CRCP

Summary

CRCP (CGRP receptor component, HGNC:17888) is a protein-coding gene on chromosome 7q11.21, encoding DNA-directed RNA polymerase III subunit RPC9 (O75575). DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. It is a common-essential gene (DepMap: required in 98.4% of cancer cell lines).

This gene encodes a membrane protein that functions as part of a receptor complex for a small neuropeptide that increases intracellular cAMP levels. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 27297 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 36 total
• GTEx eGene: eQTL in 41 tissues, sQTL in 21 (q < 0.05)
• Cancer dependency (DepMap): dependent in 98.4% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.40 (unconstrained)
• MANE Select transcript: NM_014478

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17888
Approved symbol	CRCP
Name	CGRP receptor component
Location	7q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CGRP-RCP, RCP, RCP9, C17, POLR3I
Ensembl gene	ENSG00000241258
Ensembl biotype	protein_coding
OMIM	606121
Entrez	27297

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 4 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000395326

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 1

ENST00000395326, ENST00000338592, ENST00000360415, ENST00000398684, ENST00000431089, ENST00000486848, ENST00000492264, ENST00000718079, ENST00000718080, ENST00000870873, ENST00000936880, ENST00000936881, ENST00001060215, ENST00001104919, ENST00001104920

RefSeq mRNA: 4 — MANE Select: NM_014478 NM_001040647, NM_001040648, NM_001142414, NM_014478

CCDS: CCDS47599, CCDS47600, CCDS55116, CCDS5532

Canonical transcript exons

ENST00000395326 — 6 exons

Exon	Start	End
ENSE00001927708	66114847	66114970
ENSE00003489373	66134280	66134374
ENSE00003535356	66127704	66127740
ENSE00003562900	66130744	66130842
ENSE00003620949	66145443	66145500
ENSE00004785217	66152208	66154568

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 92.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.8612 / max 175.6751, expressed in 1824 samples.

Highest expression (Bgee): calcaneal tendon, ganglionic eminence, cortical plate, islet of Langerhans, adrenal tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CRCP is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 41 tissues and its splicing (sQTL) in 21 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 62 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	2.0e-62	-0.45	7:66295242:C:G
Brain Cerebellar Hemisphere	sqtl	2.8e-30	+1.54	7:66100041:G:A
Cells Cultured fibroblasts	eqtl	3.8e-28	+0.33	7:66162490:GTCTCAC:G
Muscle Skeletal	eqtl	3.7e-23	-0.61	7:66158519:T:C
Brain Cerebellum	sqtl	4.0e-20	+1.39	7:66158519:T:C
Esophagus Mucosa	eqtl	2.9e-16	+0.71	7:66432575:A:T
Thyroid	eqtl	1.6e-14	+0.72	7:66002468:G:A
Brain Frontal Cortex BA9	sqtl	3.0e-14	+1.33	7:66382625:A:G
Cells Cultured fibroblasts	sqtl	3.7e-14	-0.37	7:66125265:C:G
Skin Sun Exposed Lower leg	eqtl	7.4e-13	-0.36	7:66359432:T:C
Brain Nucleus accumbens basal ganglia	eqtl	1.4e-11	-0.52	7:66982345:A:AC
Heart Atrial Appendage	eqtl	6.2e-11	-0.38	7:66555809:C:T
Skin Not Sun Exposed Suprapubic	eqtl	2.6e-10	+0.34	7:66195532:G:A
Esophagus Muscularis	eqtl	2.6e-10	+0.21	7:66555603:T:C
Cells EBV-transformed lymphocytes	eqtl	3.2e-10	+0.46	7:66130230:C:T
Esophagus Gastroesophageal Junction	eqtl	3.7e-10	-0.30	7:66982345:A:AC
Muscle Skeletal	sqtl	3.7e-10	-0.63	7:66228965:A:G
Artery Tibial	eqtl	3.7e-10	-0.21	7:66982345:A:AC
Brain Frontal Cortex BA9	eqtl	2.8e-09	+0.46	7:66214581:T:C
Artery Aorta	eqtl	4.3e-09	+0.68	7:66086834:C:T

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
78854	24.2491	1821
78855	8.3699	1746
78856	0.2422	94

