NOL4

Summary

NOL4 (nucleolar protein 4, HGNC:7870) is a protein-coding gene on chromosome 18q12.1, encoding Nucleolar protein 4 (O94818).

Predicted to enable RNA binding activity. Predicted to be located in nucleolus.

Source: NCBI Gene 8715 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 76 total
• MANE Select transcript: NM_003787

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7870
Approved symbol	NOL4
Name	nucleolar protein 4
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	NOLP, HRIHFB2255, CT125
Ensembl gene	ENSG00000101746
Ensembl biotype	protein_coding
OMIM	603577
Entrez	8715

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000261592, ENST00000535384, ENST00000538587, ENST00000586309, ENST00000586314, ENST00000586553, ENST00000587953, ENST00000587971, ENST00000588280, ENST00000588355, ENST00000589544, ENST00000590712, ENST00000590846, ENST00000591917, ENST00000867151

RefSeq mRNA: 19 — MANE Select: NM_003787 NM_001198546, NM_001198547, NM_001198548, NM_001198549, NM_001282527, NM_001353232, NM_001353233, NM_001353234, NM_001353235, NM_001353236, NM_001353237, NM_001384467, NM_001384468, NM_001384469, NM_001384470, NM_001384471, NM_001384472, NM_001384473, NM_003787

CCDS: CCDS11907, CCDS56058, CCDS56059, CCDS59308

Canonical transcript exons

ENST00000261592 — 11 exons

Exon	Start	End
ENSE00000916061	33957326	33957517
ENSE00002780129	33851100	33853035
ENSE00002922994	34222990	34224913
ENSE00003485784	34093465	34093597
ENSE00003519463	34105049	34105160
ENSE00003521293	33958239	33958418
ENSE00003535734	33883244	33883424
ENSE00003555572	33943065	33943178
ENSE00003589904	34019318	34019601
ENSE00003597192	34129871	34130020
ENSE00003599807	34104047	34104159

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 96.53.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3062 / max 99.1221, expressed in 311 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171622	0.7084	203
171621	0.6185	172
171619	0.4729	195
171618	0.2418	135
171617	0.1904	98
171620	0.0742	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.53	gold quality
middle temporal gyrus	UBERON:0002771	94.13	gold quality
buccal mucosa cell	CL:0002336	93.48	gold quality
endothelial cell	CL:0000115	93.29	silver quality
Brodmann (1909) area 23	UBERON:0013554	93.16	gold quality
ganglionic eminence	UBERON:0004023	91.85	gold quality
islet of Langerhans	UBERON:0000006	91.83	gold quality
entorhinal cortex	UBERON:0002728	88.54	gold quality
superior frontal gyrus	UBERON:0002661	87.87	gold quality
primary visual cortex	UBERON:0002436	86.38	gold quality
ventricular zone	UBERON:0003053	86.22	gold quality
postcentral gyrus	UBERON:0002581	86.10	gold quality
left testis	UBERON:0004533	85.95	gold quality
parietal lobe	UBERON:0001872	85.42	gold quality
cerebellar vermis	UBERON:0004720	84.97	gold quality
prefrontal cortex	UBERON:0000451	84.58	gold quality
right testis	UBERON:0004534	84.58	gold quality
sperm	CL:0000019	84.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.23	gold quality
oocyte	CL:0000023	84.00	gold quality
testis	UBERON:0000473	83.79	gold quality
occipital lobe	UBERON:0002021	83.70	gold quality
frontal cortex	UBERON:0001870	83.50	gold quality
frontal lobe	UBERON:0016525	83.49	gold quality
neocortex	UBERON:0001950	83.48	gold quality
cerebral cortex	UBERON:0000956	83.12	gold quality
temporal lobe	UBERON:0001871	82.77	gold quality
secondary oocyte	CL:0000655	82.63	gold quality
male germ cell	CL:0000015	82.29	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	45.18
E-GEOD-93593	yes	12.23
E-GEOD-81547	yes	5.17
E-ANND-3	yes	5.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

