HNRNPL

Summary

HNRNPL (heterogeneous nuclear ribonucleoprotein L, HGNC:5045) is a protein-coding gene on chromosome 19q13.2, encoding Heterogeneous nuclear ribonucleoprotein L (P14866). Splicing factor binding to exonic or intronic sites and acting as either an activator or repressor of exon inclusion. It is a common-essential gene (DepMap: required in 97.6% of cancer cell lines).

Heterogeneous nuclear RNAs (hnRNAs) which include mRNA precursors and mature mRNAs are associated with specific proteins to form heterogenous ribonucleoprotein (hnRNP) complexes. Heterogeneous nuclear ribonucleoprotein L is among the proteins that are stably associated with hnRNP complexes and along with other hnRNP proteins is likely to play a major role in the formation, packaging, processing, and function of mRNA. Heterogeneous nuclear ribonucleoprotein L is present in the nucleoplasm as part of the HNRP complex. HNRP proteins have also been identified outside of the nucleoplasm. Exchange of hnRNP for mRNA-binding proteins accompanies transport of mRNA from the nucleus to the cytoplasm. Since HNRP proteins have been shown to shuttle between the nucleus and the cytoplasm, it is possible that they also have cytoplasmic functions. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3191 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 94 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_001533

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5045
Approved symbol	HNRNPL
Name	heterogeneous nuclear ribonucleoprotein L
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000104824
Ensembl biotype	protein_coding
OMIM	603083
Entrez	3191

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay

ENST00000221419, ENST00000388749, ENST00000595164, ENST00000595443, ENST00000595804, ENST00000597731, ENST00000598985, ENST00000600233, ENST00000600741, ENST00000600873, ENST00000601047, ENST00000601449, ENST00000601664, ENST00000601813, ENST00000647557, ENST00000878169, ENST00000878170, ENST00000878171, ENST00000916355, ENST00000916356, ENST00000961196

RefSeq mRNA: 3 — MANE Select: NM_001533 NM_001005335, NM_001385651, NM_001533

CCDS: CCDS33015, CCDS33016

Canonical transcript exons

ENST00000221419 — 13 exons

Exon	Start	End
ENSE00002232828	38849700	38849986
ENSE00003509781	38837594	38837651
ENSE00003518312	38838397	38838598
ENSE00003591503	38845650	38845735
ENSE00003591746	38844008	38844104
ENSE00003624741	38838894	38839015
ENSE00003629020	38840488	38840559
ENSE00003647345	38845853	38846090
ENSE00003653811	38847316	38847434
ENSE00003658620	38837384	38837479
ENSE00003668137	38840096	38840376
ENSE00003689971	38843842	38843914
ENSE00003912275	38836370	38836780

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 126.5701 / max 726.2248, expressed in 1828 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180818	106.9054	1828
180819	10.5665	1801
180817	7.0653	1753
180816	1.1377	718
180814	0.3751	204
180820	0.2053	75
180813	0.1612	72
180811	0.1535	70

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.51	gold quality
ganglionic eminence	UBERON:0004023	99.44	gold quality
cortical plate	UBERON:0005343	99.19	gold quality
left lobe of thyroid gland	UBERON:0001120	98.92	gold quality
right lobe of thyroid gland	UBERON:0001119	98.90	gold quality
skin of abdomen	UBERON:0001416	98.88	gold quality
body of uterus	UBERON:0009853	98.85	gold quality
granulocyte	CL:0000094	98.82	gold quality
skin of leg	UBERON:0001511	98.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.81	gold quality
right uterine tube	UBERON:0001302	98.80	gold quality
rectum	UBERON:0001052	98.79	gold quality
left ovary	UBERON:0002119	98.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.78	gold quality
right testis	UBERON:0004534	98.78	gold quality
colonic epithelium	UBERON:0000397	98.77	gold quality
right ovary	UBERON:0002118	98.75	gold quality
endocervix	UBERON:0000458	98.73	gold quality
left testis	UBERON:0004533	98.72	gold quality
mucosa of stomach	UBERON:0001199	98.71	gold quality
right lung	UBERON:0002167	98.71	gold quality
left uterine tube	UBERON:0001303	98.70	gold quality
ectocervix	UBERON:0012249	98.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.69	gold quality
body of stomach	UBERON:0001161	98.67	gold quality
upper lobe of left lung	UBERON:0008952	98.66	gold quality
metanephros cortex	UBERON:0010533	98.66	gold quality
transverse colon	UBERON:0001157	98.65	gold quality
tibial nerve	UBERON:0001323	98.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.64	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.13
E-CURD-122	yes	5.32
E-GEOD-76312	no	238.68
E-MTAB-6819	no	153.15
E-MTAB-9801	no	5.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SRSF1, SRSF2, YBX1, YY1