Top tissues by expression

showing 100 of 279 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	92.18	gold quality
ganglionic eminence	UBERON:0004023	91.32	gold quality
cortical plate	UBERON:0005343	90.45	gold quality
islet of Langerhans	UBERON:0000006	89.16	gold quality
adrenal tissue	UBERON:0018303	88.85	gold quality
right lobe of liver	UBERON:0001114	88.69	gold quality
monocyte	CL:0000576	88.38	gold quality
oocyte	CL:0000023	88.03	gold quality
mononuclear cell	CL:0000842	87.97	gold quality
leukocyte	CL:0000738	87.85	gold quality
rectum	UBERON:0001052	87.74	gold quality
amniotic fluid	UBERON:0000173	87.07	gold quality
stromal cell of endometrium	CL:0002255	86.95	gold quality
prefrontal cortex	UBERON:0000451	86.84	gold quality
colonic epithelium	UBERON:0000397	86.45	gold quality
ventricular zone	UBERON:0003053	86.30	gold quality
secondary oocyte	CL:0000655	86.10	gold quality
adrenal gland	UBERON:0002369	86.05	gold quality
left adrenal gland	UBERON:0001234	85.78	gold quality
pancreas	UBERON:0001264	85.75	gold quality
popliteal artery	UBERON:0002250	85.69	gold quality
tibial artery	UBERON:0007610	85.68	gold quality
right adrenal gland	UBERON:0001233	85.57	gold quality
sural nerve	UBERON:0015488	85.46	gold quality
left adrenal gland cortex	UBERON:0035825	85.21	gold quality
anterior cingulate cortex	UBERON:0009835	85.17	gold quality
cingulate cortex	UBERON:0003027	85.08	gold quality
stomach	UBERON:0000945	85.04	gold quality
body of stomach	UBERON:0001161	84.97	gold quality
mucosa of transverse colon	UBERON:0004991	84.93	gold quality
adrenal cortex	UBERON:0001235	84.88	gold quality
body of pancreas	UBERON:0001150	84.81	gold quality
lower esophagus	UBERON:0013473	84.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	84.74	gold quality
right adrenal gland cortex	UBERON:0035827	84.69	gold quality
gall bladder	UBERON:0002110	84.67	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.58	gold quality
lower esophagus mucosa	UBERON:0035834	84.43	gold quality
transverse colon	UBERON:0001157	84.36	gold quality
aorta	UBERON:0000947	84.25	gold quality
right coronary artery	UBERON:0001625	84.25	gold quality
ectocervix	UBERON:0012249	84.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	84.22	gold quality
esophagus	UBERON:0001043	84.19	gold quality
tonsil	UBERON:0002372	84.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.07	gold quality
mucosa of stomach	UBERON:0001199	84.01	gold quality
liver	UBERON:0002107	84.00	gold quality
smooth muscle tissue	UBERON:0001135	83.82	gold quality
endocervix	UBERON:0000458	83.78	gold quality
bone marrow cell	CL:0002092	83.72	gold quality
corpus callosum	UBERON:0002336	83.65	gold quality
cerebellar cortex	UBERON:0002129	83.64	gold quality
cerebellar hemisphere	UBERON:0002245	83.64	gold quality
spinal cord	UBERON:0002240	83.61	gold quality
esophagus mucosa	UBERON:0002469	83.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.52	gold quality
nucleus accumbens	UBERON:0001882	83.50	gold quality
skin of leg	UBERON:0001511	83.49	gold quality
neocortex	UBERON:0001950	83.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.42	gold quality
lymph node	UBERON:0000029	83.40	gold quality
muscle of leg	UBERON:0001383	83.37	gold quality
left ovary	UBERON:0002119	83.20	gold quality
blood	UBERON:0000178	83.17	gold quality
right atrium auricular region	UBERON:0006631	83.15	gold quality
right frontal lobe	UBERON:0002810	83.12	gold quality
minor salivary gland	UBERON:0001830	83.11	gold quality
colon	UBERON:0001155	83.10	gold quality
amygdala	UBERON:0001876	83.07	gold quality
frontal cortex	UBERON:0001870	83.06	gold quality
metanephros cortex	UBERON:0010533	83.02	gold quality
gastrocnemius	UBERON:0001388	82.97	gold quality
caudate nucleus	UBERON:0001873	82.95	gold quality
skin of abdomen	UBERON:0001416	82.90	gold quality
vagina	UBERON:0000996	82.89	gold quality
large intestine	UBERON:0000059	82.88	gold quality
left coronary artery	UBERON:0001626	82.88	gold quality
right lung	UBERON:0002167	82.86	gold quality
cerebellum	UBERON:0002037	82.80	gold quality
descending thoracic aorta	UBERON:0002345	82.78	gold quality
hypothalamus	UBERON:0001898	82.74	gold quality
left uterine tube	UBERON:0001303	82.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.73	gold quality
right ovary	UBERON:0002118	82.71	gold quality
intestine	UBERON:0000160	82.62	gold quality
body of uterus	UBERON:0009853	82.62	gold quality
choroid plexus epithelium	UBERON:0003911	82.51	silver quality
thoracic aorta	UBERON:0001515	82.48	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.45	gold quality
coronary artery	UBERON:0001621	82.44	gold quality
fundus of stomach	UBERON:0001160	82.40	gold quality
upper lobe of left lung	UBERON:0008952	82.38	gold quality
granulocyte	CL:0000094	82.37	gold quality
ascending aorta	UBERON:0001496	82.36	gold quality
omental fat pad	UBERON:0010414	82.25	gold quality
heart left ventricle	UBERON:0002084	82.21	gold quality
spleen	UBERON:0002106	82.21	gold quality
peritoneum	UBERON:0002358	82.21	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.79
E-GEOD-100618	no	121.48
E-GEOD-99795	no	64.78

