HNRNPC

Summary

HNRNPC (heterogeneous nuclear ribonucleoprotein C, HGNC:5035) is a protein-coding gene on chromosome 14q11.2, encoding Heterogeneous nuclear ribonucleoproteins C1/C2 (P07910). Binds pre-mRNA and nucleates the assembly of 40S hnRNP particles. It is a common-essential gene (DepMap: required in 98.6% of cancer cell lines).

This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene can act as a tetramer and is involved in the assembly of 40S hnRNP particles. Multiple transcript variants encoding at least two different isoforms have been described for this gene.

Source: NCBI Gene 3183 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, autosomal dominant 74 (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 70 total — 3 pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 98.6% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004500

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5035
Approved symbol	HNRNPC
Name	heterogeneous nuclear ribonucleoprotein C
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000092199
Ensembl biotype	protein_coding
OMIM	164020
Entrez	3183

Gene structure

Transcript identifiers

Ensembl transcripts: 124 — 117 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000336053, ENST00000420743, ENST00000430246, ENST00000553300, ENST00000553444, ENST00000553614, ENST00000553753, ENST00000554383, ENST00000554417, ENST00000554455, ENST00000554539, ENST00000554891, ENST00000554969, ENST00000555127, ENST00000555137, ENST00000555176, ENST00000555215, ENST00000555309, ENST00000555585, ENST00000555883, ENST00000555914, ENST00000556142, ENST00000556226, ENST00000556513, ENST00000556628, ENST00000556897, ENST00000557033, ENST00000557157, ENST00000557201, ENST00000557336, ENST00000557442, ENST00000557768, ENST00000861378, ENST00000861379, ENST00000861380, ENST00000861381, ENST00000861382, ENST00000861383, ENST00000861384, ENST00000861385, ENST00000861386, ENST00000861387, ENST00000861388, ENST00000861389, ENST00000861390, ENST00000861391, ENST00000861392, ENST00000861393, ENST00000861394, ENST00000861395, ENST00000861396, ENST00000861397, ENST00000861398, ENST00000861399, ENST00000861400, ENST00000861401, ENST00000861402, ENST00000861403, ENST00000861404, ENST00000861405, ENST00000861406, ENST00000861407, ENST00000861408, ENST00000861409, ENST00000861410, ENST00000861411, ENST00000861412, ENST00000861413, ENST00000861414, ENST00000861415, ENST00000861416, ENST00000861417, ENST00000913879, ENST00000913880, ENST00000913881, ENST00000913882, ENST00000913883, ENST00000913884, ENST00000913885, ENST00000913886, ENST00000913887, ENST00000913888, ENST00000913889, ENST00000913890, ENST00000913891, ENST00000913892, ENST00000913893, ENST00000913894, ENST00000913895, ENST00000913896, ENST00000913897, ENST00000913898, ENST00000913899, ENST00000913900, ENST00000913901, ENST00000913902, ENST00000913903, ENST00000913904, ENST00000913905, ENST00000913906, ENST00000913907, ENST00000913908, ENST00000913909, ENST00000913910, ENST00000913911, ENST00000913912, ENST00000913913, ENST00000913914, ENST00000913915, ENST00000913916, ENST00000913917, ENST00000913918, ENST00000913919, ENST00000948335, ENST00000948336, ENST00000948337, ENST00000948338, ENST00000948339, ENST00000948340, ENST00000948341, ENST00000948342, ENST00000948343, ENST00000948344, ENST00000948345

RefSeq mRNA: 4 — MANE Select: NM_004500 NM_001077442, NM_001077443, NM_004500, NM_031314

CCDS: CCDS41915, CCDS45079

Canonical transcript exons

ENST00000553300 — 9 exons

Exon	Start	End
ENSE00001726573	21230997	21231072
ENSE00002277537	21263311	21263336
ENSE00002484154	21269298	21269442
ENSE00003481206	21211406	21211566
ENSE00003524718	21233953	21234229
ENSE00003639844	21212960	21213117
ENSE00003682034	21211810	21211923
ENSE00003786985	21230319	21230366
ENSE00003904626	21209147	21211306

