RNASE1

Summary

RNASE1 (ribonuclease A family member 1, pancreatic, HGNC:10044) is a protein-coding gene on chromosome 14q11.2, encoding Ribonuclease pancreatic (P07998). Endonuclease that catalyzes the cleavage of RNA on the 3’ side of pyrimidine nucleotides. In precision oncology, RAC1 P29S is associated with resistance to Vemurafenib + Dabrafenib in Melanoma (CIViC Level B); 1 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 77.1% of cell lines).

This gene encodes a member of the pancreatic-type of secretory ribonucleases, a subset of the ribonuclease A superfamily. The encoded endonuclease cleaves internal phosphodiester RNA bonds on the 3’-side of pyrimidine bases. It prefers poly(C) as a substrate and hydrolyzes 2’,3’-cyclic nucleotides, with a pH optimum near 8.0. The encoded protein is monomeric and more commonly acts to degrade ds-RNA over ss-RNA. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified.

Source: NCBI Gene 6035 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 121 total — 9 pathogenic, 14 likely-pathogenic
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• Cancer dependency (DepMap): dependent in 77.1% of screened cell lines
• MANE Select transcript: NM_002933

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10044
Approved symbol	RNASE1
Name	ribonuclease A family member 1, pancreatic
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RAC1
Ensembl gene	ENSG00000129538
Ensembl biotype	protein_coding
OMIM	180440
Entrez	6035

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000340900, ENST00000397967, ENST00000397970, ENST00000412779, ENST00000555698, ENST00000884083, ENST00000884084, ENST00000884085, ENST00000884086, ENST00000884087, ENST00000884088, ENST00000884089, ENST00000960487, ENST00000960488, ENST00000960489

RefSeq mRNA: 4 — MANE Select: NM_002933 NM_002933, NM_198232, NM_198234, NM_198235

CCDS: CCDS9559

Canonical transcript exons

ENST00000397967 — 2 exons

Exon	Start	End
ENSE00001867062	20802797	20802844
ENSE00001929748	20801228	20802093

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.90.

FANTOM5 (CAGE): breadth broad, TPM avg 145.4140 / max 18126.0918, expressed in 744 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142066	125.7577	717
142067	8.6711	536
142063	4.1873	132
142060	1.8323	287
142054	1.0058	204
142064	0.9282	75
142059	0.8687	180
142061	0.8183	199
142062	0.3817	136
142055	0.3117	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	99.90	gold quality
right testis	UBERON:0004534	99.90	gold quality
right lung	UBERON:0002167	99.64	gold quality
upper lobe of lung	UBERON:0008948	99.61	gold quality
upper lobe of left lung	UBERON:0008952	99.61	gold quality
synovial joint	UBERON:0002217	99.58	gold quality
testis	UBERON:0000473	99.53	gold quality
gall bladder	UBERON:0002110	99.50	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.48	gold quality
body of pancreas	UBERON:0001150	99.47	gold quality
decidua	UBERON:0002450	99.45	gold quality
peritoneum	UBERON:0002358	99.43	gold quality
omental fat pad	UBERON:0010414	99.43	gold quality
layer of synovial tissue	UBERON:0007616	99.42	gold quality
adult organism	UBERON:0007023	99.40	gold quality
mucosa of stomach	UBERON:0001199	99.37	gold quality
right coronary artery	UBERON:0001625	99.37	gold quality
right adrenal gland cortex	UBERON:0035827	99.37	gold quality
inferior vagus X ganglion	UBERON:0005363	99.35	gold quality
corpus callosum	UBERON:0002336	99.33	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.32	gold quality
body of stomach	UBERON:0001161	99.30	gold quality
apex of heart	UBERON:0002098	99.30	gold quality
spinal cord	UBERON:0002240	99.29	gold quality
right uterine tube	UBERON:0001302	99.23	gold quality
rectum	UBERON:0001052	99.19	gold quality
right adrenal gland	UBERON:0001233	99.16	gold quality
lung	UBERON:0002048	99.13	gold quality
middle frontal gyrus	UBERON:0002702	99.12	gold quality
lower lobe of lung	UBERON:0008949	99.12	gold quality

Single-cell (SCXA)

