HNRNPH1

Summary

HNRNPH1 (heterogeneous nuclear ribonucleoprotein H1, HGNC:5041) is a protein-coding gene on chromosome 5q35.3, encoding Heterogeneous nuclear ribonucleoprotein H (P31943). This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. It is a common-essential gene (DepMap: required in 92.5% of cancer cell lines).

This gene encodes a member of a subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins that complex with heterogeneous nuclear RNA. 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 may shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that bind to RNA and is very similar to the family member HNRPF. This gene may be associated with hereditary lymphedema type I. Alternatively spliced transcript variants have been described

Source: NCBI Gene 3187 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 106 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 60
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 92.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_001257293

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5041
Approved symbol	HNRNPH1
Name	heterogeneous nuclear ribonucleoprotein H1
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	hnRNPH
Ensembl gene	ENSG00000169045
Ensembl biotype	protein_coding
OMIM	601035
Entrez	3187

Gene structure

Transcript identifiers

Ensembl transcripts: 99 — 70 protein_coding, 19 retained_intron, 8 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000329433, ENST00000356731, ENST00000393432, ENST00000442819, ENST00000502632, ENST00000502904, ENST00000503105, ENST00000503664, ENST00000504348, ENST00000504549, ENST00000504779, ENST00000505087, ENST00000505811, ENST00000506721, ENST00000508103, ENST00000510411, ENST00000510431, ENST00000510678, ENST00000512273, ENST00000513225, ENST00000513230, ENST00000513972, ENST00000514332, ENST00000514731, ENST00000515158, ENST00000515446, ENST00000515481, ENST00000515714, ENST00000518548, ENST00000518602, ENST00000519056, ENST00000519455, ENST00000519707, ENST00000519943, ENST00000519958, ENST00000520415, ENST00000521116, ENST00000521173, ENST00000521720, ENST00000521790, ENST00000522256, ENST00000522958, ENST00000523136, ENST00000523137, ENST00000523449, ENST00000523921, ENST00000524179, ENST00000524180, ENST00000706924, ENST00000857810, ENST00000857811, ENST00000857812, ENST00000857813, ENST00000857814, ENST00000857815, ENST00000857816, ENST00000857817, ENST00000857818, ENST00000857819, ENST00000857820, ENST00000857821, ENST00000857822, ENST00000923830, ENST00000923831, ENST00000923832, ENST00000923833, ENST00000923834, ENST00000923835, ENST00000923836, ENST00000923837, ENST00000923838, ENST00000923839, ENST00000923840, ENST00000923841, ENST00000923842, ENST00000923843, ENST00000923844, ENST00000923845, ENST00000923846, ENST00000923847, ENST00000923848, ENST00000923849, ENST00000923850, ENST00000923851, ENST00000947133, ENST00000947134, ENST00000947135, ENST00000947136, ENST00000947137, ENST00000947138, ENST00000947139, ENST00000947140, ENST00000947141, ENST00000947142, ENST00000947143, ENST00000947144, ENST00000947145, ENST00000947146, ENST00000947147

RefSeq mRNA: 52 — MANE Select: NM_001257293 NM_001257293, NM_001363572, NM_001364225, NM_001364226, NM_001364227, NM_001364228, NM_001364229, NM_001364230, NM_001364231, NM_001364232, NM_001364233, NM_001364234, NM_001364235, NM_001364236, NM_001364237, NM_001364238, NM_001364239, NM_001364240, NM_001364241, NM_001364242, NM_001364243, NM_001364244, NM_001364245, NM_001364246, NM_001364247, NM_001364248, NM_001364250, NM_001364251, NM_001364252, NM_001364253, NM_001364254, NM_001364255, NM_001395176, NM_001395177, NM_001395178, NM_001395179, NM_001395180, NM_001395181, NM_001395182, NM_001395183, NM_001395184, NM_001395186, NM_001395187, NM_001395188, NM_001395189, NM_001395190, NM_001395191, NM_001395192, NM_001395193, NM_001395194, NM_001395195, NM_005520

