NPLOC4

Summary

NPLOC4 (NPL4 homolog, ubiquitin recognition factor, HGNC:18261) is a protein-coding gene on chromosome 17q25.3, encoding Nuclear protein localization protein 4 homolog (Q8TAT6). The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. It is a common-essential gene (DepMap: required in 98.9% of cancer cell lines).

Predicted to enable ubiquitin binding activity and ubiquitin protein ligase binding activity. Predicted to contribute to K48-linked polyubiquitin modification-dependent protein binding activity and K63-linked polyubiquitin modification-dependent protein binding activity. Involved in negative regulation of RIG-I signaling pathway; negative regulation of type I interferon production; and proteolysis involved in protein catabolic process. Located in nucleus. Part of UFD1-NPL4 complex and VCP-NPL4-UFD1 AAA ATPase complex.

Source: NCBI Gene 55666 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 87 total
• Cancer dependency (DepMap): dependent in 98.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_017921

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18261
Approved symbol	NPLOC4
Name	NPL4 homolog, ubiquitin recognition factor
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	NPL4, FLJ20657, KIAA1499
Ensembl gene	ENSG00000182446
Ensembl biotype	protein_coding
OMIM	606590
Entrez	55666

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 protein_coding, 8 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000331134, ENST00000374747, ENST00000570300, ENST00000570324, ENST00000571562, ENST00000571714, ENST00000572346, ENST00000572351, ENST00000572760, ENST00000572824, ENST00000573212, ENST00000573328, ENST00000573519, ENST00000573876, ENST00000574095, ENST00000574344, ENST00000574897, ENST00000574964, ENST00000576713, ENST00000576940, ENST00000625705, ENST00000705719

RefSeq mRNA: 2 — MANE Select: NM_017921 NM_001369698, NM_017921

CCDS: CCDS45812

Canonical transcript exons

ENST00000331134 — 17 exons

Exon	Start	End
ENSE00001292174	81556887	81559416
ENSE00002649665	81636916	81637112
ENSE00003462283	81600341	81600427
ENSE00003467597	81622166	81622278
ENSE00003530701	81572017	81572088
ENSE00003533650	81596116	81596242
ENSE00003558941	81606691	81606814
ENSE00003590910	81565505	81565607
ENSE00003604669	81610210	81610258
ENSE00003607213	81613318	81613494
ENSE00003607735	81569016	81569111
ENSE00003617854	81588944	81589104
ENSE00003647452	81604548	81604727
ENSE00003648911	81629725	81629805
ENSE00003663868	81608728	81608822
ENSE00003668038	81567417	81567533
ENSE00003689881	81597245	81597316

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 97.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.5623 / max 654.4916, expressed in 1825 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168769	52.5859	1825
168764	0.7104	382
168763	0.1984	90
168762	0.0676	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.39	gold quality
muscle of leg	UBERON:0001383	96.97	gold quality
apex of heart	UBERON:0002098	96.40	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.89	gold quality
muscle organ	UBERON:0001630	95.57	gold quality
adrenal tissue	UBERON:0018303	95.54	gold quality
stromal cell of endometrium	CL:0002255	95.50	gold quality
right testis	UBERON:0004534	94.92	gold quality
right coronary artery	UBERON:0001625	94.87	gold quality
islet of Langerhans	UBERON:0000006	94.84	gold quality
left testis	UBERON:0004533	94.80	gold quality
lower esophagus mucosa	UBERON:0035834	94.42	gold quality
heart left ventricle	UBERON:0002084	94.34	gold quality
esophagus mucosa	UBERON:0002469	94.33	gold quality
right adrenal gland	UBERON:0001233	94.27	gold quality
ascending aorta	UBERON:0001496	94.26	gold quality
thoracic aorta	UBERON:0001515	94.26	gold quality
left adrenal gland	UBERON:0001234	94.24	gold quality
cardiac ventricle	UBERON:0002082	94.18	gold quality
aorta	UBERON:0000947	94.13	gold quality
popliteal artery	UBERON:0002250	94.12	gold quality
tibial artery	UBERON:0007610	94.12	gold quality
right adrenal gland cortex	UBERON:0035827	94.12	gold quality
granulocyte	CL:0000094	94.07	gold quality
left adrenal gland cortex	UBERON:0035825	94.07	gold quality
sural nerve	UBERON:0015488	93.83	gold quality
monocyte	CL:0000576	93.80	gold quality
esophagus	UBERON:0001043	93.79	gold quality
mononuclear cell	CL:0000842	93.76	gold quality
adrenal gland	UBERON:0002369	93.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting NPLOC4, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6086	99.70	65.38	699