Detected in 34 experiment(s), a significant marker in 32.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	12752.11
E-MTAB-6678	yes	10914.47
E-MTAB-8322	yes	8798.36
E-MTAB-6701	yes	7947.51
E-MTAB-7407	yes	7077.58
E-HCAD-36	yes	5563.43
E-HCAD-15	yes	5351.96
E-MTAB-8142	yes	5130.80
E-MTAB-9906	yes	4955.99
E-HCAD-10	yes	4794.24
E-GEOD-134144	yes	3957.54
E-GEOD-84465	yes	3923.75
E-MTAB-6653	yes	3214.44
E-GEOD-124263	yes	2967.86
E-CURD-112	yes	2169.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TBP

miRNA regulators (miRDB)

20 targeting RNASE1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-6873-5P	98.45	66.14	1417
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-5194	96.77	63.91	1021

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 77.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• Human endothelial cells selectively express large amounts of pancreatic-type ribonuclease (RNase 1) (PMID:12210760)
• Results show that Glycine 38 is crucial for the full catalytic activity of the human enzyme on duplex RNA as its substitution with aspartate or alanine results in a drastic reduction in the dsRNA cleavage activity of HPR. (PMID:12237131)
• Results reveal the dendritic cell-activating activity of pancreatic ribonuclease and suggest that it is a likely participant of inflammatory and immune responses–an endogenous multifunctional immune alarmin. (PMID:15528350)
• Altogether the results suggest that the pressure-folding transition state of ribonuclease A looks like a collapsed globule with some secondary structure and a weakened hydrophobic core. This is the first direct comparison using a set of mutants. (PMID:16597833)
• RNase-1 has ribonuclease H activity. (PMID:16738129)
• Human pancreatic-ribonuclease interacts with importin alpha through different basic residues, including Lys1 and the arginine clusters 31-33 and 89-91. (PMID:16780873)
• The results were confirmed at the level of mRNA and protein, and suggested that four genes (OPCML, RNASE1, YES1 and ACK1) could play a key role in the tumorigenesis and metastasis of gastric cancer. (PMID:17109515)
• Structural and energetic aspects of the interaction between human RI (hRI) and human pancreatic ribonuclease (RNase 1), is reported. (PMID:17350650)
• Coulombic forces mediate extracellular and intracellular equilibria in a dichotomous manner that both endangers cells and defends them from the potentially lethal enzymatic activity of ribonucleases. (PMID:17705507)
• irrespective of differences in ethnic groups, RNASE1 might show markedly low heterogeneity in its genetic structure with regard to these SNPs (PMID:18219569)
• Multiple side chain conformations observed for key surface residues are proposed to be crucial for membrane binding as well as translocation and efficient RNA hydrolysis. (PMID:18495155)
• Studies illustrate of the making dimeric pancreatic RNase through removal by directed mutagenesis of most of the N-terminal alpha-helix to the remainder of the protein. (PMID:19156888)
• The nuclear transport of PE5 is critical for its cytotoxicity. (PMID:20352290)
• Vascular RNase1 and RNase5 are mainly produced by vascular endothelial cells and can serve, depending on the vascular bed, different functions in vascular homeostasis and endothelial cell responses. (PMID:21103661)
• In human pancreatic ribonuclease both glutamine 28 and arginine 39 are important for the cleavage of dsRNA. (PMID:21408145)
• The role on the dimerization process of different residues of a domain-swapped dimer human pancreatic ribonuclease variant. (PMID:21767499)
• The reduced conformational flexibility of eosinophil cationic protein can be dynamically and functionally reproduced in the RNase A scaffold. (PMID:23135272)
• Deletion of five residues in the hinge loop of pancreatic ribonuclease induces formation of a domain-swapped dimer that leads to the generation of linear aggregates of pancreatic RNase, revealed by the crystal packing. (PMID:24100329)
• Focusing on the increase in an N-glycosylated Asn residue of serum pancreatic ribonuclease 1, specifically Asn(88), affords a new diagnostic marker for pancreatic cancer (PMID:25336120)
• Data suggest that ribonuclease inhibitor (RNH1) protects HeLa cells from ribonuclease 1 (RNase 1). (PMID:27806571)
• N-glycosylation of human RNase 1 improves its resistance to both thermal denaturation and proteolytic degradation but reduces its catalytic activity.N-glycosylation of Asn34 in human RNase 1 significantly improves overall protein stability while maintaining robust catalytic activity. (PMID:30633504)
• Chromatin immunoprecipitation kinetics revealed that HDAC2 accumulates at the RNASE1 promoter upon TNF-alpha stimulation, indicating an essential role for HDAC2 in regulating RNase1 expression. Thus, proinflammatory stimulation induced recruitment of HDAC2 to attenuate histone acetylation at the RNASE1 promoter site. (PMID:31039328)
• Processing by RNase 1 forms tRNA halves and distinct Y RNA fragments in the extracellular environment. (PMID:32609822)
• Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation. (PMID:33986289)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rnase1	ENSMUSG00000035896
rattus_norvegicus	Rnase1l1	ENSRNOG00000025615
rattus_norvegicus	Rnase1	ENSRNOG00000063584
rattus_norvegicus	Rnase1l2	ENSRNOG00000069584