CCDS: CCDS4446, CCDS87357, CCDS93836

Canonical transcript exons

ENST00000393432 — 14 exons

Exon	Start	End
ENSE00001329935	179614178	179614959
ENSE00001367612	179623037	179623164
ENSE00003463071	179617989	179618060
ENSE00003489488	179620892	179621035
ENSE00003502908	179617514	179617649
ENSE00003540453	179615546	179615595
ENSE00003593633	179618145	179618323
ENSE00003648474	179619269	179619407
ENSE00003667126	179616126	179616218
ENSE00003785698	179621242	179621397
ENSE00003785874	179616869	179616958
ENSE00003963609	179623595	179623671
ENSE00003997485	179617799	179617932
ENSE00003997487	179617051	179617110

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 294.3806 / max 8575.8409, expressed in 1826 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65220	277.0081	1826
65226	2.9964	918
65211	2.6020	999
65212	1.6713	926
65219	1.6095	890
65210	1.3927	830
65207	1.2152	703
65215	1.0288	580
65209	0.9014	543
65217	0.8690	528

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of thyroid gland	UBERON:0001119	99.70	gold quality
left lobe of thyroid gland	UBERON:0001120	99.69	gold quality
metanephros cortex	UBERON:0010533	99.67	gold quality
right uterine tube	UBERON:0001302	99.66	gold quality
small intestine Peyer’s patch	UBERON:0003454	99.65	gold quality
right ovary	UBERON:0002118	99.63	gold quality
left ovary	UBERON:0002119	99.63	gold quality
calcaneal tendon	UBERON:0003701	99.62	gold quality
body of pancreas	UBERON:0001150	99.61	gold quality
right lung	UBERON:0002167	99.61	gold quality
ventricular zone	UBERON:0003053	99.60	gold quality
ganglionic eminence	UBERON:0004023	99.60	gold quality
body of uterus	UBERON:0009853	99.60	gold quality
colonic epithelium	UBERON:0000397	99.59	gold quality
right adrenal gland cortex	UBERON:0035827	99.59	gold quality
left testis	UBERON:0004533	99.58	gold quality
right testis	UBERON:0004534	99.58	gold quality
endocervix	UBERON:0000458	99.57	gold quality
right adrenal gland	UBERON:0001233	99.57	gold quality
skin of abdomen	UBERON:0001416	99.57	gold quality
body of stomach	UBERON:0001161	99.56	gold quality
minor salivary gland	UBERON:0001830	99.56	gold quality
upper lobe of left lung	UBERON:0008952	99.56	gold quality
left adrenal gland cortex	UBERON:0035825	99.56	gold quality
rectum	UBERON:0001052	99.55	gold quality
mucosa of stomach	UBERON:0001199	99.55	gold quality
tibial nerve	UBERON:0001323	99.55	gold quality
adenohypophysis	UBERON:0002196	99.55	gold quality
left adrenal gland	UBERON:0001234	99.54	gold quality
ectocervix	UBERON:0012249	99.52	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	21975.21
E-GEOD-111727	yes	4824.60
E-MTAB-9801	yes	2446.44
E-MTAB-7051	yes	2252.23
E-MTAB-5061	yes	1158.56
E-MTAB-8271	yes	874.39
E-MTAB-6108	yes	518.95
E-CURD-97	no	8836.99
E-MTAB-6819	no	8773.23
E-GEOD-124858	no	4015.63
E-MTAB-10137	no	3400.05
E-GEOD-106540	no	1716.61
E-CURD-89	no	1380.00
E-MTAB-10018	no	625.96
E-MTAB-6524	no	587.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AFF4, ATF5, BRD4, CDK9, HEXIM1, ID2, MYC, POLR2A, SRSF1, SRSF2

miRNA regulators (miRDB)

45 targeting HNRNPH1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-1183	98.75	67.10	1116
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-496	98.66	69.80	931
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-6509-3P	98.32	67.33	1343

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 34)