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 16)

• Ufd1-Npl4 is a negative regulator of retrotranslocation, delaying the retrotranslocation of endoplasmic reticulum-associated degradation substrates independently of its association with VCP (PMID:17331469)
• This favors the model where the Ufd1-Npl4 dimer forms a regulatory gate at the exit from the retrotranslocone, rather than actively promoting retrotranslocation like the p97VCP ATPase. (PMID:18586029)
• Data suggest that the human cytomegalovirus dislocation reaction in US2 cells is independent of the p97 cofactor Ufd1-Npl4, and different retrotranslocation mechanisms can employ distinct p97 ATPase complexes to dislocate substrates. (PMID:20702414)
• Data establish Cdc48/p97-Ufd1-Npl4 as a crucial negative regulator of Aurora B early in mitosis of human somatic cells and suggest that the activity of Aurora B on chromosomes needs to be restrained to ensure faithful chromosome segregation. (PMID:21486945)
• Data indicate that Npl4-Ufd1 heterodimer is required for VCP-FAF1 interaction. (PMID:23293021)
• In coordination with the P97-UFD1-NPL4 complex (P97(UFD1/NPL4)), NUB1L promotes transfer of NEDD8 to proteasome for degradation. (PMID:24019527)
• Data indicate that the p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated IkappaBalpha via the interactions between p97 and the SCF(beta-TRCP) ubiquitin ligase. (PMID:24248593)
• p97-Ufd1-Npl4 is an integral part of G2/M checkpoint signaling and thereby suppresses chromosome instability. (PMID:24429874)
• The study revealed a regulatory role of the p97-Npl4-Ufd1 complex in regulating a partial degradation of the NF-kappaB subunit p100. (PMID:26112410)
• We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. (PMID:28512218)
• Multisystem proteinopathy mutations in VCP/p97 increase NPLOC4-UFD1L binding and substrate processing. (PMID:31623962)
• Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma. (PMID:32667929)
• Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. (PMID:33402676)
• Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase. (PMID:35920641)
• Structural basis for the interaction between human Npl4 and Npl4-binding motif of human Ufd1. (PMID:36087575)
• NPLOC4 is a potential target and a poor prognostic signature in lung squamous cell carcinoma. (PMID:37993584)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nploc4	ENSDARG00000100487
mus_musculus	Nploc4	ENSMUSG00000039703
rattus_norvegicus	Nploc4	ENSRNOG00000036698
drosophila_melanogaster	Npl4	FBGN0039348
caenorhabditis_elegans		WBGENE00019120
caenorhabditis_elegans		WBGENE00019121

Protein

Protein identifiers

Nuclear protein localization protein 4 homolog — Q8TAT6 (reviewed: Q8TAT6)

All UniProt accessions (10): Q8TAT6, A0A0D9SFI9, A0A994J7H4, I3L0W3, I3L281, I3L283, I3L3I1, I3L4S2, I3L4U9, K7EJN1

UniProt curated annotations — full annotation on UniProt →

Function. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Acts as a negative regulator of type I interferon production via the complex formed with VCP and UFD1, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI.

Subunit / interactions. Heterodimer with UFD1. The heterodimer binds ubiquitinated proteins. The heterodimer binds to VCP and inhibits Golgi membrane fusion. Interacts with ZFAND2B; probably through VCP.

Subcellular location. Cytoplasm. Cytosol. Endoplasmic reticulum. Nucleus.

Tissue specificity. Expressed at highest levels in brain, heart, skeletal muscle, kidney and fetal liver.

Domain organisation. Binds ubiquitinated proteins via its RanBP2-type zinc finger.

Pathway. Protein degradation; proteasomal ubiquitin-dependent pathway.

Miscellaneous. May be due to an intron retention.