Paralogs (12): RNASE7 (ENSG00000165799), RNASE2 (ENSG00000169385), RNASE3 (ENSG00000169397), RNASE6 (ENSG00000169413), RNASE8 (ENSG00000173431), RNASE11 (ENSG00000173464), RNASE10 (ENSG00000182545), RNASE9 (ENSG00000188655), RNASE13 (ENSG00000206150), ANG (ENSG00000214274), RNASE12 (ENSG00000258436), RNASE4 (ENSG00000258818)

Protein

Protein identifiers

Ribonuclease pancreatic — P07998 (reviewed: P07998)

Alternative names: HP-RNase, RIB-1, RNase UpI-1, Ribonuclease 1, Ribonuclease A

All UniProt accessions (3): P07998, G3V357, W0UV93

UniProt curated annotations — full annotation on UniProt →

Function. Endonuclease that catalyzes the cleavage of RNA on the 3’ side of pyrimidine nucleotides. Acts on single-stranded and double-stranded RNA.

Subunit / interactions. Monomer. Interacts with and forms tight 1:1 complexes with RNH1. Dimerization of two such complexes may occur. Interaction with RNH1 inhibits this protein.

Subcellular location. Secreted.

Tissue specificity. Pancreas and other tissues and body fluids (indicating it may have other physiological functions besides its role in digestion).

Post-translational modifications. N-linked glycans are of complex type.

Similarity. Belongs to the pancreatic ribonuclease family.

RefSeq proteins (4): NP_002924, NP_937875, NP_937877, NP_937878 (=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

Enzyme classification (BRENDA):

• EC 4.6.1.18 — pancreatic ribonuclease (BRENDA: 31 organisms, 87 substrates, 129 inhibitors, 97 Km, 47 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CYTIDINE-2’,3’-CYCLIC MONOPHOSPHATE	0.31–13	24
POLY(C)	0.0409–4	17
CYTIDINYL-3’,5’-ADENOSINE	0.38–22	10
POLY(A)-POLY(U)	0.0115–0.1059	10
POLY(A)POLY(U)	0.032–0.389	10
CYCLIC 2’,3’-CYTIDINE MONOPHOSPHATE	0.0023–0.44	4
TRNA	0.0005–5	4
PENTACYTIDYLIC ACID	0.015–0.038	3
CYCLIC 2’,3’-CMP	0.46–1	2
POLY (C)	0.34–0.47	2
CYCLIC 2’,3’-UMP	3	1
UPA	0.79	1
RNA	—	0

UniProt features (45 total): strand 8, mutagenesis site 6, sequence conflict 6, binding site 5, disulfide bond 4, helix 4, glycosylation site 3, turn 3, active site 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
2E0J	X-RAY DIFFRACTION	1.6
2E0L	X-RAY DIFFRACTION	1.6
1DZA	X-RAY DIFFRACTION	1.65
2E0M	X-RAY DIFFRACTION	1.7
1E21	X-RAY DIFFRACTION	1.9
1Z7X	X-RAY DIFFRACTION	1.95
2Q4G	X-RAY DIFFRACTION	1.95
1H8X	X-RAY DIFFRACTION	2
2E0O	X-RAY DIFFRACTION	2
3F8G	X-RAY DIFFRACTION	2.6
4KXH	X-RAY DIFFRACTION	2.7
2K11	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07998-F1	92.87	0.78

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 (2): 40 (proton acceptor); 147 (proton donor)

Ligand- & substrate-binding residues (5): 113; 35; 38; 69–73; 94

Disulfide bonds (4): 54–112, 68–123, 86–138, 93–100

Glycosylation sites (3): 62, 104, 116

Mutagenesis-validated functional residues (6):

Position	Phenotype
67	substantially decreases binding affinity for rnh1 but maintains high conformational stability; when associated with d-95
95	substantially decreases binding affinity for rnh1 but maintains high conformational stability; when associated with d-67
116–117	no effect on inhibition by rnh1.
116	substantially decreases binding affinity for rnh1 but maintains high conformational stability; when associated with d-67
117	substantially decreases binding affinity for rnh1 but maintains high conformational stability; when associated with d-67
119	substantially decreases binding affinity for rnh1 but maintains high conformational stability; when associated with d-67

