NVL

Summary

NVL (nuclear VCP like, HGNC:8070) is a protein-coding gene on chromosome 1q42.11, encoding Nuclear valosin-containing protein-like (O15381). Participates in the assembly of the telomerase holoenzyme and effecting of telomerase activity via its interaction with TERT. It is a common-essential gene (DepMap: required in 98.8% of cancer cell lines).

This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) superfamily. Multiple transcript variants encoding different isoforms have been found for this gene. Two encoded proteins, described as major and minor isoforms, have been localized to distinct regions of the nucleus. The largest encoded protein (major isoform) has been localized to the nucleolus and shown to participate in ribosome biosynthesis (PMID: 15469983, 16782053), while the minor isoform has been localized to the nucleoplasmin.

Source: NCBI Gene 4931 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 118 total
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 98.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_002533

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8070
Approved symbol	NVL
Name	nuclear VCP like
Location	1q42.11
Locus type	gene with protein product
Status	Approved
Aliases	NVL2
Ensembl gene	ENSG00000143748
Ensembl biotype	protein_coding
OMIM	602426
Entrez	4931

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 14 protein_coding, 6 protein_coding_CDS_not_defined, 5 retained_intron, 3 nonsense_mediated_decay

ENST00000281701, ENST00000340871, ENST00000391875, ENST00000436927, ENST00000461466, ENST00000461546, ENST00000462893, ENST00000467882, ENST00000468088, ENST00000468673, ENST00000469075, ENST00000469968, ENST00000470903, ENST00000470989, ENST00000481213, ENST00000482491, ENST00000483094, ENST00000487758, ENST00000488718, ENST00000489194, ENST00000492281, ENST00000493060, ENST00000496393, ENST00000498767, ENST00000933815, ENST00000933816, ENST00000933817, ENST00000933818

RefSeq mRNA: 4 — MANE Select: NM_002533 NM_001243146, NM_001243147, NM_002533, NM_206840

CCDS: CCDS1541, CCDS1542, CCDS58062, CCDS58063

Canonical transcript exons

ENST00000281701 — 23 exons

Exon	Start	End
ENSE00000961781	224307991	224308263
ENSE00000961790	224287775	224287993
ENSE00000961791	224286026	224286130
ENSE00000961792	224281123	224281185
ENSE00001002549	224275339	224275458
ENSE00001002554	224289484	224289733
ENSE00001847692	224330071	224330172
ENSE00003486281	224231226	224231296
ENSE00003486934	224294267	224294411
ENSE00003494649	224326391	224326464
ENSE00003528726	224317878	224317930
ENSE00003561667	224268034	224268133
ENSE00003562294	224311800	224311857
ENSE00003595169	224300562	224300663
ENSE00003603471	224233201	224233289
ENSE00003623373	224317694	224317793
ENSE00003661495	224305034	224305166
ENSE00003670650	224236506	224236582
ENSE00003678455	224250212	224250318
ENSE00003689726	224296501	224296618
ENSE00003720531	224303723	224303857
ENSE00003787897	224304736	224304812
ENSE00003844176	224227345	224227670

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 93.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.3612 / max 465.3557, expressed in 1784 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17678	17.3612	1784

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	93.82	gold quality
calcaneal tendon	UBERON:0003701	92.73	gold quality
mucosa of transverse colon	UBERON:0004991	92.51	gold quality
ventricular zone	UBERON:0003053	90.75	gold quality
cortical plate	UBERON:0005343	90.72	gold quality
ganglionic eminence	UBERON:0004023	90.27	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.98	gold quality
cerebellar hemisphere	UBERON:0002245	89.71	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.69	gold quality
cerebellar cortex	UBERON:0002129	89.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.82	gold quality
skin of abdomen	UBERON:0001416	88.64	gold quality
adenohypophysis	UBERON:0002196	88.32	gold quality
granulocyte	CL:0000094	88.15	gold quality
skin of leg	UBERON:0001511	87.65	gold quality
rectum	UBERON:0001052	87.58	gold quality
cerebellum	UBERON:0002037	86.84	gold quality
secondary oocyte	CL:0000655	86.78	gold quality
transverse colon	UBERON:0001157	86.62	gold quality
pituitary gland	UBERON:0000007	86.53	gold quality
right uterine tube	UBERON:0001302	86.46	gold quality
adrenal tissue	UBERON:0018303	86.35	gold quality
embryo	UBERON:0000922	86.33	gold quality
left ovary	UBERON:0002119	86.13	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.90	gold quality
spleen	UBERON:0002106	85.75	gold quality
right ovary	UBERON:0002118	85.73	gold quality
zone of skin	UBERON:0000014	85.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.49	gold quality
body of uterus	UBERON:0009853	85.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.68