Similarity. Belongs to the NPL4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TAT6-1	1	yes
Q8TAT6-2	2

RefSeq proteins (2): NP_001356627, NP_060391* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001876	Znf_RanBP2	Domain
IPR007716	NPL4_Zn-bd_put	Domain
IPR007717	NPL4_C	Domain
IPR016563	Npl4	Family
IPR024682	Npl4_Ub-like_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR037518	MPN	Domain

Pfam: PF05020, PF05021, PF11543

UniProt features (55 total): strand 23, helix 15, sequence conflict 4, turn 3, mutagenesis site 3, modified residue 2, initiator methionine 1, chain 1, domain 1, zinc finger region 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7WWQ	X-RAY DIFFRACTION	2.72
9YRC	ELECTRON MICROSCOPY	2.97
7WWP	X-RAY DIFFRACTION	2.99
11TA	ELECTRON MICROSCOPY	3.58
11VE	ELECTRON MICROSCOPY	3.85
11SY	ELECTRON MICROSCOPY	4.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TAT6-F1	88.32	0.68

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 (2): 2, 179

Mutagenesis-validated functional residues (3):

Position	Phenotype
6–8	abolished interaction with vcp; when associated with a-17 and a-50.
17	abolished interaction with vcp; when associated with 6-a–a-8 and a-50.
50	abolished interaction with vcp; when associated with 6-a–a-8 and a-17.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-8951664	Neddylation
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9918487	Dengue Virus Genome Translation and Replication
R-HSA-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

MSigDB gene sets: 218 (showing top): GOBP_ENDOPLASMIC_RETICULUM_TO_CYTOSOL_TRANSPORT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_TRANSLATION, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_RESPONSE_TO_STRESS

GO Biological Process (7): ubiquitin-dependent protein catabolic process (GO:0006511), Golgi organization (GO:0007030), retrograde protein transport, ER to cytosol (GO:0030970), negative regulation of type I interferon production (GO:0032480), ERAD pathway (GO:0036503), negative regulation of RIG-I signaling pathway (GO:0039536), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (9): zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), K48-linked polyubiquitin modification-dependent protein binding (GO:0036435), ubiquitin binding (GO:0043130), protein-containing complex binding (GO:0044877), ATPase binding (GO:0051117), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), VCP-NPL4-UFD1 AAA ATPase complex (GO:0034098), UFD1-NPL4 complex (GO:0036501), nuclear outer membrane-endoplasmic reticulum membrane network (GO:0042175), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
Post-translational protein modification	1
Cellular response to chemical stress	1
Dengue Virus Infection	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
proteasomal protein catabolic process	2
polyubiquitin modification-dependent protein binding	2
binding	2
intracellular membrane-bounded organelle	2
endomembrane system	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
organelle organization	1
endomembrane system organization	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
response to endoplasmic reticulum stress	1
response to chemical	1
RIG-I signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
regulation of RIG-I signaling pathway	1
ubiquitin-dependent protein catabolic process	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-like protein binding	1
enzyme binding	1
cation binding	1
nuclear lumen	1
endoplasmic reticulum membrane	1
UFD1-NPL4 complex	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
protein-containing complex	1
membrane	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1822 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPLOC4	UFD1	Q92890	999
NPLOC4	VCP	P55072	999
NPLOC4	PHF20	Q9BVI0	926
NPLOC4	FAF2	Q96CS3	874
NPLOC4	MARCHF6	O60337	847
NPLOC4	OS9	Q13438	845
NPLOC4	SEL1L	Q9UBV2	844
NPLOC4	ANKZF1	Q9H8Y5	827
NPLOC4	PLAA	Q9Y263	821
NPLOC4	UBXN7	O94888	812
NPLOC4	DERL1	Q9BUN8	803
NPLOC4	SYVN1	Q86TM6	802
NPLOC4	FAF1	Q9UNN5	802
NPLOC4	ATXN3	P54252	801
NPLOC4	VCPIP1	Q96JH7	771

IntAct

165 interactions, top by confidence:

A	B	Type	Score
NPLOC4	VCP	psi-mi:“MI:0915”(physical association)	0.950
NPLOC4	VCP	psi-mi:“MI:0407”(direct interaction)	0.950
UFD1	VCP	psi-mi:“MI:0914”(association)	0.880
FAF2	VCP	psi-mi:“MI:0914”(association)	0.870
NPLOC4	UFD1	psi-mi:“MI:0915”(physical association)	0.860
VCP	ATXN3	psi-mi:“MI:0914”(association)	0.830
UBXN7	VCP	psi-mi:“MI:0914”(association)	0.820
VCP	UBXN7	psi-mi:“MI:0914”(association)	0.820
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
IFT70A	IFT56	psi-mi:“MI:0914”(association)	0.790
UBXN1	VCP	psi-mi:“MI:0914”(association)	0.740
COPG1	COPB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UBXN8	VCP	psi-mi:“MI:0914”(association)	0.690