miRNA regulators (miRDB)

46 targeting HNRNPL, 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-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-4717-3P	99.06	66.34	1072
HSA-MIR-887-5P	98.82	65.90	1347

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• AP-endonuclease 1 and hnRNP-L interact with a nCaRE-like repressor element in the AP-endonuclease 1 promoter (PMID:11809897)
• HnRNP L may be involved in the regulation of many other genes containing CA repeats or A/C-rich enhancers. (PMID:12447348)
• hnRNP L plays roles in enhancing stability, polyadenylation, and nucleocytoplasmic export; it does so by directly recruiting to intronless pre-mRNA processing enhancer (PPE) element-containing RNAs cofactors normally recruited to intron-containing RNAs. (PMID:16024770)
• 11 target genes of hnRNP L were describes. (PMID:18073345)
• This study determined that hnRNP L interacts specifically with the hnRNP D/AUF1 in the yeast two-hybrid system. (PMID:18202450)
• hnRNP L is an essential component of CaMKIV-regulated alternative splicing through CA repeats, with its phosphorylation likely playing a critical role. (PMID:19017650)
• These results strongly demonstrate the functional requirement of cellular hnRNP L for the HCV internal ribosome entry site activity. (PMID:19061868)
• hnRNP L cross-regulates inclusion of an analogous poison exon in the hnRNP L-like pre-mRNA, which explains the reciprocal expression of the two closely related hnRNP L proteins. (PMID:19124611)
• CA repeats in the 3’UTR of bcl-2 mRNA interact with hnRNP L in vitro and in vivo; this physical association is partially involved in the decay of bcl-2 mRNA. (PMID:19298794)
• Identification of a novel, higher eukaryotic specific subunit, heterogeneous nuclear ribonucleoprotein L (HnRNP-L)required for lysine methylation in vivo. (PMID:19332550)
• confirm the interactions of eEF1A1, p54(nrb), hnRNP-L, GAPDH and ASF/SF2 with the right terminal stem-loop domain of HDV genomic RNA in vitro (PMID:19464723)
• identified hnRNP L as a novel Sam68-interacting protein partner. (PMID:19912651)
• hnRNP L represses splicing by preventing 5’ splice site recognition of the U1 snRNP. (PMID:19946215)
• The binding of hnRNP L to an exon represses strong splice sites but enhances weak splice sites. (PMID:20122404)
• NSP 5a3a’s novel interaction with B23 and ribonuclear protein hnRNP-L implicates NSP 5a3a in cellular processes such as ribosome biogenesis and rRNA transcription . (PMID:20237420)
• Hypoxia induces translocation of nuclear hnRNP L to the cytoplasm, which markedly increases hnRNP L binding to VEGFA mRNA thereby inhibiting miRNA activity. (PMID:21343907)
• Mechanistic control of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) splice isoforms by the heterogeneous nuclear ribonuclear proteins hnRNP L, hnRNP A1, and hnRNP M. (PMID:21398516)
• HnRNPL is a key factor involved in the spermatogenesis by functional proteomic studies of azoospermia patients with sertoli cell only syndrome. (PMID:22245417)
• Constitutive deletion of splicing factor hnRNP L impedes early embryonic development of transgenic mice. (PMID:22523384)
• hnRNP L represses CD45 exon 4 by recruiting hnRNP A1 to a sequence upstream of the 5’ splice site (PMID:23394998)
