RPP40

Summary

RPP40 (ribonuclease P/MRP subunit p40, HGNC:20992) is a protein-coding gene on chromosome 6p25.1, encoding Ribonuclease P protein subunit p40 (O75818). Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5’-ends. It is a common-essential gene (DepMap: required in 96.1% of cancer cell lines).

Enables ribonuclease P RNA binding activity. Contributes to ribonuclease P activity. Involved in tRNA 5’-leader removal. Part of multimeric ribonuclease P complex.

Source: NCBI Gene 10799 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 56 total
• Cancer dependency (DepMap): dependent in 96.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_006638

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20992
Approved symbol	RPP40
Name	ribonuclease P/MRP subunit p40
Location	6p25.1
Locus type	gene with protein product
Status	Approved
Aliases	bA428J1.3
Ensembl gene	ENSG00000124787
Ensembl biotype	protein_coding
OMIM	606117
Entrez	10799

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000319533, ENST00000380051, ENST00000464646, ENST00000468105, ENST00000479782, ENST00000483546, ENST00000618533, ENST00000859759

RefSeq mRNA: 3 — MANE Select: NM_006638 NM_001286132, NM_001286133, NM_006638

CCDS: CCDS34333, CCDS69040, CCDS75391

Canonical transcript exons

ENST00000380051 — 8 exons

Exon	Start	End
ENSE00000615701	4995951	4996085
ENSE00000680925	4996222	4996420
ENSE00000680926	4998716	4998841
ENSE00001819692	4994717	4995276
ENSE00003527208	4999809	4999904
ENSE00003564081	5003880	5004037
ENSE00003628036	5002101	5002245
ENSE00003635689	5000563	5000631

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 91.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.6059 / max 51.3432, expressed in 1659 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71527	6.0757	1633
71526	0.5303	268

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.24	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.76	gold quality
adrenal tissue	UBERON:0018303	87.31	gold quality
right adrenal gland cortex	UBERON:0035827	87.24	gold quality
esophagus squamous epithelium	UBERON:0006920	86.95	gold quality
right adrenal gland	UBERON:0001233	86.86	gold quality
left adrenal gland	UBERON:0001234	85.44	gold quality
endothelial cell	CL:0000115	84.94	gold quality
pharyngeal mucosa	UBERON:0000355	84.79	gold quality
adrenal cortex	UBERON:0001235	84.52	gold quality
buccal mucosa cell	CL:0002336	84.41	silver quality
left adrenal gland cortex	UBERON:0035825	84.41	gold quality
adrenal gland	UBERON:0002369	84.36	gold quality
epithelium of esophagus	UBERON:0001976	84.25	gold quality
squamous epithelium	UBERON:0006914	82.74	gold quality
cortical plate	UBERON:0005343	82.45	gold quality
secondary oocyte	CL:0000655	81.76	gold quality
esophagus mucosa	UBERON:0002469	81.62	gold quality
gingival epithelium	UBERON:0001949	81.37	gold quality
middle temporal gyrus	UBERON:0002771	81.01	gold quality
gastrocnemius	UBERON:0001388	80.53	gold quality
muscle of leg	UBERON:0001383	79.88	gold quality
gingiva	UBERON:0001828	79.57	gold quality
Brodmann (1909) area 23	UBERON:0013554	79.30	gold quality
monocyte	CL:0000576	78.71	gold quality
penis	UBERON:0000989	78.52	gold quality
mononuclear cell	CL:0000842	78.36	gold quality
prefrontal cortex	UBERON:0000451	78.25	gold quality
leukocyte	CL:0000738	78.12	gold quality
ventricular zone	UBERON:0003053	78.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.82
E-MTAB-6379	no	584.77

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 1)

• Data idenified two cleavage sites for RNase MRP/RNase P in the coding sequence of viperin mRNA. (PMID:21053045)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpp40	ENSDARG00000017605
mus_musculus	Rpp40	ENSMUSG00000021418
rattus_norvegicus	Rpp40	ENSRNOG00000016226

Protein

Protein identifiers

Ribonuclease P protein subunit p40 — O75818 (reviewed: O75818)

Alternative names: RNase P subunit 1

All UniProt accessions (4): A0A087X1N3, F8WC38, O75818, X6RLL4

UniProt curated annotations — full annotation on UniProt →

Function. Component of ribonuclease P, a ribonucleoprotein complex that generates mature tRNA molecules by cleaving their 5’-ends. Also a component of the MRP ribonuclease complex, which cleaves pre-rRNA sequences.