BioGRID (352): NPLOC4 (Affinity Capture-MS), NPLOC4 (Two-hybrid), NPLOC4 (Affinity Capture-RNA), NPLOC4 (Affinity Capture-RNA), NPLOC4 (Affinity Capture-RNA), NPLOC4 (Co-crystal Structure), NPLOC4 (Affinity Capture-MS), NPLOC4 (Biochemical Activity), NPLOC4 (Affinity Capture-MS), NPLOC4 (Affinity Capture-MS), NPLOC4 (Affinity Capture-MS), NPLOC4 (Affinity Capture-MS), NPLOC4 (Reconstituted Complex), CD2AP (Co-fractionation), NDUFS3 (Co-fractionation)

ESM2 similar proteins: A0A8M3B525, A2AHJ4, A5PJP6, B0KWU8, B2RYM5, B5X8M4, E1C3P4, E9Q4Z2, O00763, O42611, O94967, O95630, P46736, P46737, P48553, Q15386, Q15542, Q3TLI0, Q4VA72, Q5KSL6, Q5R558, Q5R9L6, Q5RAQ5, Q5VVJ2, Q641K1, Q66GV6, Q66H62, Q69Z66, Q6RI45, Q6WKZ8, Q76N33, Q7M757, Q80U95, Q8BPM2, Q8CGF6, Q8IVH8, Q8QFR2, Q8TAT6, Q8VDD9, Q8W206

Diamond homologs: A1CS06, A1D4X8, A2Q8R9, A3GFS1, A4RN19, A5DBC9, A5DX93, A6R538, A7EGK5, A7TTC4, H2KYU6, P0C7N6, P0CP30, P0CP31, P33755, P60670, Q1DY54, Q2URI8, Q4WKD7, Q5AA50, Q5BGN5, Q6BRJ9, Q6C619, Q6CLY1, Q6FJI2, Q74ZJ1, Q7SH49, Q8TAT6, Q95QZ9, Q9ES54, Q9P780, Q9VBP9, O82264, Q9AS33, Q9LYC2

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NPLOC4	“up-regulates activity”	UFD1	binding
VCP	“up-regulates activity”	NPLOC4	binding
NPLOC4	“form complex”	“RQC complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 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
Translesion Synthesis by POLH	5	27.8×	1e-04
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	6	23.5×	5e-05
Negative regulators of DDX58/IFIH1 signaling	6	18.1×	1e-04
Dengue Virus Genome Translation and Replication	6	17.6×	1e-04
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	5	17.1×	4e-04
PINK1-PRKN Mediated Mitophagy	5	16.5×	4e-04
Ovarian tumor domain proteases	6	15.5×	2e-04
Defective CFTR causes cystic fibrosis	7	14.2×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	16	20.4×	7e-14
ubiquitin-dependent protein catabolic process	14	7.3×	4e-06
proteasome-mediated ubiquitin-dependent protein catabolic process	14	5.1×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	5
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

4104 predictions. Top by Δscore:

Variant	Effect	Δscore
17:81565503:A:AC	donor_gain	1.0000
17:81565504:C:CA	donor_gain	1.0000
17:81565504:CTGCA:C	donor_gain	1.0000
17:81565603:CTGTC:C	acceptor_gain	1.0000
17:81572010:CACTT:C	donor_loss	1.0000
17:81572011:ACTT:A	donor_loss	1.0000
17:81572012:CTT:C	donor_loss	1.0000
17:81572013:TTA:T	donor_loss	1.0000
17:81572014:TA:T	donor_loss	1.0000
17:81572015:A:AC	donor_gain	1.0000
17:81572016:C:CA	donor_gain	1.0000
17:81572016:CGT:C	donor_gain	1.0000
17:81572016:CGTCT:C	donor_gain	1.0000
17:81572085:CGTC:C	acceptor_gain	1.0000
17:81572089:C:CC	acceptor_gain	1.0000
17:81572099:C:CT	acceptor_gain	1.0000
17:81588967:A:AC	donor_gain	1.0000
17:81588968:C:CC	donor_gain	1.0000
17:81588968:CTG:C	donor_gain	1.0000
17:81588974:A:AC	donor_gain	1.0000
17:81588975:C:CC	donor_gain	1.0000
17:81596100:A:AC	donor_gain	1.0000
17:81596100:ACTGT:A	donor_gain	1.0000
17:81596101:C:CC	donor_gain	1.0000
17:81596101:CTGT:C	donor_gain	1.0000
17:81596101:CTGTC:C	donor_gain	1.0000
17:81596105:C:A	donor_gain	1.0000
17:81596239:TGTC:T	acceptor_gain	1.0000
17:81596241:TC:T	acceptor_gain	1.0000
17:81596242:CC:C	acceptor_gain	1.0000