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebellum	tissue	49.8	high
Cerebral cortex	tissue	38.6	medium
Pons	tissue	38.6
Motor cortex	tissue	38.6
Hippocampal formation	tissue	38.3
Somatosensory cortex	tissue	38.3
Prefrontal cortex	tissue	37.7
Thalamus	tissue	37.4
Occipital cortex	tissue	37.1
Substantia nigra	tissue	36.2
Hypothalamus	tissue	36.1
Entorhinal cortex	tissue	36.1
Retrosplenial and cingulate cortex	tissue	35.3
Bone marrow	tissue	35.1	not detected
Superior colliculi	tissue	34.5
Spinal cord	tissue	34.2
Retrosplenial cortex	tissue	34.1
Midbrain	tissue	33.4
Temporal cortex	tissue	33.1
Medulla oblongata	tissue	32.4
Septum	tissue	32.1
Insular cortex	tissue	31.7
Periaqueductal gray	tissue	30.6
Olfactory bulb	tissue	30.5
Putamen	tissue	30.1
Locus coeruleus	tissue	30.0
Amygdala	tissue	29.8
Ventral forebrain	tissue	29.0
Frontal cortex	tissue	27.5
Basal ganglia	tissue	26.3	medium
Caudate putamen	tissue	25.9
Corpus callosum	tissue	25.7
Postcentral gyrus	tissue	24.1
Choroid plexus	tissue	23.6
Nucleus accumbens	tissue	21.7
Hippocampus	tissue	21.7	medium
Liver	tissue	20.1	medium
Parathyroid gland	tissue	19.8	high
Pancreas	tissue	19.4	medium
Esophagus	tissue	18.8	not detected
Thyroid gland	tissue	18.7	low
Rectum	tissue	18.3	medium
Colon	tissue	17.2	medium
Smooth muscle	tissue	16.9	medium
Stomach 1	tissue	16.8	low
Breast	tissue	16.4	low
Heart muscle	tissue	16.3	medium
Vagina	tissue	16.3	not detected
Spleen	tissue	16.3	low
Fallopian tube	tissue	16.3	high
Prostate	tissue	16.2	medium
Duodenum	tissue	15.7	medium
Ovary	tissue	15.6	medium
Tonsil	tissue	15.6	low
Urinary bladder	tissue	15.5	low
Kidney	tissue	15.4	medium
Skin 1	tissue	15.2	medium
Lymph node	tissue	15.2	low
Salivary gland	tissue	15.1	low
Seminal vesicle	tissue	14.8	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal hippocampus (38.3), Subiculum (36.1), Ventral hippocampus (34.5), Ventral spinal cord (34.2), Dorsal spinal cord (33.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

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

showing 30 of 69 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-6083	99.47	68.73	2393

Functional genomics

gnomAD constraint: pLI 0.000162, LOEUF 1.4, missense Z 1.26 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000395326 — one region, missense o/e 0.74. DepMap (CRISPR cell-line fitness): dependent in 98.4% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SNU-398 (-2.769), HuH-7 (-2.74), NCI-H82 (-2.638), HCC-95 (-2.629), SNU-8 (-2.608), BICR 6 (-2.577), COV362 (-2.541), SNU-1077 (-2.538), OAW28 (-2.513), 253J (-2.489), SK-RC-52 (-2.468), JHOM-1 (-2.414), SNU-213 (-2.399), CAL-78 (-2.383), Du4475 (-2.365).