Subunit / interactions. Component of nuclear RNase P and RNase MRP ribonucleoproteins. RNase P consists of a catalytic RNA moiety and about 10 protein subunits; POP1, POP4, POP5, POP7, RPP14, RPP21, RPP25, RPP30, RPP38 and RPP40. Within the RNase P complex, POP1, POP7 and RPP25 form the ‘finger’ subcomplex, POP5, RPP14, RPP40 and homodimeric RPP30 form the ‘palm’ subcomplex, and RPP21, POP4 and RPP38 form the ‘wrist’ subcomplex. All subunits of the RNase P complex interact with the catalytic RNA. Several subunits of RNase P are also part of the RNase MRP complex. RNase MRP consists of a catalytic RNA moiety and about 8 protein subunits; POP1, POP7, RPP25, RPP30, RPP38, RPP40 and possibly also POP4 and POP5.

Subcellular location. Nucleus. Nucleolus.

Isoforms (2)

UniProt ID	Names	Canonical?
O75818-1	1	yes
O75818-2	2

RefSeq proteins (3): NP_001273061, NP_001273062, NP_006629* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013893	RNase_P_Rpp40	Family

Pfam: PF08584

Enzyme classification (BRENDA):

• EC 3.1.26.5 — ribonuclease P (BRENDA: 188 organisms, 407 substrates, 80 inhibitors, 54 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

24 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HUMAN PRE-TRNATYR	0.0001–0.0005	5
PRE-TRNATYR	—	5
PRE-TRNAASP	—	4
PTRNATYR	0.0002–0.0305	4
TRNA PRECURSOR	—	4
PRE-TRNA-TYR	0.0001	2
PRE-TRNATHR(AGT)	0.0035–0.05	2
RNASE P RIBOSWITCH A	0.0064–0.0081	2
TRNAPHE (G+1) PRECURSOR	—	2
TRNATYR	—	2
PMINI3PBUG	0.0013	1
PRE-TRNA	—	1
PRE-TRNA SUPS1 TRNASER	0.0002	1
PRE-TRNA-ASP	0.0003	1
PRE-TRNA-CYS	0.0006	1

UniProt features (37 total): strand 17, helix 11, turn 5, chain 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6AHV	X-RAY DIFFRACTION	2.6
9UH7	ELECTRON MICROSCOPY	2.84
9UH9	ELECTRON MICROSCOPY	3.47
6AHU	ELECTRON MICROSCOPY	3.66
6AHR	ELECTRON MICROSCOPY	3.92
9UHA	ELECTRON MICROSCOPY	3.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75818-F1	91.73	0.80

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-72306	tRNA processing
R-HSA-72312	rRNA processing
R-HSA-8868773	rRNA processing in the nucleus and cytosol
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 171 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_RIBOSOME_BIOGENESIS, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_MATURATION_OF_SSU_RRNA, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GENTILE_RESPONSE_CLUSTER_D3, WEI_MYCN_TARGETS_WITH_E_BOX, chr6p25, MUELLER_PLURINET, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_MATURATION_OF_5_8S_RRNA_FROM_TRICISTRONIC_RRNA_TRANSCRIPT_SSU_RRNA_5_8S_RRNA_LSU_RRNA

GO Biological Process (4): endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000447), tRNA 5’-leader removal (GO:0001682), rRNA processing (GO:0006364), tRNA processing (GO:0008033)

