Camptothecin-11 (CPT-11) in Patients With Gliomas
NCT00424554	Phase 2	COMPLETED	Low-dose Temozolomide for 2 Weeks on Brain Tumor Enzyme in Patients With Gliomas (P04602 AM1) (Completed)
NCT00463203	Phase 2	COMPLETED	Bevacizumab and Irinotecan for Patients With Primary Brain Tumors and Progression After Standard Therapy
NCT00575796	Phase 2	UNKNOWN	Weekly Vinblastine for Chemotherapy Naive Children With Progressive Low Grade Glioma (PLGGs)
NCT00589706	Phase 2	COMPLETED	A Phase II Study of Adjuvant Use of Anti-Epidermal Growth Factor Receptor EGFR-425 in High Grade Gliomas
NCT00660283	Phase 2	UNKNOWN	A Phase II Study of Gliadel, Concomitant Temozolomide and Radiation, Followed By Dose Dense Therapy With Temozolomide For Newly Diagnosed Malignant High Grade Glioma
NCT00660621	Phase 2	UNKNOWN	A Phase II Study Of Gliadel, Concomitant Temozolomide And Radiation, Followed By Dose Dense Therapy With Temozolomide Plus Bevacizumab For Newly Diagnosed Malignant High Grade Glioma
NCT00727506	Phase 2	COMPLETED	BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma
NCT00782626	Phase 2	COMPLETED	Everolimus (RAD001) for Children With Chemotherapy-Refractory Progressive or Recurrent Low-Grade Gliomas
NCT00795665	Phase 2	COMPLETED	Bevacizumab and Carmustine in Treating Patients With Relapsed or Progressive High-Grade Glioma
NCT01116661	Phase 2	TERMINATED	Safety Study of Aminolevulinic Acid (ALA) to Enhance Visualization and Resection of Tumors of the Brain
NCT01137604	Phase 2	COMPLETED	A Study in Subjects With Recurrent Malignant Glioma
NCT01140568	Phase 2	COMPLETED	Study of Platelet Derived Growth Factor Receptor (PDGFR) in Recurrent Malignant Gliomas
NCT01158651	Phase 2	COMPLETED	Everolimus for Children With NF1 Chemotherapy-Refractory Radiographic Progressive Low Grade Gliomas
NCT01204684	Phase 2	COMPLETED	Dendritic Cell Vaccine for Patients With Brain Tumors
NCT01229644	Phase 2	TERMINATED	Study of Crenolanib, a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas
NCT01351519	Phase 2	TERMINATED	A Study of Aminolevulinic Acid Used to Enhance Visualization and Surgical Removal of Brain Tumors
NCT01403311	Phase 2	UNKNOWN	A Study of Aminolevulinic Acid (ALA) to Enhance Visualization and Resection of Malignant Glial Tumors of the Brain
NCT01445691	Phase 2	WITHDRAWN	More Complete Removal of Malignant Brain Tumors by Fluorescence-Guided Surgery