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.5341 / max 325.6449, expressed in 1803 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142158	12.3523	1792
142142	0.8996	468
142159	0.7852	507
142143	0.6696	348
207140	0.4505	198
142156	0.2077	50
142155	0.1380	43
142157	0.0312	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.76	gold quality
ganglionic eminence	UBERON:0004023	99.68	gold quality
cortical plate	UBERON:0005343	99.58	gold quality
calcaneal tendon	UBERON:0003701	99.57	gold quality
monocyte	CL:0000576	99.46	gold quality
leukocyte	CL:0000738	99.46	gold quality
smooth muscle tissue	UBERON:0001135	99.45	gold quality
left ovary	UBERON:0002119	99.45	gold quality
colonic epithelium	UBERON:0000397	99.41	gold quality
right uterine tube	UBERON:0001302	99.41	gold quality
vermiform appendix	UBERON:0001154	99.40	gold quality
right ovary	UBERON:0002118	99.40	gold quality
adrenal tissue	UBERON:0018303	99.40	gold quality
gall bladder	UBERON:0002110	99.39	gold quality
endocervix	UBERON:0000458	99.38	gold quality
islet of Langerhans	UBERON:0000006	99.36	gold quality
body of uterus	UBERON:0009853	99.35	gold quality
right adrenal gland	UBERON:0001233	99.34	gold quality
right adrenal gland cortex	UBERON:0035827	99.34	gold quality
stromal cell of endometrium	CL:0002255	99.33	gold quality
adenohypophysis	UBERON:0002196	99.33	gold quality
rectum	UBERON:0001052	99.31	gold quality
left adrenal gland	UBERON:0001234	99.31	gold quality
left adrenal gland cortex	UBERON:0035825	99.31	gold quality
granulocyte	CL:0000094	99.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.29	gold quality
ectocervix	UBERON:0012249	99.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.26	gold quality
left uterine tube	UBERON:0001303	99.24	gold quality
bone marrow cell	CL:0002092	99.20	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	16.07
E-MTAB-10042	yes	6.26
E-CURD-79	no	1107.60
E-GEOD-124858	no	987.72
E-CURD-53	no	818.09
E-HCAD-10	no	42.38
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ETS2, JUN, TCF3, TP53

miRNA regulators (miRDB)

129 targeting HNRNPC, 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-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AA	99.96	70.64	3753