GO Molecular Function (5): ribonuclease P activity (GO:0004526), ribonuclease P RNA binding (GO:0033204), ribonuclease MRP activity (GO:0000171), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (7): ribonuclease MRP complex (GO:0000172), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolar ribonuclease P complex (GO:0005655), multimeric ribonuclease P complex (GO:0030681), nucleolus (GO:0005730), ribonuclease P complex (GO:0030677)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism of RNA	2
tRNA processing	1
rRNA processing in the nucleus and cytosol	1
rRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
endoribonuclease complex	2
nuclear lumen	2
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1
maturation of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1
endonucleolytic cleavage of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1
tRNA 5’-end processing	1
rRNA metabolic process	1
ribosome biogenesis	1
tRNA metabolic process	1
tRNA-specific ribonuclease activity	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
RNA binding	1
RNA endonuclease activity	1
hydrolase activity, acting on ester bonds	1
nucleic acid binding	1
binding	1
sno(s)RNA-containing ribonucleoprotein complex	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
nucleolus	1
multimeric ribonuclease P complex	1
nuclear protein-containing complex	1
ribonuclease P complex	1
intracellular membraneless organelle	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

796 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPP40	RPP30	P78346	998
RPP40	RPP38	P78345	996
RPP40	RPP25	Q9BUL9	995
RPP40	POP4	O95707	994
RPP40	POP5	Q969H6	963
RPP40	TMEM101	Q96IK0	506
RPP40	LZTS3	O60299	491
RPP40	POP1	Q99575	479
RPP40	RPP21	Q9H633	479
RPP40	PRAP1	Q96NZ9	471
RPP40	DCLRE1A	Q6PJP8	450
RPP40	RPLP1	P05386	448
RPP40	POP7	O75817	447
RPP40	UTP11	Q9Y3A2	401
RPP40	TMEM184B	Q9Y519	388

IntAct

59 interactions, top by confidence:

A	B	Type	Score
RPP25	POP7	psi-mi:“MI:0914”(association)	0.810
RPP14	RPP40	psi-mi:“MI:0915”(physical association)	0.670
RPP40	RPP21	psi-mi:“MI:0915”(physical association)	0.670
RPP14	RPP40	psi-mi:“MI:0914”(association)	0.670
POP4	POP7	psi-mi:“MI:0914”(association)	0.640
C18orf21	POP7	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
NPM1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.610
RPP21	POP7	psi-mi:“MI:0914”(association)	0.530
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
RBM4	NVL	psi-mi:“MI:0914”(association)	0.530
POP7	RPP40	psi-mi:“MI:0914”(association)	0.530
RPP25L	RPP40	psi-mi:“MI:0914”(association)	0.530
C18orf21	RPP40	psi-mi:“MI:0914”(association)	0.530
RPP40	NPM1	psi-mi:“MI:0914”(association)	0.530
SNRPC	SNRPGP15	psi-mi:“MI:0914”(association)	0.530
RPP30	RPP40	psi-mi:“MI:0914”(association)	0.530
POP4	RPP40	psi-mi:“MI:0914”(association)	0.530
RPP14	POP7	psi-mi:“MI:0914”(association)	0.530
POP1	RPP40	psi-mi:“MI:0915”(physical association)	0.400
ORF37	RPP40	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPG2	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (77): RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS), RPP40 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTR0, A0A1B0GTY4, A0A1B0GVD1, A7WNB0, A8R0V4, E9Q7F5, O55779, O70552, O75818, O93036, P01586, P03212, P03319, P03321, P04823, P0DOE0, P10260, P13206, P16837, P20880, P28907, P36340, P47939, P47940, Q02484, Q03233, Q1HVF6, Q2HRD2, Q3KSS3, Q3TTJ4, Q5BK38, Q5QR91, Q5VAN0, Q64277, Q66669, Q66672, Q6GQU0, Q6GVM5, Q6UWF9, Q86WR6

Diamond homologs: A7YWU3, O75818, Q5BK64, Q8R1F9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RPP40	“form complex”	“Ribonuclease MRP complex”	binding
RPP40	“form complex”	“Nucleolar ribonuclease P complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
tRNA processing	5	54.1×	1e-06
tRNA processing in the nucleus	8	47.7×	7e-10
rRNA processing in the nucleus and cytosol	7	34.1×	1e-07
rRNA processing	7	31.1×	1e-07
Major pathway of rRNA processing in the nucleolus and cytosol	8	15.0×	1e-06
Metabolism of RNA	10	12.6×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
tRNA processing	5	100.3×	1e-07
rRNA processing	8	27.0×	8e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1182 predictions. Top by Δscore:

Variant	Effect	Δscore
6:4996093:C:CT	acceptor_gain	1.0000
6:4996094:A:T	acceptor_gain	1.0000
6:4996221:CAGGT:C	donor_gain	1.0000
6:4996384:T:C	acceptor_gain	1.0000
6:4998837:AACAA:A	acceptor_gain	1.0000
6:4998839:CAA:C	acceptor_gain	1.0000
6:4998842:C:CC	acceptor_gain	1.0000
6:4998843:T:C	acceptor_gain	1.0000
6:4998844:T:C	acceptor_gain	1.0000
6:4998844:T:TC	acceptor_gain	1.0000
6:4998850:A:AC	acceptor_gain	1.0000
6:4998850:A:C	acceptor_gain	1.0000
6:4999800:GATAC:G	donor_loss	1.0000
6:4999801:ATAC:A	donor_loss	1.0000
6:4999802:TAC:T	donor_loss	1.0000
6:4999803:ACT:A	donor_loss	1.0000
6:4999804:CT:C	donor_loss	1.0000
6:4999805:TT:T	donor_loss	1.0000
6:4999806:TA:T	donor_loss	1.0000
6:4999807:A:AC	donor_gain	1.0000
6:4999807:ACT:A	donor_loss	1.0000
6:4999808:C:CC	donor_gain	1.0000
6:4999808:C:T	donor_loss	1.0000
6:4999808:CT:C	donor_gain	1.0000
6:4999808:CTA:C	donor_gain	1.0000
6:4999808:CTAA:C	donor_gain	1.0000
6:4999808:CTAAA:C	donor_gain	1.0000
6:4999901:TTCCC:T	acceptor_loss	1.0000
6:4999903:CC:C	acceptor_gain	1.0000
6:4999904:CC:C	acceptor_gain	1.0000

AlphaMissense

2391 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:4995229:A:T	V314D	0.987
6:4995245:A:G	W309R	0.984
6:4995245:A:T	W309R	0.984
6:4999810:A:C	F144L	0.984
6:4999810:A:T	F144L	0.984
6:4999812:A:G	F144L	0.984
6:4996253:A:G	W243R	0.983
6:4996253:A:T	W243R	0.983
6:5000616:A:G	L95P	0.982
6:4995118:A:G	L351P	0.981
6:4999886:A:G	L119P	0.981
6:4995219:A:C	F317L	0.979
6:4995219:A:T	F317L	0.979
6:4995221:A:G	F317L	0.979
6:4999898:A:G	L115S	0.979
6:5000574:A:G	L109P	0.979
6:5000578:C:G	A108P	0.979
6:4995210:G:C	S320R	0.977
6:4995210:G:T	S320R	0.977
6:4995212:T:G	S320R	0.977
6:4995235:A:G	L312P	0.977
6:5000619:G:T	A94E	0.977
6:4999856:A:G	L129P	0.975
6:5000577:G:T	A108D	0.973
6:5002244:A:T	V42D	0.973
6:5002242:A:G	S43P	0.972
6:4999872:A:C	Y124D	0.970
6:4995954:A:G	L297P	0.963
6:5000620:C:G	A94P	0.961
6:5002235:A:G	L45P	0.961

dbSNP variants (sampled 300 via entrez): RS1000012906 (6:4991441 A>G), RS1000221184 (6:4989001 C>A), RS1000347581 (6:5001508 G>A), RS1000413680 (6:4995440 C>T), RS1000478719 (6:4994625 T>G), RS1000615195 (6:4990086 G>A), RS1000680223 (6:4988664 T>C), RS1000818182 (6:4995006 C>G), RS1000964636 (6:4990250 C>T), RS1001360277 (6:5002970 G>C), RS1001372128 (6:5001254 T>C), RS1001442728 (6:5001020 A>T), RS1001504019 (6:5005107 G>C), RS1001665895 (6:5002539 G>A), RS1001680223 (6:4988520 T>A)

Disease associations

OMIM: gene MIM:606117 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	4
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	affects methylation, decreases expression, increases abundance, increases expression, affects expression	3
Cyclosporine	decreases expression, increases expression	3
Particulate Matter	affects expression, affects methylation, decreases expression, increases abundance, increases expression	3
Tretinoin	decreases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
deguelin	increases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
picoxystrobin	increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Nickel	increases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1

Clinical trials (associated diseases)

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