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CKM
TNNI1

miRNA regulators (miRDB)

45 targeting NVL, 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-4267	99.96	66.53	2368
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 98.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 10)

• interaction of NVL2 with ribosomal protein L5 is ATP-dependent and likely contributes to the nucleolar translocation of NVL2 (PMID:15469983)
• Nuclear VCP/p97-like protein 2 might regulate the association/dissociation reaction of DOB1 with pre-ribosomal particles by acting as a molecular chaperone. (PMID:16782053)
• NVL2 might facilitate the dissociation and recycling of nucleolin, thereby promoting efficient ribosome biogenesis (PMID:21474449)
• these findings suggest that NVL2 is essential for telomerase biogenesis and provides an alternative approach for inhibiting telomerase activity in cancer. (PMID:22226966)
• Results indicated that the NVL gene may contain overlapping common genetic risk factors for major depressive disorder and schizophrenia in the Han Chinese population (PMID:25891250)
• suggest that NVL2 is involved in pre-rRNA processing by associating with the nuclear exosome complex and that MPP6 is required for maintaining the integrity of this rRNA processing complex (PMID:26166824)
• results suggest that WDR74 is a novel regulatory protein of the MTR4-exsosome complex whose interaction is regulated by NVL2 and is involved in ribosome biogenesis (PMID:26456651)
• knockdown of WDR74 leads to significant defects in the pre-rRNA cleavage within the internal transcribed spacer 1, occurring in an early stage of the processing pathway. When the dissociation of WDR74 from the MTR4-containing exonuclease complex was impaired upon expression of mutant NVL2, the same processing defect, with partial migration of WDR74 from the nucleolus towards the nucleoplasm, was observed. (PMID:29107693)
• Data show that the nuclear exosome adaptors nuclear valosin-containing protein-like (NVL) and zinc finger, CCHC domain containing 8 protein (ZCCHC8) bind the Mtr4 exosome RNA helicase (MTR4) KOW domain on a surface. (PMID:31358741)
• Interactome analysis of the Tudor domain-containing protein SPF30 which associates with the MTR4-exosome RNA-decay machinery under the regulation of AAA-ATPase NVL2. (PMID:33422691)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nvl	ENSDARG00000025605
mus_musculus	Nvl	ENSMUSG00000026516
rattus_norvegicus	Nvl	ENSRNOG00000003629
drosophila_melanogaster	smid	FBGN0016983
caenorhabditis_elegans		WBGENE00003119

Paralogs (5): PEX6 (ENSG00000124587), PEX1 (ENSG00000127980), AFG2A (ENSG00000145375), VCP (ENSG00000165280), AFG2B (ENSG00000171763)

Protein

Protein identifiers

Nuclear valosin-containing protein-like — O15381 (reviewed: O15381)

All UniProt accessions (8): O15381, A0A087WV72, C9J6P7, C9JP83, E7EWK7, E9PGD8, E9PH71, F8WF01

UniProt curated annotations — full annotation on UniProt →

Function. Participates in the assembly of the telomerase holoenzyme and effecting of telomerase activity via its interaction with TERT. Involved in both early and late stages of the pre-rRNA processing pathways. Spatiotemporally regulates 60S ribosomal subunit biogenesis in the nucleolus. Catalyzes the release of specific assembly factors, such as WDR74, from pre-60S ribosomal particles through the ATPase activity.

Subunit / interactions. Interacts with NCL/nucleolin. Isoform 1 and isoform 2 interact with TERT and isoform 1 exhibits a higher binding affinity for TERT compared to isoform 2. Isoform 1 interacts with MTREX in an ATP-dependent manner; the interaction is required to associate NVL with nuclear RNA exosome. Isoform 1 interacts with RPL5 in an ATP-dependent manner. Interacts with WDR74 (through WDR repeats); the interaction is independent of RNA or pre-60S ribosome particles.

Subcellular location. Nucleus. Nucleoplasm Nucleus. Nucleolus. Nucleoplasm.