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 98.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• phosphorylation of heterogeneous nuclear ribonucleoprotein C1/C2 in response to physiologic levels of hydrogen peroxide in endothelial cells (PMID:11877401)
• nuclear ribonucleoproteins C1 and C2 are part of the RNP complex that forms on XIAP IRES, the cellular levels of hnRNPC1 and -C2 parallel the activity of XIAP IRES and the overexpression of hnRNPC1-C2 specifically enhanced translation of XIAP IRES (PMID:12482981)
• hnRNP C, via internal ribosomal entry site binding, modulates translation of c-myc mRNA in a cell cycle phase-dependent manner (PMID:12509468)
• the acidic C-terminal domain of hnRNP-C1/C2 could be a regulatory domain and may play an important role in the regulation of mRNA binding by hnRNP-C1/C2. (PMID:12564933)
• a novel nuclear export is activated by the ROCK signaling pathway to exclude hnRNP C1/C2 from nucleus, by which the compartmentalization of specific hnRNP components is disturbed in apoptotic cells (PMID:15494373)
• CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C (PMID:15687492)
• findings suggest that hnRNP C1 has a role in positive-strand RNA synthesis in poliovirus-infected cells, possibly at the level of initiation (PMID:15731220)
• upstream element in human papillomavirus type 16 interacted specifically with CstF-64, hnRNP C1/C2 & polypyrimidine tract binding protein, suggesting these factors were enhancing or regulating polyadenylation at the HPV-16 early polyadenylation signal (PMID:15767428)
• Direct in vivo interaction of hnRNPC with the urokinase receptor mRNA 3’UTR was demonstrated. (PMID:16010978)
• Results describe the purification of a locus control region-associated remodeling complex consisting of heterogeneous nuclear ribonucleoprotein C1/C2, SWI/SNF, and MeCP1 as a single homogeneous complex. (PMID:16217013)
• These results demonstrate that hnRNP C1/C2 is involved in maintenance of cellular homeostasis besides cellular differentiation and proliferation. (PMID:16960656)
• in addition to its RNA-processing functions, hnRNP C1/C2 may be a key determinant of the temporal patterns of VDRE occupancy (PMID:17071612)
• regulation of IRES-mediated translation by hnRNP C1/C2 and Unr might be important in mitosis (PMID:17159903)
• A novel cis-element in the 5’ coding region of p53 mRNA and its interaction with heterogeneous nuclear ribonucleoprotein (hnRNP)C1/C2, is described. (PMID:18296503)
• Intracellular NS1 protein of dengue virus interacts with hnRNP C1/C2. (PMID:18471994)
• The RNA binding domain of heterogeneous nuclear ribonuclear protein C binds and stabilizes urokinase-type plasminogen activator receptor (uPAR) mRNA, attributing the key role of this domain in hnRNPC-mediated uPAR regulation in lung epithelial cells. (PMID:18494499)
• The H(2)O(2) responsive pre-mRNA binding protein hnRNP-C is up-regulated in atherosclerosis. (PMID:18508286)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• anti-hnRNP C1/C2 antibody hampered splicing of SMN1 exon 7, but did not affect splicing of SMN2 exon 7 (PMID:19628962)
• endogenous hnRNP C and PTEN interact and co-localize within the nucleus (PMID:19740742)
• The authors report here that the 5’ end of poliovirus negative-strand RNA is capable of interacting with endogenous hnRNP C, as well as with poliovirus nonstructural proteins. (PMID:20164237)
• The authors propose that hnRNP C interacts with poliovirus RNA and replication proteins to increase the efficiency of viral genomic RNA synthesis. (PMID:20189623)
• FMRP represses translation by recruiting APP mRNA to processing bodies, whereas hnRNP C promotes APP translation by displacing FMRP, thereby relieving the translational block. (PMID:20473314)
• HNRNP C recognizes uridine tracts with a defined long-range spacing consistent with HNRNP particle organization. (PMID:20601959)
• Studies indicated that DDX21, HNRNPC, and RCC2 were isolated from Ku86 multicomponent complex in response to DNA damage. (PMID:20873769)
• One of the identified proteins, hnRNPC, was found to interact with small hepatitis delta virus antigen in vitro and in vivo in human liver cells. (PMID:21774814)
• p27kip1 upregulated by hnRNPC1/2 antagonizes CagA-mediated pathogenesis. (PMID:22404445)
• study shows mechanism by which Pol II transcripts are classified according to length; heterotetramer of hnRNP C1/C2 measures the length of the transcripts like a molecular ruler, by binding to unstructured RNA regions longer than 200 to 300 nucleotides (PMID:22461616)
• The data indicated that hnRNPC controls the aggressiveness of glioblastoma cells through the regulation of PDCD4. Silencing of hnRNPC lowered miR-21 levels, in turn increasing the expression of PDCD4, suppressing Akt and p70S6K activation. (PMID:22907752)
• By preventing U2AF65 binding to Alu elements, hnRNP C plays a critical role as a genome-wide sentinel protecting the transcriptome. (PMID:23374342)
• Heterogeneous nuclear ribonucleoprotein C is a key regulator of BRCA gene expression and homologous recombination-based DNA repair. (PMID:23585894)
• down-regulation of MALAT-1 expression compromised the cytoplasmic translocation of hnRNP C in the G2/M phase and resulted in G2/M arrest (PMID:23973260)
• PTBP1 and hnRNP C repress exon 3 inclusion, and that downregulation of PTBP1 inhibited BIM-mediated apoptosis. (PMID:24743263)
• HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform. (PMID:25354590)
• m(6)A-switch-regulated HNRNPC-binding activities affect the abundance as well as alternative splicing of target mRNAs, demonstrating the regulatory role of m(6)A-switches on gene expression and RNA maturation (PMID:25719671)
• Our results suggested that hnRNP C1 controls HPV16 late gene expression. (PMID:25878250)
• These findings suggest that hnRNP C1/C2 is involved in dengue virus replication at the stage of viral RNA synthesis. (PMID:25890165)
• APP levels then decrease progressively as a function of age in close relationship with the gradual normalization of FMRP and hnRNP C levels. (PMID:26048669)
• These data indicate that hnRNPC1/C2 binds to both DNA and RNA and influences both gene expression and RNA splicing, but these actions do not appear to be linked through 1,25(OH)2D-mediated induction of transcription. (PMID:27672039)
• These data suggest an interplay between CELF2 and hnRNP C as the mechanistic basis for activation-dependent alternative splicing of TRAF3 exon 8. (PMID:28031331)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hnrnpc	ENSMUSG00000060373
rattus_norvegicus	LOC100911576	ENSRNOG00000011621