Literature-anchored findings (GeneRIF, showing 14)

• Expression of CGRP-RCP was detected in CD34+ cells and also in some mature granulocyte samples, providing evidence that CGRP-RCP may be regulated independently of RAMP1 and CRLR in hematopoietic cells. (PMID:11937264)
• human CGRP-RCP is the genuine orthologue of C17. CGRP-RCP was found to functionally replace C17 in Deltarpc17 yeast cells; CGRP-RCP was identified in a purified human Pol III preparation. (PMID:12482973)
• inhibition of ACE seems to augment CGRP catabolism. (PMID:16406141)
• Increased mRNA expression CGRP-RCP in gravid myometrium supports the possibility of involvement of CGRP in the control of myometrial contractility. (PMID:17853344)
• A peptide mimetic demonstrates that 12 residues of family B member CGRP receptor proximal C-terminus are required for this receptor’s expression and localization at the cell membrane. (PMID:18636754)
• analysis of the effects of antagonists to the CGRP receptor (PMID:19053766)
• Data describe the role of residues 23-60 of the calcitonin receptor-like receptor in binding with interaction sites within the N-terminus of the calcitonin gene-related peptide receptor. (PMID:19913063)
• The extracellular protein domains corresponding to residues 23-133 of calcitonin receptor-like receptor and residues 26-117 of receptor activity-modifying protein 1 (RAMP1) are shown to be sufficient for formation of a stable, folded monodisperse complex. (PMID:20099900)
• This study demonstrates the detailed expression of CGRP and its receptor components within spinal trigeminal nucleus in the brainstem and in the spinal cord at C1-level (PMID:22074408)
• In this review, the influence of the CGRP family peptides in reproduction and pregnancy is explored and discussed. (PMID:25015815)
• data reinforce and clarify our understanding of CGRP receptor localization, and provide evidence that antagonist antibodies bind to target sites in the trigeminovascular system of primates that are involved in the pathology of migraine (PMID:27155150)
• CGRP family of receptors displays both ligand- and RAMP-dependent signaling bias among the Galphas, Galphai, and Galphaq/11 pathways. (PMID:27566546)
• both anti-CGRP and anti-CGRP receptor monoclonal antibodies (mABs) completed clinical development, and the first representatives of these 2 classes are available on the market. MABs are approved for prevention of migraine attacks in chronic or episodic migraine, involving long-term treatments. (PMID:31018157)
• Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models. (PMID:38743922)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	crcp	ENSDARG00000069373
mus_musculus	Crcp	ENSMUSG00000025532
rattus_norvegicus	Crcp	ENSRNOG00000071267
drosophila_melanogaster	Polr3I	FBGN0030801
caenorhabditis_elegans		WBGENE00044924

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1100818) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal head morphology	1
abnormal coat/hair pigmentation	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	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
Bos taurus	A0JN61	93.2%	Diamond
Cavia porcellus	Q60482	85.9%	Diamond
Schizosaccharomyces pombe 972h-	Q9C0Z9	34.5%	Diamond
Saccharomyces cerevisiae S288C	P47076	30.8%	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
LINC00174	ncRNA	285908
ASL	protein-coding	435
TPST1	protein-coding	8460
GUSB	protein-coding	2990

Protein

Protein identifiers

DNA-directed RNA polymerase III subunit RPC9 — O75575 (reviewed: O75575)

Alternative names: Calcitonin gene-related peptide-receptor component protein

All UniProt accessions (4): A0ABB0MV56, A0ABB0MV70, O75575, H7BY40

UniProt curated annotations — full annotation on UniProt →

Function. DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. With POLR3H/RPC8 forms a mobile stalk that protrudes from Pol III core and functions primarily in transcription initiation. Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway. Accessory protein for the calcitonin gene-related peptide (CGRP) receptor. It modulates CGRP responsiveness in a variety of tissues.