• hnRNPH and F regulate DM20 splicing by recruiting U1snRNP and hnRNPH plays a primary role in DM20 splice site selection in vivo (PMID:19244236)
• the discovery overexpression of GPD1 and RRBP1 proteins and lack of expression for HNRNPH1 and SERPINB6 proteins which are new candidate biomarkers of colon cancer. (PMID:19425502)
• Interactions between different hnRNP proteins bound to distinct locations on a pre-mRNA can change its conformation to affect splicing decisions. (PMID:19926721)
• the G-stretches within exon 9B regulate RAGE alternative splicing via interaction with hnRNP H (PMID:20028692)
• working model in which rpL3 recruits hnRNP H1 and, through cooperation with other splicing factors, promotes selection of the alternative splice site (PMID:20100605)
• A-Raf prevents cancer cell apoptosis contingent on the expression of the heterogeneous nuclear ribonucleoprotein H (hnRNP H) splice factor, which is required for the correct transcription and expression of a-raf. (PMID:20145135)
• Results suggest that hnRNP H and F are nuclear shuttling proteins whose posttranslational modifications may alter interaction with transportin 1, nuclear localization, and hence function. (PMID:20308327)
• altered function of hnRNP H1/H2 in tumor cells is a novel determinant of aberrant thymidine phosphorylase splicing thereby resulting in acquired chemoresistance to TP-activated fluoropyrimidine anticancer drugs. (PMID:21068389)
• Nuclear heterogeneous nuclear ribonucleo-protein H expression was related to survival in colorectal cancer. (PMID:21194727)
• Insight on the crucial role of hnRNP H1 in the regulation of the alternative splicing of the rpL3 gene. (PMID:21705779)
• spatial interactions of hnRNPH1, NF45, and C14orf166 with HCVc174 likely modulate HCV or cellular functions during acute and chronic HCV infection (PMID:21823664)
• hnRNPH activity appears to be involved in the pathogenesis and progression of malignant gliomas as the centre of a splicing oncogenic switch (PMID:21915099)
• These results suggest that increased level of hnRNP-H and PDIA3 expression in Dengue virus infected THP1 cells assist in the viral replication by suppressing the TNF-alpha production. (PMID:22207023)
• The REST N exon is a very versatile sequence with a complex array of splicing signals, and its activation in H69 cells depends on the relative amounts of hnRNP H and U2AF65. (PMID:22792276)
• These results support a working hypothesis that a late viral protein HPV16 L1, which is down regulated by hnRNP H early in the viral life cycle may provide an auto-regulatory positive feedback loop that allows the rapid production of HPV capsid proteins through suppression of the function of hnRNP H at the late stage of the viral life cycle. (PMID:23261416)
• In pediatric T-acute lymphoblastic leukemia, we have identified 2 RNA processing genes, that is, HNRNPH1/5q35 and DDX3X/Xp11.3 as new MLLT10 fusion partners. (PMID:23673860)
• Global splicing analysis with RNA-seq revealed that exons carrying the hnRNP H-binding GGGGG motif are predisposed to be skipped compared to those carrying the SRSF1-binding GGAGG motif in both human and mouse brains. (PMID:26282582)
• vRSF3 and hnRNP H1 are the first splicing factors identified which regulate the production of these functionally distinct HER2 splice variants and therefore maybe important for the regulation of HER2 signaling. (PMID:26367347)
• Our findings define novel roles for hnRNPH1 as a putative oncogene, splicing factor, and an auxiliary AR coregulator. (PMID:26553749)
• The different alternative transcript variants of HNRNPH1 exhibited different expression changes during tumorigenesis. Its mRNA and protein were overexpressed in esophageal squamous cell carcinoma and associated with poorer differentiation of tumor cells. (PMID:27621578)
• Together, these data implicate C9ORF72 GGGGCC expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. (PMID:27623008)
• hnRNP H binds to two specific G-runs in exon 5a of ACHE and activates the distal alternative 3 splice site (ss) between exons 5a and 5b. Furthermore, hnRNP H competes for binding of CstF64 to the overlapping binding sites in exon 5a, and suppresses the selection of a cryptic polyadenylation site, which additionally ensures transcription of the distal 3 ss required for the generation of AChET isoform. (PMID:28180311)
• High HNRNPH1 expression is associated with castration-resistant prostate cancer. (PMID:28844715)
• serum exosomal hnRNPH1 mRNA levels in hepatocellular carcinoma (HCC) patients were remarkably higher than in the other groups; exosomal hnRNPH1 mRNA levels in HCC patients were associated with the Child-Pugh classification, portal vein tumor emboli, lymph node metastasis, TNM stage and overall survival; findings suggested that serum exosomal hnRNPH1 mRNA could be an effective marker for HCC in high HBV prevalence areas (PMID:29252188)
• Sequestration of hnRNP H altered the splicing of target transcripts in C9 amyotrophic lateral sclerosis patients with GGGGCC expansion in the C9ORF72 gene. Here, the show that this signature also occurs in half of 50 postmortem sporadic, amyotrophic lateral sclerosis/frontotemporal dementia brains lacking GGGGCC expansion in the C9ORF72 gene. (PMID:30003873)
• this study is the first to identify hnRNP F/H and K as regulators of Mcl-1 alternative splicing. (PMID:30468106)
• LINC00162 overexpression increased the sensitivity, enhanced cell cycle arrest and apoptosis induced by 5-aza-dC, but did not affect its DNA demethylation effect. Mechanistically, LINC00162 interacted with an RNA splicing protein, HNRNPH1, and decreased splicing of an anti-apoptotic splicing variant, BCL-XL. LINC00162 may have translational value to predict patients who will respond to 5-aza-dC. (PMID:30914798)
• demonstrate that hnRNP H1 and PTBP1 regulate TCF3 AS reciprocally, and that position-dependent interactions between these factors are essential for proper TCF3 MEAS (PMID:31391218)
• Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing. (PMID:32160292)
• Burkitt lymphoma-related TCF3 mutations alter TCF3 alternative splicing by disrupting hnRNPH1 binding. (PMID:32449435)
• Heterogenous Nuclear Ribonucleoprotein H1 Promotes Colorectal Cancer Progression through the Stabilization of mRNA of Sphingosine-1-Phosphate Lyase 1. (PMID:32630435)
• A novel HNRNPH1::ERG rearrangement in aggressive acute myeloid leukemia. (PMID:35503261)
• Variants in HNRNPH1 are associated with high myopia in humans and ocular coloboma in zebrafish. (PMID:35989590)
• Viral hijacking of hnRNPH1 unveils a G-quadruplex-driven mechanism of stress control. (PMID:39094585)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hnrnph1	ENSMUSG00000007850
rattus_norvegicus	Hnrnph2	ENSRNOG00000003399