Paralogs (6): RALY (ENSG00000125970), HNRNPCL1 (ENSG00000179172), HNRNPCL4 (ENSG00000179412), RALYL (ENSG00000184672), HNRNPCL2 (ENSG00000275774), HNRNPCL3 (ENSG00000277058)

Protein

Protein identifiers

Heterogeneous nuclear ribonucleoproteins C1/C2 — P07910 (reviewed: P07910)

All UniProt accessions (16): P07910, B4DSU6, B4DY08, G3V251, G3V2D6, G3V2H6, G3V2Q1, G3V3K6, G3V4C1, G3V4M8, G3V4W0, G3V555, G3V575, G3V576, G3V5V7, G3V5X6

UniProt curated annotations — full annotation on UniProt →

Function. Binds pre-mRNA and nucleates the assembly of 40S hnRNP particles. Interacts with poly-U tracts in the 3’-UTR or 5’-UTR of mRNA and modulates the stability and the level of translation of bound mRNA molecules. Single HNRNPC tetramers bind 230-240 nucleotides. Trimers of HNRNPC tetramers bind 700 nucleotides. May play a role in the early steps of spliceosome assembly and pre-mRNA splicing. N6-methyladenosine (m6A) has been shown to alter the local structure in mRNAs and long non-coding RNAs (lncRNAs) via a mechanism named ’m(6)A-switch’, facilitating binding of HNRNPC, leading to regulation of mRNA splicing.

Subunit / interactions. Tetramer composed of 3 copies of isoform C1 and 1 copy of isoform C2. Assembly of 3 tetramers with bound pre-mRNA gives rise to a 19S complex that interacts with HNRNPA2B1 tetramers. Component of the 40S hnRNP particle. Identified in the spliceosome C complex. Interacts with IGF2BP1. Interacts with DHX9; this interaction is direct, enhanced probably by their concomitant binding to RNA and mediates the attachment to actin filaments. Interacts with PPIA/CYPA. Interacts with YWHAE.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated on Ser-260 and Ser-299 in resting cells. Phosphorylated on Ser-253 and on 1 serine residue in the poly-Ser stretch at position 238 in response to hydrogen peroxide. Sumoylated. Sumoylation reduces affinity for mRNA. Ubiquitinated and degraded after nucleo-cytoplasmic transport by YWHAE.

Disease relevance. Intellectual developmental disorder, autosomal dominant 74 (MRD74) [MIM:620688] An autosomal dominant disorder characterized by global developmental delay, including delay of motor skills and speech delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the RRM HNRPC family. RALY subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
P07910-1	C2	yes
P07910-2	C1
P07910-3	3
P07910-4	4

RefSeq proteins (4): NP_001070910, NP_001070911, NP_004491, NP_112604 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR017347	hnRNP_C	Family
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR051186	RRM_HNRPC/RALY_subfam	Family

Pfam: PF00076

UniProt features (73 total): modified residue 20, cross-link 13, compositionally biased region 6, sequence conflict 6, strand 5, sequence variant 4, turn 4, splice variant 3, helix 3, region of interest 2, mutagenesis site 2, initiator methionine 1, chain 1, domain 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3LN4	X-RAY DIFFRACTION	1.3
1TXP	SOLUTION NMR
1WF2	SOLUTION NMR
2MXY	SOLUTION NMR
2MZ1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07910-F1	70.63	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (33): 2, 109, 113, 115, 121, 162, 166, 176, 233, 238, 239, 241, 253, 260, 299, 306, 8, 50, 89, 94 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
197	no effect on sumoylation.
250	loss of sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-9013418	RHOBTB2 GTPase cycle
R-HSA-9013422	RHOBTB1 GTPase cycle
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 407 (showing top): GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, PID_TELOMERASE_PATHWAY, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, ATACCTC_MIR202, MORF_UBE2I, GOBP_3_UTR_MEDIATED_MRNA_STABILIZATION, MORF_HDAC1, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORF_RAD21, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, GGGTGGRR_PAX4_03