• Induction of caspase-9b expression is due to activation of hnRNP L via phosphorylation to compete/inhibit hnRNP U association with exon 3 of Casp9 mRNA. (PMID:23396972)
• functional component of hnRNP LL is consistent with the fact that the full-length hnRNP LL has a greater silencing activity than hnRNP L (PMID:23646903)
• HnRNP L and hnRNP LL antagonistically modulate PTB-mediated splicing suppression of CHRNA1 pre-mRNA. (PMID:24121633)
• hnRNP L is a potential biomarker for the diagnosis of HBV-HCC and show that hnRNP L contributes to HCC progression. (PMID:24125732)
• Data show that alternative exons with weak 5’ splice site sequences specifically show a strong correlation between hnRNP L binding and hnRNP L-dependent splicing regulation. (PMID:24164894)
• THRIL has a role in regulating TNFalpha expression through its interaction with hnRNPL (PMID:24371310)
• Results show that HNRNPL represses splicing when bound to intronic regions upstream of alternative exons, and in contrast, activates splicing when bound to the downstream intron. (PMID:24526010)
• HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform. (PMID:25354590)
• Our results reveal that hnRNP L is a new regulator for CD44 V10 exon splicing. (PMID:25623890)
• hnRNP K and hnRNP L may serve as A1CF-like cofactors in AID-mediated class switch recombination and somatic hypermutation (PMID:25902538)
• Data suggest that incorporation of 3(S)-methyl-beta-alanine into a short alpha-helical region of nucleic acid binding domain of hnRNP LL significantly stabilizes helix without affecting its DNA binding properties. (PMID:25982410)
• The study presents the structural characterization of the RNA recognition motif domains of hnRNP-L and demonstrate their function in repressing exon 4 of SLC2A2. (PMID:26051023)
• hnRNP L controls inclusion of a broad spectrum of alternative cassette exons in T cells. (PMID:26437669)
• hnRNPA2B1, hnRNPD, hnRNPL , and YBX1 might play important roles in gastric cancer tumorigenesis. (PMID:26805816)
• HNRNPL acts as the adaptor to combine the two substructures and form the intact Sam68 nuclear body through the interaction of two sets of RNA recognition motifs with the putative architectural RNA in the respective substructures. (PMID:27377249)
• uc.345 could upregulate the hnRNPL expression and that inhibition of (hnRNPL) dampens the tumorigenesis capability of uc.345. (PMID:27689400)
• High expression of HnRNP L is associated with oral squamous cell carcinoma. (PMID:27808105)
• High HNRNPL expression is associated with prostate cancer. (PMID:28038443)
• hnRNP-L contributes to poor prognosis and tumor progression of BC by inhibiting the intrinsic apoptotic signaling and enhancing MAPK signaling pathways (PMID:28088793)
• hnRNP L inhibits proximal 5’SS but promotes two consecutive distal 5’SS splicing, antagonizing SRSF1 roles in KLF6 pre-mRNA splicing. (PMID:28119102)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	hnrnpl	ENSDARG00000035324
danio_rerio	hnrnpl2	ENSDARG00000059303
mus_musculus	Hnrnpl	ENSMUSG00000015165
rattus_norvegicus	Hnrnpl	ENSRNOG00000020235
rattus_norvegicus		ENSRNOG00000078765
drosophila_melanogaster	sm	FBGN0003435
caenorhabditis_elegans		WBGENE00016624

Paralogs (5): PTBP1 (ENSG00000011304), PTBP2 (ENSG00000117569), PTBP3 (ENSG00000119314), HNRNPLL (ENSG00000143889), RBM20 (ENSG00000203867)