Subunit / interactions. Component of the RNA polymerase III complex consisting of 17 subunits: a ten-subunit horseshoe-shaped catalytic core composed of POLR3A/RPC1, POLR3B/RPC2, POLR1C/RPAC1, POLR1D/RPAC2, POLR3K/RPC10, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5; a mobile stalk composed of two subunits POLR3H/RPC8 and CRCP/RPC9, protruding from the core and functioning primarily in transcription initiation; and additional subunits homologous to general transcription factors of the RNA polymerase II machinery, POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer required for transcription initiation and POLR3D/RPC4-POLR3E/RPC5 heterodimer involved in both transcription initiation and termination.

Subcellular location. Nucleus. Cell membrane.

Tissue specificity. Ubiquitous. Most prevalent in testis.

Similarity. Belongs to the eukaryotic RPC9 RNA polymerase subunit family.

Isoforms (4)

UniProt ID	Names	Canonical?
O75575-1	1	yes
O75575-2	2
O75575-3	3
O75575-4	4

RefSeq proteins (4): NP_001035737, NP_001035738, NP_001135886, NP_055293* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005574	Rpb4/RPC9	Family
IPR006590	RNA_pol_Rpb4/RPC9_core	Domain
IPR010997	HRDC-like_sf	Homologous_superfamily
IPR038324	Rpb4/RPC9_sf	Homologous_superfamily
IPR038846	RPC9	Family

Pfam: PF03874

UniProt features (18 total): helix 8, strand 4, splice variant 3, chain 1, region of interest 1, turn 1

Structure

Experimental structures (PDB)

29 structures by resolution:

PDB	Title	Method	Resolution (Å)
7AE1	Cryo-EM structure of human RNA Polymerase III elongation complex 1	ELECTRON MICROSCOPY	2.8
9K39	Human RNA Polymerase III de novo transcribing complex 8 (TC8)	ELECTRON MICROSCOPY	2.8
7D58	cryo-EM structure of human RNA polymerase III in elongating state	ELECTRON MICROSCOPY	2.9
9K36	Human RNA Polymerase III de novo transcribing complex 12 (TC12)	ELECTRON MICROSCOPY	2.9
9K2G	Human RNA Polymerase III de novo transcribing complex 13 (TC13)	ELECTRON MICROSCOPY	3
9K3U	Human RNA Polymerase III de novo transcribing complex 5 (TC5)	ELECTRON MICROSCOPY	3
7AE3	Cryo-EM structure of human RNA Polymerase III elongation complex 3	ELECTRON MICROSCOPY	3.1
7D59	cryo-EM structure of human RNA polymerase III in apo state	ELECTRON MICROSCOPY	3.1
9K38	Human RNA Polymerase III de novo transcribing complex 6 (TC6)	ELECTRON MICROSCOPY	3.1
9FSO	Human RNA Polymerase III Class III Open Pre-initiation Complex 1 (OC1)	ELECTRON MICROSCOPY	3.28
7A6H	Cryo-EM structure of human apo RNA Polymerase III	ELECTRON MICROSCOPY	3.3
9LXN	Human RNA Polymerase III de novo transcribing complex 5 (TC5)(without 3’dATP)	ELECTRON MICROSCOPY	3.3
7DU2	RNA polymerase III EC complex in post-translocation state	ELECTRON MICROSCOPY	3.35
9FSP	RNA Polymerase III Class III Open Pre-initation Complex 2 (OC2)	ELECTRON MICROSCOPY	3.39
7AEA	Cryo-EM structure of human RNA Polymerase III elongation complex 2	ELECTRON MICROSCOPY	3.4
8IUH	RNA polymerase III pre-initiation complex open complex 1	ELECTRON MICROSCOPY	3.4
7DN3	Structure of Human RNA Polymerase III elongation complex	ELECTRON MICROSCOPY	3.5
9K3V	Human RNA Polymerase III de novo transcribing complex 4 (TC4)	ELECTRON MICROSCOPY	3.5
9LKT	Human RNA Polymerase III de novo transcribing complex 10 (TC10)	ELECTRON MICROSCOPY	3.5
9FSQ	RNA Polymerase III Class III Melting Pre-Initiation Complex (MC)	ELECTRON MICROSCOPY	3.51
7FJI	human Pol III elongation complex	ELECTRON MICROSCOPY	3.6
7FJJ	human Pol III pre-termination complex	ELECTRON MICROSCOPY	3.6
9LXO	Human RNA Polymerase III de novo transcribing complex 6 (TC6)(without 3’dATP)	ELECTRON MICROSCOPY	3.6
9FSR	RNA Polymerase III Class III Open Mini Pre-initiation Complex 1 (OC1-mini)	ELECTRON MICROSCOPY	3.76
8ITY	human RNA polymerase III pre-initiation complex closed DNA 1	ELECTRON MICROSCOPY	3.9
7AST	Apo Human RNA Polymerase III	ELECTRON MICROSCOPY	4
8IUE	RNA polymerase III pre-initiation complex melting complex 1	ELECTRON MICROSCOPY	4.1
9FSS	RNA Polymerase III Class III Open Mini Pre-Initiation complex 2 (OC2-mini)	ELECTRON MICROSCOPY	4.14
9K3B	Human RNA Polymerase III de novo transcribing complex 10 overall (TC10-overall)	ELECTRON MICROSCOPY	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75575-F1	83.31	0.59