GO Biological Process (7): mRNA splicing, via spliceosome (GO:0000398), osteoblast differentiation (GO:0001649), chromatin remodeling (GO:0006338), RNA splicing (GO:0008380), negative regulation of telomere maintenance via telomerase (GO:0032211), 3’-UTR-mediated mRNA stabilization (GO:0070935), mRNA processing (GO:0006397)

GO Molecular Function (9): RNA binding (GO:0003723), mRNA 3’-UTR binding (GO:0003730), poly(U) RNA binding (GO:0008266), nucleosomal DNA binding (GO:0031492), identical protein binding (GO:0042802), telomerase RNA binding (GO:0070034), N6-methyladenosine-containing RNA reader activity (GO:1990247), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (13): chromatin (GO:0000785), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), telomerase holoenzyme complex (GO:0005697), cytosol (GO:0005829), actin cytoskeleton (GO:0015629), membrane (GO:0016020), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), catalytic step 2 spliceosome (GO:0071013), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
RHOBTB GTPase Cycle	2
SUMO E3 ligases SUMOylate target proteins	1
mRNA Splicing	1
Metabolism of RNA	1
mRNA 3’-end processing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
RNA processing	2
RNA binding	2
binding	2
nuclear protein-containing complex	2
ribonucleoprotein complex	2
catalytic complex	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
ossification	1
cell differentiation	1
chromatin organization	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
mRNA stabilization	1
mRNA metabolic process	1
nucleic acid binding	1
mRNA binding	1
poly-pyrimidine tract binding	1
chromatin DNA binding	1
nucleosome binding	1
protein binding	1
protein-RNA adaptor activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
cytoskeleton	1
cellular_component	1
extracellular vesicle	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
protein-containing complex	1

Protein interactions and networks

STRING

4406 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HNRNPC	HNRNPA2B1	P22626	993
HNRNPC	HNRNPA1	P09651	989
HNRNPC	PTBP1	P26599	982
HNRNPC	DHX9	Q08211	959
HNRNPC	YTHDF1	Q9BYJ9	941
HNRNPC	YTHDC1	Q96MU7	921
HNRNPC	HNRNPU	Q00839	916
HNRNPC	HNRNPAB	Q99729	913
HNRNPC	HNRNPM	P52272	912
HNRNPC	MATR3	P43243	900
HNRNPC	TARDBP	Q13148	899
HNRNPC	FUS	P35637	882
HNRNPC	METTL3	Q86U44	878
HNRNPC	YTHDC2	Q9H6S0	877
HNRNPC	HNRNPL	P14866	875

IntAct

501 interactions, top by confidence:

A	B	Type	Score
HNRNPC	HNRNPC	psi-mi:“MI:0915”(physical association)	0.860
HNRNPC	KPNA3	psi-mi:“MI:0915”(physical association)	0.850
KPNA3	HNRNPC	psi-mi:“MI:0915”(physical association)	0.850
KPNA4	HNRNPC	psi-mi:“MI:0915”(physical association)	0.830
HNRNPC	KPNA4	psi-mi:“MI:0915”(physical association)	0.830
HNRNPC	HNRNPA1	psi-mi:“MI:0915”(physical association)	0.790
DDX21	HNRNPC	psi-mi:“MI:0915”(physical association)	0.750
RALYL	HNRNPC	psi-mi:“MI:0915”(physical association)	0.740
HNRNPC	RALYL	psi-mi:“MI:0915”(physical association)	0.740
RBM41	HNRNPC	psi-mi:“MI:0915”(physical association)	0.740
HNRNPC	RBM41	psi-mi:“MI:0915”(physical association)	0.740
RALY	HNRNPC	psi-mi:“MI:0915”(physical association)	0.740
CDC5L	HNRNPC	psi-mi:“MI:0915”(physical association)	0.730
HNRNPC	SDCBP	psi-mi:“MI:0915”(physical association)	0.720
SUMO1	HNRNPC	psi-mi:“MI:0915”(physical association)	0.720
SDCBP	HNRNPC	psi-mi:“MI:0915”(physical association)	0.720
HNRNPC	SUMO1	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (1015): HNRNPC (Two-hybrid), HNRNPC (Two-hybrid), KPNA2 (Two-hybrid), KPNA3 (Two-hybrid), KPNA4 (Two-hybrid), LMO2 (Two-hybrid), SDCBP (Two-hybrid), UBE2I (Two-hybrid), SUMO1 (Two-hybrid), ZFYVE26 (Two-hybrid), RBM41 (Two-hybrid), RALYL (Two-hybrid), SUMO1P1 (Two-hybrid), HNRNPC (Affinity Capture-MS), HNRNPC (Affinity Capture-MS)