Protein

Protein identifiers

Heterogeneous nuclear ribonucleoprotein L — P14866 (reviewed: P14866)

All UniProt accessions (7): A0A3B3ITJ4, A0A9L9PXI4, B4DVF8, P14866, M0QXS5, M0QYL7, M0R1W6

UniProt curated annotations — full annotation on UniProt →

Function. Splicing factor binding to exonic or intronic sites and acting as either an activator or repressor of exon inclusion. Exhibits a binding preference for CA-rich elements. Component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and associated with most nascent transcripts. Associates, together with APEX1, to the negative calcium responsive element (nCaRE) B2 of the APEX2 promoter. As part of a ribonucleoprotein complex composed at least of ZNF827, HNRNPK and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation. Regulates alternative splicing of a core group of genes involved in neuronal differentiation, likely by mediating H3K36me3-coupled transcription elongation and co-transcriptional RNA processing via interaction with CHD8.

Subunit / interactions. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Interacts with HNRNPLL. Interacts with APEX1; the interaction is DNA-dependent. Component of a complex with SETD2. Interacts with ELAVL1. Part of a transcription inhibitory ribonucleoprotein complex composed at least of the circular RNA circZNF827, ZNF827 and HNRNPK. Interacts with CHD8 in an RNA-dependent manner. Interacts with FBXO16.

Subcellular location. Nucleus. Nucleoplasm. Cytoplasm.

Post-translational modifications. Several isoelectric forms of the L protein are probably the results of post-translational modifications. Phosphorylation at Ser-544 by CaMK4 enhances interaction with a CaMK4-responsive RNA element (CaRRE1), and prevents inclusion of the stress axis-regulated exon (STREX) of the KCNMA1 potassium channel transcripts upon membrane depolarization. Ubiquitinated by the SCF-FBXO16 E3 ubiquitin ligase, leading to proteasomal degradation.

Domain organisation. RRM domain 2 has moderate RNA-binding affinity. RRM domains 3 and 4 may facilitate RNA looping when binding to two appropriately separated binding sites within the same target pre-mRNA.

Miscellaneous. Excess hnRNP L activates NMD of its own mRNA by promoting the inclusion of a ‘poison exon’ containing a premature stop codon and leading to nonsense-mediated decay. It also cross-regulates inclusion of an analogous ‘poison exon’ in the hnRNP L-like pre-mRNA.

Isoforms (2)

UniProt ID	Names	Canonical?
P14866-1	1	yes
P14866-2	2

RefSeq proteins (3): NP_001005335, NP_001372580, NP_001524* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR006536	HnRNP-L/PTB	Family
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR021790	PTBP1-like_RRM2	Domain
IPR034816	hnRNP-L_RRM3	Domain
IPR034817	hnRNPL_RRM4	Domain
IPR035005	hnRNPL_RRM1	Domain
IPR035008	hnRNPL_RRM2	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR055204	HNRNPL_RRM	Domain

Pfam: PF00076, PF11835, PF13893, PF22976

UniProt features (72 total): strand 21, modified residue 10, helix 10, mutagenesis site 7, compositionally biased region 6, cross-link 5, domain 4, turn 4, region of interest 2, chain 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7EVR	X-RAY DIFFRACTION	1.8
3TO8	X-RAY DIFFRACTION	1.82
3R27	X-RAY DIFFRACTION	2.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14866-F1	74.42	0.44

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 (15): 52, 101, 185, 269, 291, 298, 354, 358, 381, 544, 59, 62, 136, 302, 568

Mutagenesis-validated functional residues (7):