203 targeting NOL4, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-559	99.95	72.28	3609

Literature-anchored findings (GeneRIF, showing 5)

• NOL4 was identified as a highly specific promoter methylated gene associated with head and neck squamous cell carcinoma (PMID:24337411)
• the cosegregation of an intronic rare variant in NOL4 in one family, and a haplotype consisting of three variants in the noncoding region of IRF6 (introns 1, 8 and 3’UTR) in the other family, are reported. (PMID:29666346)
• Cancer Testis Antigen, NOL4, Is an Immunogenic Antigen Specifically Expressed in Small-Cell Lung Cancer. (PMID:34065612)
• NOL4 is a novel nuclear marker of small cell carcinoma and other neuroendocrine neoplasms. (PMID:36282054)
• Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene. (PMID:36710296)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nol4	ENSMUSG00000041923
rattus_norvegicus	Nol4	ENSRNOG00000014775

Paralogs (1): NOL4L (ENSG00000197183)

Protein

Protein identifiers

Nucleolar protein 4 — O94818 (reviewed: O94818)

Alternative names: Nucleolar-localized protein

All UniProt accessions (6): O94818, K7EID6, K7EIK8, K7ENM5, K7EPC5, K7EQ17

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Expressed predominantly in fetal brain, adult brain and testis.

Isoforms (4)

UniProt ID	Names	Canonical?
O94818-1	1	yes
O94818-2	2
O94818-3	3
O94818-4	4

RefSeq proteins (19): NP_001185475, NP_001185476, NP_001185477, NP_001185478, NP_001269456, NP_001340161, NP_001340162, NP_001340163, NP_001340164, NP_001340165, NP_001340166, NP_001371396, NP_001371397, NP_001371398, NP_001371399, NP_001371400, NP_001371401, NP_001371402, NP_003778* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR039788	NOL4/NOL4L	Family
IPR056549	HTH_NOL4	Domain

Pfam: PF23079

UniProt features (18 total): compositionally biased region 9, region of interest 4, splice variant 3, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94818-F1	64.67	0.32

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 223 (showing top): ATF_B, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, TGCGCANK_UNKNOWN, RORA1_01, GCANCTGNY_MYOD_Q6, SP3_Q3, AREB6_01, CREBP1_Q2, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, MORF_RAD51L3, SP1_Q2_01, SREBP1_02, CREB_Q4

GO Biological Process (0):

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (2): nucleolus (GO:0005730), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleic acid binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1240 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOL4	PAF1	Q8N7H5	571
NOL4	LHFPL4	Q7Z7J7	513
NOL4	FAM185A	Q8N0U4	462
NOL4	LHFPL3	Q86UP9	432
NOL4	TEX2	Q8IWB9	430
NOL4	SHTN1	A0MZ66	401
NOL4	FBXL13	Q8NEE6	391
NOL4	LRRC3B	Q96PB8	384
NOL4	C1orf115	Q9H7X2	378
NOL4	SLC15A2	Q16348	375
NOL4	BIRC7	Q96CA5	374
NOL4	FILIP1L	Q4L180	372
NOL4	TMEM150B	A6NC51	362
NOL4	SIRAL2	Q9NWS6	355
NOL4	CCDC7	Q96M83	351

IntAct

24 interactions, top by confidence:

A	B	Type	Score
CTBP1	CBX4	psi-mi:“MI:0914”(association)	0.700
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
SKA3	NOL4	psi-mi:“MI:0914”(association)	0.640
SKA3	CCDC85C	psi-mi:“MI:0914”(association)	0.530
TEX9	NOL4	psi-mi:“MI:0914”(association)	0.530
NOL4	CHMP2A	psi-mi:“MI:0915”(physical association)	0.370
CHMP2A	NOL4	psi-mi:“MI:0915”(physical association)	0.370
ABL1	NOL4	psi-mi:“MI:0915”(physical association)	0.370
NOL4	PTCHD1	psi-mi:“MI:0915”(physical association)	0.370
NOL4	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
MAGEA11	NOL4	psi-mi:“MI:0915”(physical association)	0.370
CTBP2	NOL4	psi-mi:“MI:0915”(physical association)	0.370
NOL4	SNAPC5	psi-mi:“MI:0915”(physical association)	0.370
PIP	RBM47	psi-mi:“MI:0914”(association)	0.350
NOL4	ZNF195	psi-mi:“MI:0914”(association)	0.350
CTBP1	SEC16A	psi-mi:“MI:2364”(proximity)	0.270
KLF12		psi-mi:“MI:2364”(proximity)	0.270
KLF3	MCRIP1	psi-mi:“MI:2364”(proximity)	0.270
KLF8	USP27X	psi-mi:“MI:2364”(proximity)	0.270
NOL4	PRMT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (76): NOL4 (Two-hybrid), NOL4 (Two-hybrid), SNAPC5 (Two-hybrid), FAM9B (Two-hybrid), NOL4 (Affinity Capture-MS), NOL4 (Affinity Capture-MS), NOL4 (Two-hybrid), NOL4 (Two-hybrid), SNAPC5 (Two-hybrid), NOL4 (Affinity Capture-MS), NOL4 (Affinity Capture-MS), NOL4 (Affinity Capture-MS), NOL4 (Two-hybrid), NOL4 (Synthetic Lethality), NOL4 (Synthetic Lethality)

ESM2 similar proteins: A1L209, A2AWT3, B0W8L4, B1PM81, B3M881, B3NHQ1, B4GZZ4, B4IFU5, B4J1U4, B4J1U5, B4KY72, B4LDA6, B4MVH6, B4PJ01, B4QPV0, F4IDY7, O94818, O94880, P61406, P97496, Q08AX9, Q14CW9, Q17CJ5, Q2LYX9, Q3UG20, Q498T3, Q5RBA1, Q5RIX9, Q5TYQ8, Q5ZK36, Q5ZKG2, Q66KD5, Q69ZW3, Q6DD45, Q6DFC8, Q6P2L6, Q7PXG4, Q7ZUF2, Q7ZX31, Q8IZD2

Diamond homologs: O94818, P60954, Q5RFT9, Q6DIB4, Q96MY1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3605 predictions. Top by Δscore:

Variant	Effect	Δscore
18:33883242:A:AC	donor_gain	1.0000
18:33883243:C:CC	donor_gain	1.0000
18:33883243:CCA:C	donor_gain	1.0000
18:33883339:T:TA	donor_gain	1.0000
18:33943179:C:CC	acceptor_gain	1.0000
18:33957515:CAT:C	acceptor_gain	1.0000
18:33958234:CTCA:C	donor_loss	1.0000
18:33958235:TCA:T	donor_loss	1.0000
18:33958236:CA:C	donor_loss	1.0000
18:33958237:A:AC	donor_gain	1.0000
18:33958237:ACAT:A	donor_loss	1.0000
18:33958238:C:CA	donor_gain	1.0000
18:33958238:CA:C	donor_gain	1.0000
18:33958238:CAT:C	donor_gain	1.0000
18:33958238:CATT:C	donor_gain	1.0000
18:33958238:CATTA:C	donor_gain	1.0000
18:33958414:GGAGA:G	acceptor_gain	1.0000
18:33958415:GAGA:G	acceptor_gain	1.0000
18:33958416:AGA:A	acceptor_gain	1.0000
18:33958417:GA:G	acceptor_gain	1.0000
18:33958419:C:CC	acceptor_gain	1.0000
18:34093458:GGCTT:G	donor_loss	1.0000
18:34093459:GCTTA:G	donor_loss	1.0000
18:34093460:CTTAC:C	donor_loss	1.0000
18:34093461:TTAC:T	donor_loss	1.0000
18:34093462:T:TG	donor_loss	1.0000
18:34093463:A:AC	donor_gain	1.0000
18:34093463:A:C	donor_loss	1.0000
18:34093463:ACCAT:A	donor_gain	1.0000
18:34093464:C:CC	donor_gain	1.0000