AlphaMissense

4025 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:81589044:A:G	L394P	1.000
17:81604591:A:G	L264P	1.000
17:81604621:C:T	G254E	1.000
17:81604657:C:G	R242T	1.000
17:81604720:C:A	R221M	1.000
17:81604720:C:G	R221T	1.000
17:81606710:G:T	A212D	1.000
17:81606721:G:C	C208W	1.000
17:81606722:C:A	C208F	1.000
17:81606722:C:G	C208S	1.000
17:81606723:A:G	C208R	1.000
17:81606723:A:T	C208S	1.000
17:81606730:A:C	C205W	1.000
17:81606731:C:A	C205F	1.000
17:81606731:C:G	C205S	1.000
17:81606731:C:T	C205Y	1.000
17:81606732:A:G	C205R	1.000
17:81606732:A:T	C205S	1.000
17:81606745:C:A	W200C	1.000
17:81606745:C:G	W200C	1.000
17:81606747:A:G	W200R	1.000
17:81606747:A:T	W200R	1.000
17:81606765:A:G	C194R	1.000
17:81608746:A:G	L171P	1.000
17:81610222:G:C	C141W	1.000
17:81610223:C:T	C141Y	1.000
17:81610224:A:G	C141R	1.000
17:81610231:G:C	C138W	1.000
17:81610232:C:G	C138S	1.000
17:81610232:C:T	C138Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000021564 (17:81629991 A>G,T), RS1000023393 (17:81591698 G>T), RS1000023886 (17:81577138 C>T), RS1000095527 (17:81590671 G>A,T), RS1000171361 (17:81559706 G>A), RS1000176451 (17:81564271 A>T), RS1000179298 (17:81611436 GCCT>G), RS1000202766 (17:81637097 G>A), RS1000206678 (17:81635035 A>T), RS1000232136 (17:81586215 G>A,T), RS1000234797 (17:81572702 C>T), RS1000237825 (17:81634833 T>C), RS1000289970 (17:81567337 G>A,C), RS1000303599 (17:81597062 G>C), RS1000325207 (17:81582794 G>C)

Disease associations

OMIM: gene MIM:606590 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000685_3	Eye color traits	9.000000e-14
GCST003219_14	Advanced age-related macular degeneration	2.000000e-11
GCST003997_35	Myopia	2.000000e-18
GCST004601_178	Red blood cell count	1.000000e-09
GCST004621_199	Red cell distribution width	1.000000e-11
GCST005580_70	Intraocular pressure	7.000000e-12
GCST005990_23	Non-albumin protein levels	3.000000e-10
GCST006804_163	Red cell distribution width	8.000000e-09
GCST007160_28	Refractive astigmatism	2.000000e-09
GCST009462_69	Optic disc size	5.000000e-25
GCST009963_17	Cataracts (operation)	2.000000e-12
GCST010002_133	Refractive error	2.000000e-50
GCST012013_2	Cataracts	2.000000e-18
GCST90000654_69	Central corneal thickness	5.000000e-11
GCST90002390_544	Mean corpuscular hemoglobin	3.000000e-11
GCST90002392_34	Mean corpuscular volume	7.000000e-12
GCST90002396_680	Mean reticulocyte volume	5.000000e-11
GCST90002397_377	Mean spheric corpuscular volume	4.000000e-12
GCST90002403_325	Red blood cell count	1.000000e-17
GCST90002404_186	Red cell distribution width	1.000000e-13
GCST90014268_38	Cataracts	1.000000e-42

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0003949	eye color
EFO:1001492	atrophic macular degeneration
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
sodium arsenite	increases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	2
bisphenol S	increases expression, decreases methylation	2
Acrolein	affects cotreatment, increases expression, increases oxidation, increases abundance	2
Ozone	increases oxidation, increases abundance, affects cotreatment, increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	2
bisphenol F	increases expression	1
NMS-873	affects binding, increases reaction	1
urushiol	decreases expression	1
lasiocarpine	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, decreases methylation	1
beta-lapachone	increases expression	1
cobaltous chloride	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
NCS 382	increases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Temozolomide	increases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	increases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation	1
Ethanol	increases abundance, increases expression, affects cotreatment	1
Arsenic	affects reaction, increases degradation	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1581	NCI-H716	Cancer cell line	Male

Clinical trials (associated diseases)

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