Position	Phenotype
105	6-fold decrease in rna-binding affinity.
132	4-fold increase in rna-binding affinity.
141	15-fold decrease in rna-binding affinity; when associated with a-174.
172	1-fold increase in rna-binding affinity.
174	15-fold decrease in rna-binding affinity; when associated with a-174.
504	significant decrease in rna-binding affinity.
506	significant decrease in rna-binding affinity.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 238 (showing top): RNGTGGGC_UNKNOWN, TGCGCANK_UNKNOWN, KAAB_FAILED_HEART_ATRIUM_DN, GCM_MSN, PAL_PRMT5_TARGETS_UP, SP3_Q3, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, KOINUMA_COLON_CANCER_MSI_UP, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, HSIAO_HOUSEKEEPING_GENES, GGGTGGRR_PAX4_03, PRAMOONJAGO_SOX4_TARGETS_DN, PUJANA_CHEK2_PCC_NETWORK

GO Biological Process (5): regulation of alternative mRNA splicing, via spliceosome (GO:0000381), RNA processing (GO:0006396), mRNA processing (GO:0006397), regulation of RNA splicing (GO:0043484), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (6): transcription cis-regulatory region binding (GO:0000976), RNA binding (GO:0003723), mRNA binding (GO:0003729), pre-mRNA intronic binding (GO:0097157), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (10): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), membrane (GO:0016020), ribonucleoprotein granule (GO:0035770), pronucleus (GO:0045120), synapse (GO:0045202), extracellular exosome (GO:0070062), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
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	4
binding	2
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA processing	1
mRNA metabolic process	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
nucleic acid binding	1
RNA binding	1
pre-mRNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
supramolecular complex	1
nucleus	1
cell junction	1
extracellular vesicle	1
protein-containing complex	1

Protein interactions and networks

STRING

4890 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HNRNPL	HNRNPA2B1	P22626	981
HNRNPL	ILF3	Q12906	972
HNRNPL	HNRNPC	P07910	875
HNRNPL	HNRNPA1	P09651	852
HNRNPL	HNRNPM	P52272	848
HNRNPL	HNRNPDL	O14979	842
HNRNPL	PTBP1	P26599	842
HNRNPL	HNRNPK	P61978	776
HNRNPL	HNRNPH1	P31943	748
HNRNPL	SRSF1	Q07955	740
HNRNPL	U2AF2	P26368	731
HNRNPL	SFPQ	P23246	716
HNRNPL	MED23	Q9ULK4	712
HNRNPL	HNRNPU	Q00839	705
HNRNPL	SYNCRIP	O60506	703

IntAct

244 interactions, top by confidence:

A	B	Type	Score
HNRNPC	KPNA3	psi-mi:“MI:0914”(association)	0.850
IFIT2	IFIT3	psi-mi:“MI:0914”(association)	0.780
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
RBM45	HNRNPA1	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HNRNPK	HNRNPL	psi-mi:“MI:0915”(physical association)	0.650
HNRNPK	HNRNPL	psi-mi:“MI:0403”(colocalization)	0.650
HNRNPK	HNRNPL	psi-mi:“MI:0914”(association)	0.650
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
IGF2BP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
HNRNPL	HNRNPA2B1	psi-mi:“MI:0914”(association)	0.620
HNRNPL	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.620
RBM45	HNRNPL	psi-mi:“MI:0915”(physical association)	0.580
RBM45	HNRNPL	psi-mi:“MI:0403”(colocalization)	0.580
HNRNPD	HNRNPDL	psi-mi:“MI:0914”(association)	0.560
ELAVL2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460

BioGRID (2242): HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), HNRNPL (Protein-peptide), HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-MS), HNRNPL (Affinity Capture-RNA), ACTR3 (Co-fractionation), ATP6V1F (Co-fractionation), CSE1L (Co-fractionation), DHX15 (Co-fractionation), DPH5 (Co-fractionation)