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9613829	Chaperone Mediated Autophagy
R-HSA-9615710	Late endosomal microautophagy
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells
R-HSA-1266738	Developmental Biology
R-HSA-9612973	Autophagy
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 194 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MODULE_52, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, WALLACE_PROSTATE_CANCER_RACE_UP, GRUETZMANN_PANCREATIC_CANCER_DN, MCLACHLAN_DENTAL_CARIES_UP, GOMF_NUCLEASE_ACTIVITY, GOZGIT_ESR1_TARGETS_DN, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, MODULE_66, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_DEFENSE_RESPONSE_TO_GRAM_POSITIVE_BACTERIUM

GO Biological Process (1): defense response to Gram-positive bacterium (GO:0050830)

GO Molecular Function (8): nucleic acid binding (GO:0003676), ribonuclease A activity (GO:0004522), RNA nuclease activity (GO:0004540), hydrolase activity (GO:0016787), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (2): extracellular exosome (GO:0070062), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Autophagy	2
Developmental Cell Lineages of the Exocrine Pancreas	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
nuclease activity	2
catalytic activity	2
defense response to bacterium	1
RNA endonuclease activity	1
phosphorus-oxygen lyase activity	1
catalytic activity, acting on RNA	1
catalytic activity, acting on a nucleic acid	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1227 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASE1	CYCS	P00001	964
RNASE1	MB	P02144	930
RNASE1	RNASET2	O00584	773
RNASE1	ALB	P02768	772
RNASE1	LALBA	P00709	709
RNASE1	TG	P01266	678
RNASE1	PNP	P00491	655
RNASE1	GLUD1	P00367	639
RNASE1	RNASEL	Q05823	637
RNASE1	DNASE1	P24855	632
RNASE1	GLUD2	P49448	588
RNASE1	INS	P01308	577
RNASE1	ANXA5	P08758	545
RNASE1	PRTFDC1	Q9NRG1	542
RNASE1	CA8	P35219	535

IntAct

21 interactions, top by confidence:

A	B	Type	Score
RNASE1	RNH1	psi-mi:“MI:0915”(physical association)	0.850
RNASE1	RNH1	psi-mi:“MI:0914”(association)	0.850
RNH1	RNASE1	psi-mi:“MI:0407”(direct interaction)	0.850
RNASE1	RNH1	psi-mi:“MI:0407”(direct interaction)	0.850
RNASE1	TRIM7	psi-mi:“MI:0915”(physical association)	0.560
RNASE1		psi-mi:“MI:0902”(rna cleavage)	0.440
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
Dnajc3	RNASE1	psi-mi:“MI:0915”(physical association)	0.400
RELA	RNASE1	psi-mi:“MI:0915”(physical association)	0.370
RNASE1	HNRNPA1	psi-mi:“MI:0914”(association)	0.350
RNASE1	TRIM7	psi-mi:“MI:0915”(physical association)	0.000
	RNASE1	psi-mi:“MI:0915”(physical association)	0.000
RNASE1		psi-mi:“MI:0915”(physical association)	0.000
deoB	RNASE1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): RNH1 (Affinity Capture-MS), BUD31 (Affinity Capture-MS), NMNAT1 (Affinity Capture-MS), C2orf49 (Affinity Capture-MS), RNASE1 (Affinity Capture-Luminescence), RNH1 (Affinity Capture-Luminescence), TRIM7 (Two-hybrid), RNH1 (Affinity Capture-Luminescence), RNASE1 (Affinity Capture-MS), RNH1 (Affinity Capture-MS), BUD31 (Affinity Capture-MS), NMNAT1 (Affinity Capture-MS), C2orf49 (Affinity Capture-MS), STRBP (Affinity Capture-MS), ADAR (Affinity Capture-MS)

ESM2 similar proteins: A1YLB9, O46525, O46526, O46527, O46528, O46529, O46530, O46531, O46532, O46533, O46534, P00683, P07998, P08904, P39873, P61821, P61822, P81649, Q8SPN3, Q8SPN4, Q8SPN5, Q8SPZ4, Q8SPZ5, Q8SPZ6, Q8SPZ7, Q8SPZ8, Q8SQ04, Q8SQ05, Q8SQ06, Q8SQ07, Q8SQ08, Q8SQ09, Q8SQ11, Q8SQ12, Q8SQ13, Q8SQ14, Q8TDE3, Q8WN67, Q93091, Q9D244

Diamond homologs: B3EWJ0, O55004, P00657, P00658, P00659, P00660, P00662, P00663, P00664, P00665, P00666, P00667, P00668, P00669, P00671, P00672, P00673, P00674, P00675, P00676, P00677, P00678, P00679, P00680, P00681, P00682, P00683, P00684, P00685, P00686, P04059, P04060, P07847, P07848, P07849, P07998, P15467, P15468, P16414, P19644

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

The RAC1 P29S mutation is the third most common protein-coding hotspot mutation in melanomas, ocurring in 4-9%. A preclinical study has shown that this mutation confers resistance to BRAF inhibition in-vitro.