Human Protein Atlas

Protein class: Predicted intracellular proteins, RNA polymerase related proteins, Essential proteins

Protein evidence: Evidence at protein level

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

Antibody reliability (HPA): IH approved · IF approved

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 12; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

12 pathways:

ID	Pathway	Evidence
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA	curated
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-749476	RNA Polymerase III Abortive And Retractive Initiation	electronic
R-HSA-73780	RNA Polymerase III Chain Elongation	electronic
R-HSA-74158	RNA Polymerase III Transcription	—
R-HSA-76046	RNA Polymerase III Transcription Initiation	—
R-HSA-76061	RNA Polymerase III Transcription Initiation From Type 1 Promoter	electronic
R-HSA-76066	RNA Polymerase III Transcription Initiation From Type 2 Promoter	electronic
R-HSA-76071	RNA Polymerase III Transcription Initiation From Type 3 Promoter	electronic
R-HSA-73980	RNA Polymerase III Transcription Termination	electronic

MSigDB gene sets: 151 (showing top): MORF_RAGE, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_INITIATION_FROM_TYPE_3_PROMOTER, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_RNA_POLYMERASE_III_CHAIN_ELONGATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GOCC_SECRETORY_GRANULE, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MODULE_379, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_DEFENSE_RESPONSE_TO_VIRUS, GOMF_PEPTIDE_RECEPTOR_ACTIVITY, MORF_PML, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP

GO Biological Process (8): transcription by RNA polymerase III (GO:0006383), transcription initiation at RNA polymerase III promoter (GO:0006384), termination of RNA polymerase III transcription (GO:0006386), innate immune response (GO:0045087), defense response to virus (GO:0051607), immune system process (GO:0002376), DNA-templated transcription initiation (GO:0006352), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (4): nucleotide binding (GO:0000166), calcitonin gene-related peptide receptor activity (GO:0001635), DNA-directed RNA polymerase activity (GO:0003899), protein binding (GO:0005515)

GO Cellular Component (9): acrosomal vesicle (GO:0001669), nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase III complex (GO:0005666), cytosol (GO:0005829), plasma membrane (GO:0005886), DNA polymerase III complex (GO:0009360), DNA-directed RNA polymerase complex (GO:0000428), RNA polymerase complex (GO:0030880)

Reactome top-level categories

5 top-level categories:

Category	Pathways
RNA Polymerase III Transcription	4
RNA Polymerase III Transcription Initiation	3
Innate Immune System	1
Immune System	1
Gene expression (Transcription)	1

GO top-level categories

30 GO namespaces:

Category	Terms
DNA-templated transcription	2
transcription by RNA polymerase III	2
RNA biosynthetic process	2
cellular anatomical structure	2
DNA-templated transcription initiation	1
DNA-templated transcription termination	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
biological_process	1
G protein-coupled receptor activity	1
signal transduction	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
calcitonin family receptor activity	1
5’-3’ RNA polymerase activity	1
binding	1
secretory granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
DNA-directed RNA polymerase complex	1
nuclear protein-containing complex	1
cytoplasm	1
membrane	1
cell periphery	1
DNA polymerase complex	1
RNA polymerase complex	1
transferase complex, transferring phosphorus-containing groups	1
intracellular protein-containing complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
termination of RNA polymerase III transcription	BP	direct assay
transcription by RNA polymerase III	BP	direct assay
transcription initiation at RNA polymerase III promoter	BP	direct assay
DNA polymerase III complex	CC	direct assay
RNA polymerase III complex	CC	direct assay
DNA-directed RNA polymerase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 776 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRCP	RAMP1	O60894	926
CRCP	CALCRL	Q16602	905
CRCP	ADM	P35318	809
CRCP	POLR3F	Q9H1D9	713
CRCP	POLR3C	Q9BUI4	710
CRCP	POLR3E	Q9NVU0	692
CRCP	POLR1C	O15160	658
CRCP	POLR3D	P05423	646
CRCP	POLR3H	Q9Y535	644
CRCP	POLR3G	O15318	597
CRCP	POLR3K	Q9Y2Y1	584
CRCP	RAMP2	O60895	548
CRCP	RAMP3	O60896	546
CRCP	POLR2E	P19388	543
CRCP	POLR1D	P0DPB6	541