ESM2 similar proteins: A0A1W2P872, A1L1C7, A4IIM2, B2RYD2, F1LQ48, O57406, O88532, O95319, P14866, P28659, P51513, P57723, P57724, Q28HE9, Q2PFW9, Q32PX7, Q3U0V1, Q3US41, Q4QQT3, Q4R535, Q58A45, Q5F3T7, Q5NVC8, Q5R8Y8, Q5R995, Q5U231, Q640Q5, Q6DGV1, Q6GPM1, Q6NXG1, Q6P0B1, Q6PF35, Q792H5, Q7T2T1, Q7TSY6, Q7ZXE2, Q80WA4, Q8R081, Q8UVD9, Q91WJ8

Diamond homologs: F1LQ48, P14866, Q8R081, Q8WVV9, Q921F4, Q9FGL9, Q9MAC5, Q6ICX4, E9PT37, P0DW16, P17225, P25299, P26599, Q00438, Q29099, Q3UQS8, Q5T481, Q66H20, Q8WN55, Q91Z31, Q9UKA9, O95758, Q8BHD7, Q9Z118

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CAMK4	up-regulates	HNRNPL	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 184 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
mRNA Polyadenylation	25	16.8×	3e-21
Processing of Capped Intron-Containing Pre-mRNA	21	13.2×	1e-15
Dengue Virus Genome Translation and Replication	5	12.1×	4e-03
mRNA Splicing - Major Pathway	29	12.1×	4e-21
mRNA 3’-end processing	8	12.0×	3e-05
mRNA Splicing	13	10.9×	2e-08
RNA Polymerase II Transcription Termination	6	10.1×	2e-03
Transport of Mature mRNA derived from an Intron-Containing Transcript	8	9.3×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytoplasmic translation	7	41.3×	4e-08
alternative mRNA splicing, via spliceosome	7	28.1×	6e-07
regulation of mRNA splicing, via spliceosome	5	26.4×	8e-05
negative regulation of mRNA splicing, via spliceosome	5	22.8×	2e-04
mRNA stabilization	7	15.3×	3e-05
mRNA export from nucleus	8	14.1×	1e-05
negative regulation of translation	11	12.8×	2e-07
mRNA splicing, via spliceosome	23	12.5×	7e-16

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	1
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1898 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38836688:T:TA	donor_gain	1.0000
19:38837376:ATACT:A	donor_loss	1.0000
19:38837377:TACT:T	donor_loss	1.0000
19:38837378:AC:A	donor_loss	1.0000
19:38837378:ACT:A	donor_loss	1.0000
19:38837379:CTC:C	donor_loss	1.0000
19:38837379:CTCA:C	donor_gain	1.0000
19:38837380:TCAC:T	donor_loss	1.0000
19:38837381:CA:C	donor_loss	1.0000
19:38837381:CACTT:C	donor_loss	1.0000
19:38837382:A:AC	donor_gain	1.0000
19:38837382:A:C	donor_loss	1.0000
19:38837382:A:T	donor_loss	1.0000
19:38837383:C:CA	donor_gain	1.0000
19:38837383:C:CC	donor_gain	1.0000
19:38837383:CT:C	donor_gain	1.0000
19:38837383:CTT:C	donor_gain	1.0000
19:38837383:CTTG:C	donor_gain	1.0000
19:38837383:CTTGG:C	donor_gain	1.0000
19:38837475:CTCAC:C	acceptor_gain	1.0000
19:38837476:TCAC:T	acceptor_gain	1.0000
19:38837477:CAC:C	acceptor_gain	1.0000
19:38837477:CACC:C	acceptor_gain	1.0000
19:38837478:AC:A	acceptor_gain	1.0000
19:38837479:CC:C	acceptor_gain	1.0000
19:38837483:A:AC	acceptor_gain	1.0000
19:38837484:T:C	acceptor_gain	1.0000
19:38837484:T:TC	acceptor_gain	1.0000
19:38837487:C:CT	acceptor_gain	1.0000
19:38837488:A:T	acceptor_gain	1.0000