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — HNSC, MEL, SKCM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	14
Uncertain significance	62
Likely benign	12
Benign	4

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1727258	NM_006908.5(RAC1):c.475G>A (p.Ala159Thr)	Pathogenic
1727259	NM_006908.5(RAC1):c.184G>A (p.Glu62Lys)	Pathogenic
2446363	NM_006908.5(RAC1):c.181C>G (p.Gln61Glu)	Pathogenic
2446365	NM_006908.5(RAC1):c.202C>A (p.Arg68Ser)	Pathogenic
2446366	NM_006908.5(RAC1):c.202C>G (p.Arg68Gly)	Pathogenic
3377146	NM_006908.5(RAC1):c.94T>C (p.Tyr32His)	Pathogenic
445280	NM_006908.5(RAC1):c.53G>A (p.Cys18Tyr)	Pathogenic
625787	GRCh37/hg19 7p22.1(chr7:6385256-6431775)	Pathogenic
986286	NM_006908.5(RAC1):c.77A>G (p.Asn26Ser)	Pathogenic
1027690	NM_006908.5(RAC1):c.168G>C (p.Trp56Cys)	Likely pathogenic
1176531	NM_006908.5(RAC1):c.493C>G (p.Leu165Val)	Likely pathogenic
1333690	NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys)	Likely pathogenic
2431922	NM_006908.5(RAC1):c.190T>C (p.Tyr64His)	Likely pathogenic
2503252	NM_006908.5(RAC1):c.394A>G (p.Lys132Glu)	Likely pathogenic
2577934	NM_006908.5(RAC1):c.122_123delinsAC (p.Ser41Tyr)	Likely pathogenic
3235757	NM_006908.5(RAC1):c.129T>A (p.Asn43Lys)	Likely pathogenic
4072487	NM_006908.5(RAC1):c.103A>G (p.Thr35Ala)	Likely pathogenic
4082372	NM_006908.5(RAC1):c.178G>A (p.Gly60Arg)	Likely pathogenic
445282	NM_006908.5(RAC1):c.470G>A (p.Cys157Tyr)	Likely pathogenic
445285	NM_006908.5(RAC1):c.151G>C (p.Val51Leu)	Likely pathogenic
4532075	NM_006908.5(RAC1):c.171T>G (p.Asp57Glu)	Likely pathogenic
4539929	NM_006908.5(RAC1):c.348A>C (p.Lys116Asn)	Likely pathogenic
4823705	NM_006908.5(RAC1):c.479T>C (p.Leu160Pro)	Likely pathogenic

SpliceAI

1552 predictions. Top by Δscore:

Variant	Effect	Δscore
7:6374766:GACGG:G	donor_gain	1.0000
7:6374769:GG:G	donor_gain	1.0000
7:6374770:GG:G	donor_gain	1.0000
7:6387210:A:AG	acceptor_gain	1.0000
7:6387211:G:GA	acceptor_gain	1.0000
7:6387211:GA:G	acceptor_gain	1.0000
7:6387211:GAGC:G	acceptor_gain	1.0000
7:6387211:GAGCT:G	acceptor_gain	1.0000
7:6387279:ACTGT:A	donor_gain	1.0000
7:6387280:CTGT:C	donor_gain	1.0000
7:6387282:GT:G	donor_gain	1.0000
7:6387283:TG:T	donor_loss	1.0000
7:6387284:G:GG	donor_gain	1.0000
7:6387285:TA:T	donor_loss	1.0000
7:6387286:AA:A	donor_loss	1.0000
7:6392042:G:GG	donor_gain	1.0000
7:6400120:TTGTA:T	acceptor_loss	1.0000
7:6400121:TGTAG:T	acceptor_loss	1.0000
7:6400122:GTAGG:G	acceptor_loss	1.0000
7:6400123:TAG:T	acceptor_loss	1.0000
7:6400125:G:GT	acceptor_loss	1.0000
7:6400125:GGAT:G	acceptor_gain	1.0000
7:6401866:A:AG	acceptor_gain	1.0000
7:6401866:AGT:A	acceptor_gain	1.0000
7:6401867:G:GG	acceptor_gain	1.0000
7:6401867:GTG:G	acceptor_gain	1.0000
7:6401867:GTGGT:G	acceptor_gain	1.0000
7:6402021:GAGA:G	donor_gain	1.0000
14:20802091:AGCC:A	acceptor_loss	0.9900
14:20802092:GC:G	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000195821 (14:20804296 A>G), RS1000550363 (14:20800882 C>A,G), RS1001354929 (14:20803508 TGTTCTTATCTACA>T), RS1001553639 (14:20802766 G>A), RS1001584779 (14:20802268 C>A,G,T), RS1001709315 (14:20803856 G>T), RS1002055236 (14:20803572 C>T), RS1002551349 (14:20804282 G>A), RS1002585902 (14:20804052 T>C), RS1002743390 (14:20802848 C>T), RS1002988173 (14:20802165 G>C,T), RS1003697966 (14:20801096 C>T), RS1004151918 (14:20801399 G>C), RS1005014366 (14:20803511 T>G), RS1005507513 (14:20801502 C>A,T)

Disease associations

OMIM: gene MIM:180440 | disease phenotypes: MIM:617751, MIM:617755

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 48	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (2): intellectual disability, autosomal dominant 48 (MONDO:0030913), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596)

Orphanet (2): Microcephaly-corpus callosum and cerebellar vermis hypoplasia-facial dysmorphism-intellectual disability syndrom (Orphanet:500159), BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001762_486	Obesity-related traits	8.000000e-08
GCST004621_109	Red cell distribution width	8.000000e-09
GCST005194_226	Coronary artery disease	1.000000e-07
GCST005951_155	Body mass index	1.000000e-08
GCST006585_924	Blood protein levels	3.000000e-25
GCST007930_20	Medication use (agents acting on the renin-angiotensin system)	2.000000e-08
GCST008870_29	Keratinocyte cancer (MTAG)	1.000000e-08
GCST008871_72	Basal cell carcinoma	1.000000e-06
GCST010241_117	Apolipoprotein A1 levels	5.000000e-35
GCST010245_82	LDL cholesterol levels	5.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005190	urinary nitrogen measurement
EFO:0009188	Red cell distribution width
EFO:0004340	body mass index
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0010176	keratinocyte carcinoma
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5425 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 3 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
RAC1 P29S	Vemurafenib + Dabrafenib	Melanoma	Resistance	CIViC B	EID7669 +1
RAC1 P29S	PLX4720	Skin Melanoma	Resistance	CIViC D	EID8056

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 5 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.57	Ki	27	nM	CHEMBL401150
7.57	Ki	27	nM	CHEMBL455775

PubChem BioAssay actives

2 with measured affinity, of 45 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [[(2R,3S,5R)-5-(2,4-dioxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] hydrogen phosphate	345852: Inhibition of RNase A	ki	0.0270	uM
[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,5R)-5-(2,4-dioxopyrimidin-1-yl)-2-(phosphonooxymethyl)oxolan-3-yl] hydrogen phosphate	718194: Inhibition of RNase A	ki	0.0270	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	3
tetrabromobisphenol A	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases abundance	2
2,4,6-tribromophenol	decreases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium bichromate	decreases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Air Pollutants, Occupational	affects expression	1
Allergens	decreases abundance, increases expression, affects cotreatment	1
Aspirin	increases expression	1
Atrazine	increases expression	1
Vehicle Emissions	decreases abundance, increases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Calcitriol	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Silicon Dioxide	decreases expression	1

ChEMBL screening assays

17 unique, capped per target: 16 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1026631	Binding	Induction of protein photodamage of ribonuclease A assessed as increase in protein carbonyl content at 10 uM treated 30 mins before 2.5 J/cm'2 UVA irradiation by electrophoresis	Thiopyrano[2,3-e]indol-2-ones: angelicin heteroanalogues with potent photoantiproliferative activity. — Bioorg Med Chem
CHEMBL2209165	ADMET	Prodrug activation assessed as half life for ribonuclease 1 mediated 4-hydroxytamoxifen release in MES-NaOH buffer at pH 6.0 by HPLC analysis	Ribonuclease-Activated Cancer Prodrug. — ACS Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1D9	Ubigene THP-1 RNASE1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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