ESM2 similar proteins: B2RXH8, B7ZW38, C0SUW7, F4JP52, F4JQZ3, F4JTI1, F4KIA8, G3V9R8, O48802, O60812, O77768, P07910, P0DMR1, P19600, P93831, Q08BJ2, Q08DJ0, Q0VFL3, Q0VFL7, Q0WNR6, Q0WUR5, Q10MI4, Q149C2, Q3ED78, Q41583, Q5DU00, Q5RA82, Q5VN06, Q5XIN3, Q64012, Q6K641, Q84PB3, Q84UI6, Q86SE5, Q86XZ4, Q8BTF8, Q8K1N4, Q8RWQ4, Q8S4P4, Q8S4P6

Diamond homologs: B2RXH8, B7ZW38, G3V9R8, O60812, O77768, P07910, P0DMR1, P19600, Q08DJ0, Q0VFL7, Q5RA82, Q64012, Q86SE5, Q8BTF8, Q9UKM9, Q9V3V0, Q9Z204, Q16629, Q3T106, Q8BL97, Q9W4D2, P38996, Q13247, Q29RT0, Q3B7L6, Q9WX39, F4JHI7, O22315, P84103, P84104, Q10145, Q3SZR8, Q74ZS6, Q94901, Q9FYB7, Q9LIS2, Q9XFR5, G3V6S8, P26686, Q23121

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CSNK1A1	down-regulates	HNRNPC	phosphorylation
CSNK1A1	“down-regulates activity”	HNRNPC	phosphorylation
CSNK2A1	“down-regulates activity”	HNRNPC	phosphorylation
CSNK2A2	unknown	HNRNPC	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 147 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
Maturation of DENV proteins	6	13.4×	2e-03
Antimicrobial mechanism of IFN-stimulated genes	6	12.4×	2e-03
Diseases of signal transduction by growth factor receptors and second messengers	9	5.4×	7e-03
Cytokine Signaling in Immune system	11	4.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	6	16.7×	6e-04
mRNA stabilization	5	14.2×	5e-03
G1/S transition of mitotic cell cycle	6	9.3×	7e-03
mRNA splicing, via spliceosome	10	7.1×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	30
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2691760	NM_004500.4(HNRNPC):c.754del (p.Asp252fs)	Pathogenic
3766075	NM_004500.4(HNRNPC):c.296G>A (p.Arg99Gln)	Pathogenic
973074	NM_004500.4(HNRNPC):c.850_876del (p.Arg284_Asp292del)	Pathogenic

SpliceAI

1776 predictions. Top by Δscore:

Variant	Effect	Δscore
14:21211302:TCCAG:T	acceptor_gain	1.0000
14:21211303:CCAG:C	acceptor_gain	1.0000
14:21211303:CCAGC:C	acceptor_gain	1.0000
14:21211304:CAG:C	acceptor_gain	1.0000
14:21211304:CAGC:C	acceptor_gain	1.0000
14:21211305:AG:A	acceptor_gain	1.0000
14:21211305:AGC:A	acceptor_loss	1.0000
14:21211306:GCTG:G	acceptor_loss	1.0000
14:21211307:C:CC	acceptor_gain	1.0000
14:21211307:CT:C	acceptor_loss	1.0000
14:21211309:G:C	acceptor_gain	1.0000
14:21211309:G:GC	acceptor_gain	1.0000
14:21211317:C:CT	acceptor_gain	1.0000
14:21211386:T:A	donor_gain	1.0000
14:21211391:T:A	donor_gain	1.0000
14:21211400:TTTCA:T	donor_loss	1.0000
14:21211401:TTCA:T	donor_loss	1.0000
14:21211402:TCAC:T	donor_loss	1.0000
14:21211403:CAC:C	donor_loss	1.0000
14:21211405:C:G	donor_loss	1.0000
14:21211425:T:TA	donor_gain	1.0000
14:21211455:T:TA	donor_gain	1.0000
14:21211562:CTCTA:C	acceptor_gain	1.0000
14:21211563:TCTA:T	acceptor_loss	1.0000
14:21211564:CTA:C	acceptor_gain	1.0000
14:21211565:TA:T	acceptor_gain	1.0000
14:21211565:TAC:T	acceptor_loss	1.0000
14:21211567:C:CC	acceptor_gain	1.0000
14:21211567:CTGCG:C	acceptor_loss	1.0000
14:21211568:T:A	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000034143 (14:21253416 G>C), RS1000066094 (14:21258209 G>A), RS1000067378 (14:21259758 C>T), RS1000077475 (14:21257969 T>C), RS1000102943 (14:21208836 T>C), RS1000115646 (14:21223223 C>T), RS1000178670 (14:21265709 C>T), RS1000233319 (14:21232841 G>A,C), RS1000287677 (14:21233852 A>C), RS1000300624 (14:21222958 TG>T), RS1000315944 (14:21239489 T>A), RS1000335245 (14:21259996 G>A,C), RS1000346472 (14:21264818 A>C), RS1000391594 (14:21238263 T>C), RS1000444036 (14:21227507 T>G)

Disease associations

OMIM: gene MIM:164020 | disease phenotypes: MIM:620688

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder, autosomal dominant 74	Strong	Autosomal dominant

Mondo (1): intellectual developmental disorder, autosomal dominant 74 (MONDO:0958203)

Orphanet (0):

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000448	Prominent nose
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000601	Hypotelorism
HP:0000750	Delayed speech and language development
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001344	Absent speech
HP:0001511	Intrauterine growth retardation
HP:0002069	Bilateral tonic-clonic seizure
HP:0002188	Delayed CNS myelination
HP:0002194	Delayed gross motor development
HP:0002342	Moderate intellectual disability
HP:0002360	Sleep disturbance
HP:0002870	Obstructive sleep apnea
HP:0003593	Infantile onset
HP:0010862	Delayed fine motor development
HP:0010864	Severe intellectual disability
HP:0011147	Typical absence seizure
HP:0011968	Feeding difficulties
HP:0031936	Delayed ability to walk

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001135_5	Bipolar disorder	2.000000e-06
GCST008103_155	Bipolar disorder	6.000000e-06
GCST008839_563	Height	2.000000e-12

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2216742 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.90	Kd	127.1	nM	CHEMBL3752910
6.90	ED50	127.1	nM	CHEMBL3752910
5.12	Kd	7542	nM	CHEMBL5653589
5.12	ED50	7542	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 13 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148528: Binding affinity to human HNRNPC incubated for 45 mins by Kinobead based pull down assay	kd	0.1271	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148528: Binding affinity to human HNRNPC incubated for 45 mins by Kinobead based pull down assay	kd	7.5421	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
sodium arsenite	increases abundance, affects reaction, increases expression, affects cotreatment, affects binding (+2 more)	5
bisphenol A	decreases methylation, decreases expression, affects cotreatment	4
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
Doxorubicin	affects expression, decreases expression	2
Fluorouracil	increases expression	2
Hydrogen Peroxide	decreases response to substance, affects expression, affects binding	2
Methotrexate	decreases expression	2
Ozone	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
quinone	decreases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, increases expression	1
uranyl acetate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2217168	Binding	Binding affinity to HNRPC in human HepG2 cell lysate after 1 hr by capture compound based LC/MS analysis	Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). — J Med Chem

Cellosaurus cell lines

4 cell lines: 4 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D0VI	EMCi225-A	Induced pluripotent stem cell	Male
CVCL_D0VJ	EMCi225-B	Induced pluripotent stem cell	Male
CVCL_D0VK	EMCi225-C	Induced pluripotent stem cell	Male
CVCL_D0VL	EMCi225-D	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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