AlphaMissense

3871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:38836746:G:C	F582L	1.000
19:38836746:G:T	F582L	1.000
19:38836747:A:G	F582S	1.000
19:38836748:A:G	F582L	1.000
19:38836748:A:T	F582I	1.000
19:38836749:A:C	C581W	1.000
19:38836750:C:T	C581Y	1.000
19:38836751:A:G	C581R	1.000
19:38836753:A:G	L580S	1.000
19:38836755:C:A	K579N	1.000
19:38836755:C:G	K579N	1.000
19:38836757:T:C	K579E	1.000
19:38837406:G:C	N563K	1.000
19:38837406:G:T	N563K	1.000
19:38837431:G:T	A555D	1.000
19:38837450:A:G	W549R	1.000
19:38837450:A:T	W549R	1.000
19:38837455:A:G	L547P	1.000
19:38837458:A:G	L546P	1.000
19:38837461:C:A	G545V	1.000
19:38837461:C:T	G545E	1.000
19:38837462:C:G	G545R	1.000
19:38837462:C:T	G545R	1.000
19:38837604:G:C	F535L	1.000
19:38837604:G:T	F535L	1.000
19:38837605:A:C	F535C	1.000
19:38837605:A:G	F535S	1.000
19:38837606:A:G	F535L	1.000
19:38838431:G:T	A508D	1.000
19:38838433:G:C	N507K	1.000

dbSNP variants (sampled 300 via entrez): RS1000113012 (19:38843275 T>C), RS1000219686 (19:38851631 G>A,C), RS1000355165 (19:38851918 G>A), RS1000417755 (19:38851795 G>A,C), RS1000523865 (19:38843775 T>C,G), RS1000559688 (19:38848394 GAA>G), RS1000696993 (19:38849081 G>A,C), RS1000720053 (19:38853626 C>T), RS1000761400 (19:38847961 A>C), RS1001046309 (19:38849234 T>C,G), RS1001208369 (19:38839842 T>C), RS1001410739 (19:38839183 G>A,C), RS1001702099 (19:38840009 C>T), RS1001867453 (19:38854201 G>A), RS1001901955 (19:38851553 C>A,T)

Disease associations

OMIM: gene MIM:603083 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (2): neuromuscular disease (MONDO:0019056), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Neuromuscular disease (Orphanet:68381)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005025_38	Anti-saccade response	2.000000e-06
GCST006999_4	Logical memory (immediate recall) in mild cognitive impairment	4.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006874	antisaccade response measurement
EFO:0004874	memory performance

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009468	Neuromuscular Diseases	C10.668

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724651 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.38	Kd	41.98	nM	CHEMBL5653589
7.38	ED50	41.98	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148534: Binding affinity to human HNRNPL incubated for 45 mins by Kinobead based pull down assay	kd	0.0420	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases reaction, increases abundance	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Doxorubicin	decreases expression, decreases response to substance	2
Valproic Acid	decreases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	decreases sumoylation	1
heclin	decreases expression, decreases reaction	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases 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	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
cupric oxide	decreases expression	1
quinoline	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
indioside D	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bromovanin	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651576	Binding	Binding affinity to human HNRNPL incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT03272802	PHASE2/PHASE3	UNKNOWN	Treatment Effect of Edaravone in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00860951	PHASE1/PHASE2	COMPLETED	P300 Brain Computer Interface Keyboard to Operate Assistive Technology
NCT02362425	PHASE1/PHASE2	COMPLETED	Antioxidant Therapy in RYR1-Related Congenital Myopathy
NCT00001201	Not specified	COMPLETED	Evaluation of Neuromuscular Disease
NCT00002044	Not specified	COMPLETED	A Pilot Study To Evaluate the Effect of Retrovir (Zidovudine: AZT) in the Treatment of Human Immunodeficiency Virus (HIV) Associated Dementia and Neuromuscular Diseases
NCT00004553	Not specified	COMPLETED	Electromyography to Diagnose Neuromuscular Disorders
NCT00015470	Not specified	COMPLETED	Diagnostic Evaluation of Patients With Neuromuscular Disease