Tissue specificity. Widely expressed. Highest level of expression in heart, placenta, skeletal muscle, pancreas and retina.

Similarity. Belongs to the AAA ATPase family.

Isoforms (5)

UniProt ID	Names	Canonical?
O15381-1	1, NVLp.2	yes
O15381-2	2, NVLp.1
O15381-3	3
O15381-4	4
O15381-5	5

RefSeq proteins (4): NP_001230075, NP_001230076, NP_002524, NP_996671 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031996	NVL2_nucleolin-bd	Domain
IPR038100	NLV2_N_sf	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR050168	AAA_ATPase_domain	Family

Pfam: PF00004, PF16725, PF17862

UniProt features (64 total): helix 13, mutagenesis site 11, modified residue 7, strand 6, region of interest 5, compositionally biased region 5, splice variant 4, sequence variant 3, turn 3, short sequence motif 3, binding site 2, chain 1, cross-link 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2X8A	X-RAY DIFFRACTION	2.6
9BJI	ELECTRON MICROSCOPY	2.83
9NYP	ELECTRON MICROSCOPY	2.86
9BJJ	ELECTRON MICROSCOPY	3.06
6RO1	X-RAY DIFFRACTION	3.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15381-F1	72.46	0.19

Functional residue map

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

Ligand- & substrate-binding residues (2): 305–312; 622–629

Post-translational modifications (8): 70, 134, 138, 156, 191, 211, 215, 208

Mutagenesis-validated functional residues (11):

Position	Phenotype
51–52	loss of nucleolar localization and interaction with rpl5.
85–86	decreased nuclear localization. complete loss of nuclear localization; when associated with 218-a–a-220 and 230-a–a-23
173	abolishes binding to mtrex.
175	impairs binding to mtrex.
176	impairs the binding of mtrex.
218–220	decreased nuclear localization; when associated with 230-a–a-232. complete loss of nuclear localization; when associate
230–232	decreased nuclear localization when associated with 218-a–a-220. complete loss of nuclear localization; when associated
311	loss of atp-binding. significant reduction in interaction with tert and in telomerase activity. loss of interaction with
365	decreases 60s ribosomes synthesis. strongly decreases 60s ribosomal subunit synthesis, enhances interaction with wdr74 a
628	loss of atp-binding. no effect on interaction with tert, mtrex and rpl5 and on telomerase activity. significant reductio
682	decreases 60s ribosomes synthesis. strongly decreases 60s ribosomal subunit synthesis, enhances interaction with wdr74 a

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 155 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_TELOMERE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_BINDING, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, GOBP_PROTEIN_RNA_COMPLEX_ORGANIZATION, BYSTROEM_CORRELATED_WITH_IL5_DN, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_POSITIVE_REGULATION_OF_TELOMERE_MAINTENANCE, AACTTT_UNKNOWN

GO Biological Process (7): rRNA processing (GO:0006364), positive regulation of protein binding (GO:0032092), positive regulation of telomere maintenance (GO:0032206), ribosome biogenesis (GO:0042254), ribosomal large subunit biogenesis (GO:0042273), regulation of protein localization to nucleolus (GO:1904749), telomerase holoenzyme complex assembly (GO:1905323)

GO Molecular Function (7): RNA binding (GO:0003723), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), preribosome binding (GO:1990275), nucleotide binding (GO:0000166), protein binding (GO:0005515), protein-containing complex binding (GO:0044877)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), telomerase holoenzyme complex (GO:0005697), nucleolus (GO:0005730), membrane (GO:0016020), nuclear exosome (RNase complex) (GO:0000176)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	3
ribosome biogenesis	2
ribonucleoprotein complex biogenesis	2
binding	2
cellular anatomical structure	2
nuclear protein-containing complex	2
RNA processing	1
rRNA metabolic process	1
protein binding	1
regulation of protein binding	1
positive regulation of binding	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
regulation of protein localization to nucleus	1
protein localization to nucleolus	1
protein-RNA complex assembly	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
ribonucleoprotein complex binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
intracellular membrane-bounded organelle	1
catalytic complex	1
ribonucleoprotein complex	1
intracellular membraneless organelle	1
exosome (RNase complex)	1
nucleus	1