IntAct

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

6 partners by confidence:

Partner	Interaction type	MIscore	Records
ZMIZ2	physical association	0.560	6
TCF12	physical association	0.560	3
NUDT3	physical association	0.400	1
PRPF40A	association	0.350	1
SRC	association	0.350	1
VAV2	physical association	0.000	1

BioGRID (140 interactions; top human partners by supporting records): POLR1C (Co-fractionation; 6 records), POLR3E (Co-fractionation; 6 records), POLR1D (Co-fractionation; 5 records), POLR2F (Co-fractionation; 5 records), POLR3A (Co-fractionation; 5 records), POLR3B (Co-fractionation; 5 records), POLR3D (Affinity Capture-MS; 5 records), POLR3H (Affinity Capture-MS; 4 records), POLR2H (Co-fractionation; 3 records), POLR3GL (Affinity Capture-MS; 3 records), POLR3K (Co-fractionation; 3 records), POLR2E (Affinity Capture-MS; 2 records), POLR2K (Affinity Capture-MS; 2 records), POLR2L (Affinity Capture-MS; 2 records), POLR3C (Co-fractionation; 2 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
CRCP	“form complex”	“RNA Polymerase III”	binding

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
RNA polymerase III complex	15	POLR3C, POLR3A, POLR3G, POLR3K, POLR3F, CRCP, POLR1C, POLR2K, POLR3D, POLR1D, POLR3E, POLR3H, POLR2H, POLR2L, POLR3B

Disease & clinical

Genetic variants

Variant evidence for CRCP: 36 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	0
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 29 predictions of 539):

Position(s)	Effect	Δscore	Sites
7:66127702–66127703	acceptor_loss	1.0000	5
7:66130742–66130743	acceptor_loss	1.0000	5
7:66145501–66145502	donor_loss	1.0000	5
7:66114966	donor_gain	0.9900
7:66114971–66114972	donor_loss	0.9900	4
7:66115032	donor_gain	0.9900
7:66115609	acceptor_gain	0.9900
7:66127703	acceptor_loss	0.9900
7:66127741–66127742	donor_loss	0.9900	5
7:66130743	acceptor_loss	0.9900

AlphaMissense

330 missense substitutions predicted likely pathogenic (of 982 scored), across 91 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
N88	8	0.958	0.998
E82	7	0.988	0.997
E15	7	0.972	0.985
E48	7	0.938	0.980
E102	7	0.916	0.976
E105	7	0.847	0.930
E96	7	0.824	0.958
E106	7	0.781	0.954
P91	6	0.971	0.996
N13	6	0.914	0.995
V101	6	0.865	0.992
V95	6	0.852	0.984
Q98	6	0.839	0.946
C58	6	0.838	0.991
F69	6	0.836	0.934
T44	6	0.824	0.959
F17	6	0.733	0.818
S12	5	0.987	0.997
Y47	5	0.971	0.994
R107	5	0.968	0.996

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	3.45e-08
Kidney Chromophobe (TCGA)	unfavorable	9.72e-05

Disease associations

OMIM: gene MIM:606121 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST008059_201	Estimated glomerular filtration rate	3e-10
GCST000943_3	Aortic root size	4e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenate	increases expression, increases abundance	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects methylation, increases abundance	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects expression	1
Hydrogen Peroxide	affects expression	1
Methotrexate	decreases expression	1
Nitrogen Dioxide	affects methylation, increases abundance	1
Plant Extracts	increases expression, affects cotreatment	1
Thimerosal	decreases expression	1
Thiram	increases expression	1
Cyclosporine	increases expression	1
Asbestos, Crocidolite	decreases expression	1

Clinical trials (associated diseases)

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