Paralogs (8): HNRNPH3 (ENSG00000096746), ESRP2 (ENSG00000103067), ESRP1 (ENSG00000104413), HNRNPH2 (ENSG00000126945), GRSF1 (ENSG00000132463), HNRNPF (ENSG00000169813), RBM12B (ENSG00000183808), RBM12 (ENSG00000244462)

Protein

Protein identifiers

Heterogeneous nuclear ribonucleoprotein H — P31943 (reviewed: P31943)

All UniProt accessions (23): P31943, A0A384MEJ3, A0A9L9PY23, D6R9D3, D6RAM1, D6RBM0, D6RDL0, D6RDU3, D6RF17, D6RFM3, D6RIT2, D6RIU0, E5RGV0, E5RJ94, E7EN40, E7EQJ0, E9PCY7, G8JLB6, H0YAQ2, H0YB39, H0YBD7, H0YBK1, H0YBW2

UniProt curated annotations — full annotation on UniProt →

Function. This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Mediates pre-mRNA alternative splicing regulation. Inhibits, together with CUGBP1, insulin receptor (IR) pre-mRNA exon 11 inclusion in myoblast. Binds to the IR RNA. Binds poly(RG).

Subunit / interactions. Part of a ternary complex containing FUBP2, PTBP1, PTBP2 and HNRNPH1. Identified in the spliceosome C complex. Interacts with IGF2BP1. Interacts with CUGBP1; the interaction is RNA-dependent. Interacts with MBNL1; the interaction in RNA-independent.

Subcellular location. Nucleus. Nucleoplasm.

Tissue specificity. Expressed ubiquitously.

Disease relevance. Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects (NEDCDS) [MIM:620083] An autosomal dominant disorder characterized by global developmental delay, severely impaired intellectual development with poor or absent speech, characteristic dysmorphic facial features, and variable skeletal abnormalities. Additional features include feeding difficulties, inability to walk or walking with an abnormal gait, and cerebellar or other abnormalities on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Each quasi-RRM repeat bound poly(RG), while only the N-terminal QRRM bound poly(RC) and poly(RU). None of the repeats bound detectable amounts of poly(RA).

Induction. Up-regulated in myotonic dystrophy pathophysiology (DM).