Protein interactions and networks

STRING

2741 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NVL	WDR74	Q6RFH5	765
NVL	MDN1	Q9NU22	665
NVL	RPL5	P46777	647
NVL	GNL2	Q13823	626
NVL	MTREX	P42285	624
NVL	NOP53	Q9NZM5	618
NVL	UTP18	Q9Y5J1	600
NVL	WDR12	Q9GZL7	593
NVL	RSL24D1	Q9UHA3	524
NVL	TEX10	Q9NXF1	504
NVL	EBNA1BP2	Q99848	490
NVL	GNL3L	Q9NVN8	490
NVL	WDR18	Q9BV38	479
NVL	TERT	O14746	465
NVL	LSG1	Q9H089	459

IntAct

140 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MECP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
RPL7A	NOP56	psi-mi:“MI:0914”(association)	0.640
NPM1	NVL	psi-mi:“MI:0914”(association)	0.610
PLEKHO1	UBA6	psi-mi:“MI:0914”(association)	0.530
MECP2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ZNF512	ZNF724	psi-mi:“MI:0914”(association)	0.530
RBM34	NVL	psi-mi:“MI:0914”(association)	0.530
RRP8	NVL	psi-mi:“MI:0914”(association)	0.530
PES1	AP3B1	psi-mi:“MI:0914”(association)	0.530
PRR11	NVL	psi-mi:“MI:0914”(association)	0.530
MAK16	NVL	psi-mi:“MI:0914”(association)	0.530
ZNF71	NVL	psi-mi:“MI:0914”(association)	0.530
MAGEB10	GTPBP10	psi-mi:“MI:0914”(association)	0.530
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
PPAN	PPM1G	psi-mi:“MI:0914”(association)	0.530
RBM4	NVL	psi-mi:“MI:0914”(association)	0.530
RPL7A	NVL	psi-mi:“MI:0914”(association)	0.530

BioGRID (208): NVL (Affinity Capture-RNA), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS), NVL (Two-hybrid), NVL (Affinity Capture-MS), NVL (Proximity Label-MS), NVL (Proximity Label-MS), UBE2I (Two-hybrid), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS), NVL (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A0U1RPR8, A0A7N9VSG0, A7YSY2, D3ZX08, D4A2B7, O15381, O19114, O43542, O43824, O88202, P32794, P40694, P51839, P51840, P52333, P52785, P54777, P55205, Q02846, Q08DH8, Q0VA52, Q13608, Q14CH7, Q1HG60, Q2NKY8, Q3U6U5, Q3UMC0, Q3ZBE0, Q5BJS0, Q5E9L5, Q5JTZ9, Q5PQY6, Q5R607, Q5RCH4, Q6NZB1, Q6ZSI9, Q7L2E3, Q80SX8, Q8NB90

Diamond homologs: A0A061IR73, A0A7N9VSG0, A4G0S4, A6UQT3, A6VHR1, A7YSY2, A9A916, C4QXI8, C4R6C2, D1CDT8, D4A2B7, G1X4S3, G1X7C7, G3GXG9, O05209, O13764, O14325, O15381, O18413, O26824, O28303, O28972, O43933, O60058, O74941, P03974, P23787, P24004, P25694, P32794, P33289, P33760, P34124, P36966, P41836, P46462, P46463, P46468, P54609, P54774

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 142 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
Peptide chain elongation	16	23.3×	5e-16
Viral mRNA Translation	16	23.3×	5e-16
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	16	23.1×	5e-16
Selenocysteine synthesis	16	22.1×	6e-16
Eukaryotic Translation Termination	16	22.1×	6e-16
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	16	21.6×	7e-16
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	16	21.6×	7e-16
Formation of a pool of free 40S subunits	16	20.6×	1e-15

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	17	26.5×	4e-17
ribosomal large subunit biogenesis	6	22.4×	4e-05
translation	17	14.7×	7e-13
ribosomal small subunit biogenesis	7	13.4×	1e-04
rRNA processing	10	11.9×	3e-06
RNA processing	6	11.0×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — GBM.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3932 predictions. Top by Δscore:

Variant	Effect	Δscore
1:224231220:GCTTA:G	donor_loss	1.0000
1:224231221:CTTA:C	donor_loss	1.0000
1:224231222:TTA:T	donor_loss	1.0000
1:224231223:TA:T	donor_loss	1.0000
1:224231224:A:C	donor_loss	1.0000
1:224233195:TTGTA:T	donor_loss	1.0000
1:224233196:TGTA:T	donor_loss	1.0000
1:224233197:GTACC:G	donor_loss	1.0000
1:224233198:TA:T	donor_loss	1.0000
1:224233199:A:AG	donor_loss	1.0000
1:224233200:C:G	donor_loss	1.0000
1:224233285:CGCCC:C	acceptor_gain	1.0000
1:224233287:CCC:C	acceptor_gain	1.0000
1:224233288:CC:C	acceptor_gain	1.0000
1:224233288:CCC:C	acceptor_gain	1.0000
1:224233289:CC:C	acceptor_gain	1.0000
1:224233290:C:CC	acceptor_gain	1.0000
1:224236504:A:AC	donor_gain	1.0000
1:224236505:C:CG	donor_gain	1.0000
1:224236578:CCATT:C	acceptor_gain	1.0000
1:224236579:CATTC:C	acceptor_gain	1.0000
1:224250205:TAC:T	donor_loss	1.0000
1:224250206:ACT:A	donor_loss	1.0000
1:224250207:CTC:C	donor_loss	1.0000
1:224250207:CTCA:C	donor_gain	1.0000
1:224250210:A:AC	donor_gain	1.0000
1:224250210:ACTT:A	donor_loss	1.0000
1:224250211:C:CG	donor_gain	1.0000
1:224250211:CT:C	donor_gain	1.0000
1:224250211:CTT:C	donor_gain	1.0000

AlphaMissense

5594 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:224268041:G:C	N725K	0.999
1:224268041:G:T	N725K	0.999
1:224268102:A:G	L705P	0.999
1:224275376:T:A	E682V	0.999
1:224275388:A:T	I678K	0.999
1:224275444:A:C	S659R	0.999
1:224275444:A:T	S659R	0.999
1:224275446:T:G	S659R	0.999
1:224275451:C:T	G657D	0.999
1:224281148:A:T	V646D	0.999
1:224289638:A:G	L474P	0.999
1:224294318:C:A	R425M	0.999
1:224303769:C:T	G305E	0.999
1:224303778:A:G	L302P	0.999
1:224233278:A:G	L793P	0.998
1:224250286:G:T	R739S	0.998
1:224268039:C:G	R726T	0.998
1:224268040:T:C	R726G	0.998
1:224268048:G:T	A723D	0.998
1:224268099:A:G	L706P	0.998
1:224275368:C:G	A685P	0.998
1:224275375:T:A	E682D	0.998
1:224275375:T:G	E682D	0.998
1:224275376:T:C	E682G	0.998
1:224275376:T:G	E682A	0.998
1:224275377:C:T	E682K	0.998
1:224275379:T:A	D681V	0.998
1:224275379:T:G	D681A	0.998
1:224275388:A:C	I678R	0.998
1:224275430:C:G	R664P	0.998

dbSNP variants (sampled 300 via entrez): RS1000059545 (1:224305818 C>G), RS1000100799 (1:224260610 A>C), RS1000145440 (1:224277813 C>T), RS1000176736 (1:224294173 A>G), RS1000208753 (1:224237257 C>T), RS1000214726 (1:224281579 C>A,G,T), RS1000227631 (1:224293748 A>G), RS1000233919 (1:224241575 G>A), RS1000286487 (1:224241851 C>T), RS1000306325 (1:224331503 G>A), RS1000312255 (1:224313074 G>A,T), RS1000337086 (1:224231114 C>A,T), RS1000388589 (1:224274876 G>A), RS1000389493 (1:224230959 C>T), RS1000389772 (1:224320437 A>C)

Disease associations

OMIM: gene MIM:602426 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000856_1	Major depressive disorder	4.000000e-06
GCST011743_68	HDL cholesterol levels in HIV infection	8.000000e-06
GCST90002390_338	Mean corpuscular hemoglobin	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases abundance, increases expression	3
bisphenol A	increases expression, decreases expression	2
Arsenic	increases abundance, increases expression, affects methylation	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
abrine	increases expression	1
bisphenol S	affects expression	1
picoxystrobin	increases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	decreases expression, decreases reaction	1
Gallic Acid	increases expression	1
Lead	affects expression	1
Methyl Methanesulfonate	increases expression	1
Ribonucleotides	affects binding	1
Tetrachlorodibenzodioxin	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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