AlphaMissense

4223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:33852861:A:G	L633P	1.000
18:33852870:A:G	L630P	1.000
18:33852880:C:G	A627P	1.000
18:33852883:A:G	S626P	1.000
18:33852885:C:G	R625P	1.000
18:33852891:A:G	L623S	1.000
18:33852893:A:C	F622L	1.000
18:33852893:A:T	F622L	1.000
18:33852894:A:C	F622C	1.000
18:33852894:A:G	F622S	1.000
18:33852895:A:G	F622L	1.000
18:33852900:G:T	A620D	1.000
18:33852901:C:G	A620P	1.000
18:33852904:A:G	S619P	1.000
18:33852909:C:G	R617P	1.000
18:33852913:A:C	Y616D	1.000
18:33852913:A:G	Y616H	1.000
18:33852921:A:T	V613D	1.000
18:33852924:A:G	L612P	1.000
18:33943120:G:T	A496D	1.000
18:33943129:A:C	L493W	1.000
18:33943129:A:G	L493S	1.000
18:33957353:C:A	R467S	1.000
18:33957353:C:G	R467S	1.000
18:33957354:C:A	R467M	1.000
18:33957354:C:G	R467T	1.000
18:33957356:G:C	C466W	1.000
18:33957357:C:T	C466Y	1.000
18:33957358:A:G	C466R	1.000
18:33957362:C:A	K464N	1.000

dbSNP variants (sampled 300 via entrez): RS1000009923 (18:34013169 T>A,C), RS1000013499 (18:34006788 G>A), RS1000016982 (18:34106217 T>C), RS1000024258 (18:34064583 A>T), RS1000032671 (18:34099009 A>G), RS1000033774 (18:34196305 T>C), RS1000044873 (18:33887259 A>G), RS1000056546 (18:33881625 C>A,T), RS1000066416 (18:33921853 C>G,T), RS1000070605 (18:33879880 A>G), RS1000075856 (18:34006013 C>G), RS1000084954 (18:33982065 A>T), RS1000090667 (18:34143988 A>G), RS1000094861 (18:34056013 T>C), RS1000099482 (18:34028595 G>A)

Disease associations

OMIM: gene MIM:603577 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000509_1	Response to citalopram treatment	9.000000e-06
GCST001585_16	Breast size	9.000000e-06
GCST002829_19	Urate levels in overweight individuals	8.000000e-06
GCST002875_25	Diisocyanate-induced asthma	7.000000e-06
GCST002875_51	Diisocyanate-induced asthma	5.000000e-06
GCST003429_36	Morning vs. evening chronotype	2.000000e-08
GCST006940_32	Neurociticism	1.000000e-09
GCST007201_255	Schizophrenia	3.000000e-07
GCST007201_307	Schizophrenia	5.000000e-07
GCST007565_201	Morning person	9.000000e-23
GCST007565_202	Morning person	8.000000e-30
GCST007576_328	Chronotype	8.000000e-30
GCST007576_409	Chronotype	3.000000e-09
GCST011494_79	Daytime nap	1.000000e-14
GCST011703_28	Smoking initiation	9.000000e-09
GCST90026415_4	Mild obesity-related type 2 diabetes	6.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0006995	response to diisocyanate
EFO:0007660	neuroticism measurement
EFO:0008328	chronotype measurement
EFO:0007828	daytime rest measurement
EFO:0005670	smoking initiation

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, decreases methylation, increases methylation	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	decreases expression, affects cotreatment	2
Valproic Acid	decreases methylation, increases expression	2
Aflatoxin B1	decreases expression	2
methyleugenol	decreases expression	1
trichostatin A	increases expression	1
sodium arsenite	affects methylation	1
perfluorooctanoic acid	decreases expression	1
coumarin	decreases phosphorylation	1
beta-methylcholine	affects expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Carbamazepine	affects expression	1
Silicon Dioxide	decreases expression	1
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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