RefSeq proteins (52): NP_001244222, NP_001350501, NP_001351154, NP_001351155, NP_001351156, NP_001351157, NP_001351158, NP_001351159, NP_001351160, NP_001351161, NP_001351162, NP_001351163, NP_001351164, NP_001351165, NP_001351166, NP_001351167, NP_001351168, NP_001351169, NP_001351170, NP_001351171, NP_001351172, NP_001351173, NP_001351174, NP_001351175, NP_001351176, NP_001351177, NP_001351179, NP_001351180, NP_001351181, NP_001351182, NP_001351183, NP_001351184, NP_001382105, NP_001382106, NP_001382107, NP_001382108, NP_001382109, NP_001382110, NP_001382111, NP_001382112, NP_001382113, NP_001382115, NP_001382116, NP_001382117, NP_001382118, NP_001382119, NP_001382120, NP_001382121, NP_001382122, NP_001382123, NP_001382124, NP_005511 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR012996	Znf_CHHC	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR050666	ESRP	Family

Pfam: PF00076, PF08080

UniProt features (46 total): strand 10, modified residue 9, helix 6, repeat 4, cross-link 3, sequence variant 3, domain 3, chain 2, region of interest 2, turn 2, initiator methionine 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7ZUG	X-RAY DIFFRACTION	1.07
6DHS	X-RAY DIFFRACTION	3.5
2LXU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31943-F1	62.91	0.00

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 (12): 1, 2, 23, 54, 63, 233, 233, 246, 310, 35, 87, 98

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-6803529	FGFR2 alternative splicing
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: 367 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, ELVIDGE_HYPOXIA_DN, TGCGCANK_UNKNOWN, GCM_NPM1, REACTOME_SIGNALING_BY_FGFR, CGGAARNGGCNG_UNKNOWN, ATGTTAA_MIR302C, PUJANA_CHEK2_PCC_NETWORK, BILD_HRAS_ONCOGENIC_SIGNATURE, CEBP_Q2, CHIBA_RESPONSE_TO_TSA_DN, AMIT_EGF_RESPONSE_120_HELA, REACTOME_MRNA_3_END_PROCESSING, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOBP_RNA_SPLICING

GO Biological Process (5): mRNA splicing, via spliceosome (GO:0000398), RNA processing (GO:0006396), regulation of RNA splicing (GO:0043484), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (5): RNA binding (GO:0003723), poly(U) RNA binding (GO:0008266), identical protein binding (GO:0042802), nucleic acid binding (GO:0003676), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), membrane (GO:0016020), catalytic step 2 spliceosome (GO:0071013), ribonucleoprotein complex (GO:1990904), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by FGFR2	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	3
RNA processing	2
binding	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
mRNA metabolic process	1
nucleic acid binding	1
poly-pyrimidine tract binding	1
protein binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
protein-containing complex	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

3968 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HNRNPH1	HNRNPA1	P09651	959
HNRNPH1	HNRNPM	P52272	919
HNRNPH1	ILF3	Q12906	906
HNRNPH1	PTBP1	P26599	895
HNRNPH1	SRSF5	Q13243	881
HNRNPH1	SRSF1	Q07955	875
HNRNPH1	ILF2	Q12905	860
HNRNPH1	SRSF2	Q01130	859
HNRNPH1	MATR3	P43243	843
HNRNPH1	KHSRP	Q92945	842
HNRNPH1	RBFOX2	O43251	815
HNRNPH1	HNRNPC	P07910	813
HNRNPH1	SRSF3	P23152	808
HNRNPH1	HNRNPU	Q00839	808
HNRNPH1	HNRNPDL	O14979	804

IntAct

382 interactions, top by confidence:

A	B	Type	Score
SUN2	LMNA	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HNRNPH1	MSI2	psi-mi:“MI:0915”(physical association)	0.670
HNRNPH1	HNRNPM	psi-mi:“MI:0915”(physical association)	0.670
HNRNPH1	MRPL53	psi-mi:“MI:0915”(physical association)	0.670
HNRNPH1	HNRNPF	psi-mi:“MI:0915”(physical association)	0.670
HNRNPH1	NUDT16L1	psi-mi:“MI:0915”(physical association)	0.670
HNRNPH1	TARDBP	psi-mi:“MI:0915”(physical association)	0.670
POLR1C	HNRNPH1	psi-mi:“MI:0915”(physical association)	0.600
HNRNPH1	POLR1C	psi-mi:“MI:0915”(physical association)	0.600
HNRNPH1	UBE2I	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	DDX17	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	PEX5	psi-mi:“MI:0915”(physical association)	0.560
RBFOX2	HNRNPH1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	PATZ1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	RBM38	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	MAGED1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	DZIP3	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	LNX1	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	RAMAC	psi-mi:“MI:0915”(physical association)	0.560
HNRNPH1	SPG21	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (1856): HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Reconstituted Complex), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-RNA), BASP1 (Co-fractionation), HNRNPAB (Co-fractionation), HNRNPH1 (Co-fractionation)

ESM2 similar proteins: A0A8C0TYJ0, B2GV05, F1LQ48, O14639, O35737, O60907, O70133, P09851, P14866, P20936, P31943, P49336, P50904, P52597, P52756, P55795, P70333, Q01973, Q08211, Q08E27, Q1RMU5, Q28141, Q3SZF3, Q5E9J1, Q5PYH5, Q5R6Y5, Q5R874, Q5RD26, Q60HC3, Q6AY09, Q6P3N6, Q6PAC9, Q6PHK6, Q794E4, Q811D0, Q8AVS4, Q8BWD8, Q8JH47, Q8K4G5, Q8R081

Diamond homologs: A1L1G1, A8WPC5, B2RYD2, B2RYJ8, O35737, P31943, P52597, P55795, P70333, Q12849, Q22708, Q3SZF3, Q3US41, Q5E9J1, Q5RD26, Q5ZLR4, Q60HC3, Q6AY09, Q6DEZ7, Q6NXG1, Q794E4, Q7ZVR8, Q7ZY29, Q8C5Q4, Q8K0G8, Q8R3C6, Q8VHV7, Q9BJZ5, Q9H6T0, Q9Z2X1, P31942, Q9Y4C8, Q15020, Q5REG1, Q9JLI8, Q5RBM8, Q8R4X3, Q8SQ27, Q9NTZ6, Q66JV4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PTBP2	“up-regulates activity”	HNRNPH1	binding
HNRNPH1	“up-regulates quantity by expression”	SRC	“post transcriptional regulation”
MAPK1	unknown	HNRNPH1	phosphorylation
HNRNPH1	“down-regulates quantity”	TERF2	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 127 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
Processing of Capped Intron-Containing Pre-mRNA	9	9.0×	3e-04
Neddylation	11	6.4×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	6	19.2×	5e-04
G1/S transition of mitotic cell cycle	6	10.8×	3e-03
mRNA splicing, via spliceosome	9	7.4×	2e-03
protein ubiquitination	11	4.1×	8e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	63
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1711740	NM_001257293.2(HNRNPH1):c.618dup (p.Pro207fs)	Pathogenic
1711741	NM_001257293.2(HNRNPH1):c.1240_1243dup (p.Gln415fs)	Pathogenic
1711742	NM_001257293.2(HNRNPH1):c.617G>A (p.Arg206Gln)	Pathogenic
2663288	NM_001257293.2(HNRNPH1):c.956T>A (p.Ile319Asn)	Pathogenic
3602979	NM_001257293.2(HNRNPH1):c.224_227del (p.Arg75fs)	Pathogenic
985769	NM_001257293.2(HNRNPH1):c.616C>T (p.Arg206Trp)	Pathogenic
1307829	NM_001257293.2(HNRNPH1):c.595C>T (p.Arg199Ter)	Likely pathogenic
3377121	NM_001257293.2(HNRNPH1):c.1216_1220del (p.Ser406fs)	Likely pathogenic

SpliceAI

2319 predictions. Top by Δscore:

Variant	Effect	Δscore
5:179616867:A:AC	donor_gain	1.0000
5:179616868:C:CC	donor_gain	1.0000
5:179616868:CA:C	donor_gain	1.0000
5:179616883:C:A	donor_gain	1.0000
5:179617034:T:TA	donor_gain	1.0000
5:179617039:G:C	donor_gain	1.0000
5:179617507:CACT:C	donor_loss	1.0000
5:179617510:TTA:T	donor_loss	1.0000
5:179617512:A:AC	donor_gain	1.0000
5:179617512:ACG:A	donor_gain	1.0000
5:179617513:C:A	donor_loss	1.0000
5:179617513:C:CA	donor_gain	1.0000
5:179617513:CG:C	donor_gain	1.0000
5:179617513:CGC:C	donor_gain	1.0000
5:179617513:CGCA:C	donor_gain	1.0000
5:179617513:CGCAT:C	donor_gain	1.0000
5:179617540:G:C	donor_gain	1.0000
5:179617645:AAAAA:A	acceptor_gain	1.0000
5:179617646:AAAA:A	acceptor_gain	1.0000
5:179617647:AAA:A	acceptor_gain	1.0000
5:179617648:AA:A	acceptor_gain	1.0000
5:179617648:AACT:A	acceptor_loss	1.0000
5:179617650:C:CC	acceptor_gain	1.0000
5:179617650:CT:C	acceptor_loss	1.0000
5:179617651:T:C	acceptor_loss	1.0000
5:179617796:TACAT:T	donor_loss	1.0000
5:179617797:A:AC	donor_gain	1.0000
5:179617798:C:CC	donor_gain	1.0000
5:179617798:C:CT	donor_loss	1.0000
5:179617798:CA:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000091706 (5:179623847 C>G,T), RS1000144967 (5:179613924 G>A), RS1000209177 (5:179614992 A>C,G), RS1000241502 (5:179624112 C>G,T), RS1000260148 (5:179619676 C>G,T), RS1000342167 (5:179630283 C>G,T), RS1000433097 (5:179613798 A>C), RS1000751160 (5:179615918 T>C), RS1000751738 (5:179629186 A>C), RS1000977716 (5:179623483 C>G), RS1001366605 (5:179630125 G>C,T), RS1001529515 (5:179621357 G>A,T), RS1001569695 (5:179615722 C>G,T), RS1001603924 (5:179631624 G>C), RS1001652359 (5:179625689 G>A,C)

Disease associations

OMIM: gene MIM:601035 | disease phenotypes: MIM:620083

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects	Strong	Autosomal dominant
neurodevelopmental disorder	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (2): neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects (MONDO:0859301), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): Neurodevelopmental delay-brain malformations-skeletal defects-intellectual disability syndrome (Orphanet:662207)

HPO phenotypes

60 total (30 of 60 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000348	High forehead
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000418	Narrow nasal ridge
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000543	Optic disc pallor
HP:0000581	Blepharophimosis
HP:0000639	Nystagmus
HP:0000678	Dental crowding
HP:0000768	Pectus carinatum
HP:0000938	Osteopenia
HP:0001166	Arachnodactyly
HP:0001188	Hand clenching
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001320	Cerebellar vermis hypoplasia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003518_46	Daytime sleep phenotypes	1.000000e-06
GCST003518_7	Daytime sleep phenotypes	7.000000e-07
GCST90002389_274	Lymphocyte percentage of white cells	3.000000e-11
GCST90002399_434	Neutrophil percentage of white cells	1.000000e-12

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3797013 (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
5.23	Kd	5859	nM	CHEMBL3752910
5.23	ED50	5859	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 11 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148531: Binding affinity to human HNRNPH1 incubated for 45 mins by Kinobead based pull down assay	kd	5.8592	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment, increases abundance	3
Cadmium	increases expression, decreases expression, decreases reaction, increases abundance, increases palmitoylation	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	3
sodium arsenite	decreases expression, affects splicing, increases abundance, affects cotreatment	2
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	2
Arsenic Trioxide	increases expression	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Air Pollutants	increases oxidation, increases expression, affects cotreatment, decreases expression, increases abundance	2
Caffeine	decreases expression, decreases phosphorylation	2
Cisplatin	decreases expression, increases expression, affects cotreatment	2
Ozone	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Rotenone	decreases expression, affects splicing	2
Valproic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
chlorophyllin	decreases expression	1
deoxynivalenol	increases expression	1
trichostatin A	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
afimoxifene	decreases expression	1
sulforaphane	affects binding	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3803744	Binding	Binding affinity to HNRNPH1 in HEK293 proteomes at 20 uM incubated for 16 hrs by TAMRA biotin-azide dye based LC-MS/MS analysis	Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice