NHP2

Summary

NHP2 (NHP2 ribonucleoprotein, HGNC:14377) is a protein-coding gene on chromosome 5q35.3, encoding H/ACA ribonucleoprotein complex subunit 2 (Q9NX24). Required for ribosome biogenesis and telomere maintenance. It is a selective cancer dependency (DepMap: 89.7% of cell lines).

This gene is a member of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of rRNA processing and modification and have been classified into two families: C/D and H/ACA. The H/ACA snoRNPs also include the DKC1, NOLA1 and NOLA3 proteins. These four H/ACA snoRNP proteins localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. The four H/ACA snoRNP proteins are also components of the telomerase complex. This gene encodes a protein related to Saccharomyces cerevisiae Nhp2p. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55651 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dyskeratosis congenita, autosomal recessive 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 205 total — 3 pathogenic
• Phenotypes (HPO): 86
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 89.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_017838

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14377
Approved symbol	NHP2
Name	NHP2 ribonucleoprotein
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20479
Ensembl gene	ENSG00000145912
Ensembl biotype	protein_coding
OMIM	606470
Entrez	55651

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 retained_intron

ENST00000274606, ENST00000314397, ENST00000502263, ENST00000510363, ENST00000511078, ENST00000514354, ENST00000697323, ENST00000890268, ENST00000940843, ENST00000940844

RefSeq mRNA: 3 — MANE Select: NM_017838 NM_001034833, NM_001396110, NM_017838

CCDS: CCDS34308, CCDS4432

Canonical transcript exons

ENST00000274606 — 4 exons

Exon	Start	End
ENSE00000972982	178153491	178153560
ENSE00000972983	178150888	178150993
ENSE00001614289	178149463	178149838
ENSE00001839144	178153658	178153885

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 122.7334 / max 521.1633, expressed in 1823 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65153	115.6994	1823
65154	6.3986	1711
65152	0.6354	372

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	98.70	gold quality
esophagus mucosa	UBERON:0002469	98.53	gold quality
epithelium of esophagus	UBERON:0001976	98.52	gold quality
gingiva	UBERON:0001828	98.39	gold quality
gingival epithelium	UBERON:0001949	98.32	gold quality
oral cavity	UBERON:0000167	98.29	gold quality
prefrontal cortex	UBERON:0000451	98.25	gold quality
nucleus accumbens	UBERON:0001882	98.24	gold quality
caudate nucleus	UBERON:0001873	98.20	gold quality
adult organism	UBERON:0007023	98.14	gold quality
putamen	UBERON:0001874	98.13	gold quality
lower esophagus mucosa	UBERON:0035834	98.12	gold quality
skin of leg	UBERON:0001511	98.10	gold quality
ganglionic eminence	UBERON:0004023	98.09	gold quality
skin of abdomen	UBERON:0001416	98.04	gold quality
embryo	UBERON:0000922	98.03	gold quality
squamous epithelium	UBERON:0006914	98.01	gold quality
cingulate cortex	UBERON:0003027	98.00	gold quality
anterior cingulate cortex	UBERON:0009835	98.00	gold quality
esophagus	UBERON:0001043	97.96	gold quality
zone of skin	UBERON:0000014	97.90	gold quality
amygdala	UBERON:0001876	97.90	gold quality
right frontal lobe	UBERON:0002810	97.89	gold quality
pharyngeal mucosa	UBERON:0000355	97.88	gold quality
mammalian vulva	UBERON:0000997	97.86	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.83	gold quality
ectocervix	UBERON:0012249	97.83	gold quality
left ovary	UBERON:0002119	97.80	gold quality
penis	UBERON:0000989	97.75	gold quality
body of pancreas	UBERON:0001150	97.66	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	2046.12
E-HCAD-8	yes	53.42
E-CURD-122	yes	17.73
E-MTAB-8271	yes	10.68
E-MTAB-9067	no	730.37
E-MTAB-7606	no	687.37
E-CURD-112	no	3.95
E-GEOD-125970	no	3.29
E-HCAD-13	no	3.15
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

11 targeting NHP2, 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-2110	99.96	66.68	1930
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-4446-3P	97.91	64.29	991
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-4724-3P	97.57	67.31	785

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 89.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• NOLA2 expression in patients with squamous cell lung cancer increased by 70% which makes it a highly informative marker of squamous cell lung cancer (PMID:15889794)
• The analysis of two other proteins, NHP2 and GAR1, that together with dyskerin and NOP10 are key components of telomerase and small nucleolar ribonucleoprotein (snoRNP) complexes, is described. (PMID:18523010)
• Effects of dyskeratosis congenita mutations in NHP2 on assembly of H/ACA pre-RNPs (PMID:20008900)
• Indian aplastic anemia patients did not have NHP2 mutations. (PMID:25906515)
• In this work, we have uncovered a putative role of epigenetic regulation in a subset of human snoRNP complexes that are involved in the site-specific modification of RNA. We find that a subset of box C/D snoRNAs are methylated at the 1n position and that this blocks both 15.5k binding and the formation of the kinked conformation in vivo. (PMID:28623187)
• NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Hoyeraal-Hreidarsson syndrome. (PMID:31985013)
• NHP2 downregulation counteracts hTR-mediated activation of the DNA damage response at ALT telomeres. (PMID:33595114)
• A novel mutation (p.Y24N) in NHP2 leads to idiopathic pulmonary fibrosis and lung carcinoma chronic obstructive lung disease by disrupting the expression and nucleocytoplasmic localization of NHP2. (PMID:36933847)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nhp2	ENSDARG00000069422
mus_musculus	Nhp2	ENSMUSG00000001056
rattus_norvegicus	Nhp2	ENSRNOG00000075550
drosophila_melanogaster	NHP2	FBGN0029148
caenorhabditis_elegans		WBGENE00012964

Paralogs (3): RPL7A (ENSG00000148303), RSL1D1 (ENSG00000171490), RPL10A (ENSG00000198755)

Protein

Protein identifiers

H/ACA ribonucleoprotein complex subunit 2 — Q9NX24 (reviewed: Q9NX24)

Alternative names: Nucleolar protein family A member 2, snoRNP protein NHP2

All UniProt accessions (4): D6RC52, D6RCB9, Q9NX24, J3QSY4

UniProt curated annotations — full annotation on UniProt →

Function. Required for ribosome biogenesis and telomere maintenance. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA. This involves the isomerization of uridine such that the ribose is subsequently attached to C5, instead of the normal N1. Each rRNA can contain up to 100 pseudouridine (‘psi’) residues, which may serve to stabilize the conformation of rRNAs. May also be required for correct processing or intranuclear trafficking of TERC, the RNA component of the telomerase reverse transcriptase (TERT) holoenzyme.

Subunit / interactions. Part of the H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which contains NHP2/NOLA2, GAR1/NOLA1, NOP10/NOLA3, and DKC1/NOLA4, which is presumed to be the catalytic subunit. The complex contains a stable core formed by binding of one or two NOP10-DKC1 heterodimers to NHP2; GAR1 subsequently binds to this core via DKC1. The complex binds a box H/ACA small nucleolar RNA (snoRNA), which may target the specific site of modification within the RNA substrate. During assembly, the complex contains NAF1 instead of GAR1/NOLA1. The complex also interacts with TERC, which contains a 3’-terminal domain related to the box H/ACA snoRNAs. Specific interactions with snoRNAs or TERC are mediated by GAR1 and NHP2. Associates with NOLC1/NOPP140. H/ACA snoRNPs interact with the SMN complex, consisting of SMN1 or SMN2, GEMIN2/SIP1, DDX20/GEMIN3, and GEMIN4. This is mediated by interaction between GAR1 and SMN1 or SMN2. The SMN complex may be required for correct assembly of the H/ACA snoRNP complex. Component of the telomerase holoenzyme complex composed of one molecule of TERT, one molecule of WRAP53/TCAB1, two molecules of H/ACA ribonucleoprotein complex subunits DKC1, NOP10, NHP2 and GAR1, and a telomerase RNA template component (TERC). The telomerase holoenzyme complex is associated with TEP1, SMG6/EST1A and POT1.

Subcellular location. Nucleus. Nucleolus. Cajal body.

Tissue specificity. Expressed in brain, colon, heart, kidney, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen, testis and thymus. Also expressed at lower levels in the liver.

Disease relevance. Dyskeratosis congenita, autosomal recessive, 2 (DKCB2) [MIM:613987] A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the eukaryotic ribosomal protein eL8 family.

RefSeq proteins (3): NP_001030005, NP_001383039, NP_060308* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002415	H/ACA_rnp_Nhp2-like	Family
IPR004038	Ribosomal_eL8/eL30/eS12/Gad45	Domain
IPR018492	Ribosomal_eL8/Nhp2	Family
IPR029064	Ribosomal_eL30-like_sf	Homologous_superfamily
IPR050257	eL8/uL1-like	Family

Pfam: PF01248

UniProt features (23 total): helix 7, strand 4, cross-link 4, turn 3, sequence variant 3, chain 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8OUE	ELECTRON MICROSCOPY	2.7
9QB2	ELECTRON MICROSCOPY	3
8OUF	ELECTRON MICROSCOPY	3.1
7TRC	ELECTRON MICROSCOPY	3.3
7BGB	ELECTRON MICROSCOPY	3.4
9QB3	ELECTRON MICROSCOPY	3.9
7V9A	ELECTRON MICROSCOPY	3.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX24-F1	80.73	0.42

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 (5): 19, 3, 5, 5, 5

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-171319	Telomere Extension By Telomerase
R-HSA-6790901	rRNA modification in the nucleus and cytosol

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): snoRNA guided rRNA pseudouridine synthesis (GO:0000454), telomere maintenance via telomerase (GO:0007004), rRNA pseudouridine synthesis (GO:0031118), snRNA pseudouridine synthesis (GO:0031120), telomerase RNA localization to Cajal body (GO:0090671), mRNA splicing, via spliceosome (GO:0000398), rRNA processing (GO:0006364), ribosome biogenesis (GO:0042254)

GO Molecular Function (6): RNA binding (GO:0003723), mRNA 3’-UTR binding (GO:0003730), U3 snoRNA binding (GO:0034511), box H/ACA snoRNA binding (GO:0034513), telomerase RNA binding (GO:0070034), protein binding (GO:0005515)

GO Cellular Component (11): chromosome, telomeric region (GO:0000781), nucleoplasm (GO:0005654), telomerase holoenzyme complex (GO:0005697), sno(s)RNA-containing ribonucleoprotein complex (GO:0005732), box H/ACA snoRNP complex (GO:0031429), box H/ACA scaRNP complex (GO:0072589), box H/ACA telomerase RNP complex (GO:0090661), nucleus (GO:0005634), nucleolus (GO:0005730), Cajal body (GO:0015030), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Extension of Telomeres	1
rRNA processing in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear protein-containing complex	4
catalytic complex	3
box H/ACA RNP complex	3
pseudouridine synthesis	2
snoRNA binding	2
nuclear lumen	2
ribonucleoprotein complex	2
rRNA pseudouridine synthesis	1
telomerase activity	1
RNA-templated DNA biosynthetic process	1
telomere maintenance via telomere lengthening	1
telomere-telomerase complex assembly	1
rRNA modification	1
snRNA modification	1
RNA localization to Cajal body	1
telomerase RNA localization	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
RNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
ribonucleoprotein complex biogenesis	1
nucleic acid binding	1
mRNA binding	1
RNA binding	1
binding	1
chromosomal region	1
cellular anatomical structure	1
nucleolus	1
Cajal body	1
telomerase holoenzyme complex	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
nuclear ribonucleoprotein granule	1
protein-containing complex	1

Protein interactions and networks

STRING

4501 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NHP2	DKC1	O60832	999
NHP2	NOP10	Q9NPE3	999
NHP2	WRAP53	Q9BUR4	998
NHP2	TERT	O14746	997
NHP2	GAR1	Q9NY12	987
NHP2	SHQ1	Q6PI26	979
NHP2	NOP58	Q9Y2X3	963
NHP2	FBL	P22087	953
NHP2	RUVBL2	Q9Y230	935
NHP2	TINF2	Q9BSI4	890
NHP2	CTC1	Q2NKJ3	888
NHP2	NOP56	O00567	879
NHP2	RUVBL1	P82276	840
NHP2	RTEL1	Q9NZ71	797
NHP2	TERF1	P54274	757

IntAct

76 interactions, top by confidence:

A	B	Type	Score
NHP2	NOP10	psi-mi:“MI:0915”(physical association)	0.920
NOP10	NHP2	psi-mi:“MI:0915”(physical association)	0.920
DKC1	TERT	psi-mi:“MI:0915”(physical association)	0.750
NHP2	DKC1	psi-mi:“MI:0914”(association)	0.730
YBX1	SSB	psi-mi:“MI:0914”(association)	0.710
FOXK2	DVL2	psi-mi:“MI:0914”(association)	0.640
HTT	NHP2	psi-mi:“MI:0915”(physical association)	0.560
HMBOX1	DKC1	psi-mi:“MI:0914”(association)	0.500
Snu13		psi-mi:“MI:0915”(physical association)	0.400
NOS1AP	NHP2	psi-mi:“MI:0915”(physical association)	0.370
NHP2	MYL2	psi-mi:“MI:0915”(physical association)	0.370
JMJD6	NHP2	psi-mi:“MI:0915”(physical association)	0.370
GAR1	TAF1	psi-mi:“MI:0914”(association)	0.350
NAF1	C1orf226	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
NP	KPNA4	psi-mi:“MI:0914”(association)	0.350
NP	HNRNPAB	psi-mi:“MI:0914”(association)	0.350
NP	KPNA6	psi-mi:“MI:0914”(association)	0.350
NP	TRIM66	psi-mi:“MI:0914”(association)	0.350
RRP1B	ZNF785	psi-mi:“MI:0914”(association)	0.350
COX15	SNRPGP15	psi-mi:“MI:0914”(association)	0.350

BioGRID (174): NHP2 (Two-hybrid), NHP2 (Affinity Capture-MS), NHP2 (Affinity Capture-MS), NHP2 (Affinity Capture-MS), NHP2 (Affinity Capture-MS), NHP2 (Affinity Capture-MS), NHP2 (Co-fractionation), NHP2 (Co-fractionation), NHP2 (Co-fractionation), NHP2 (Co-fractionation), NHP2 (Co-fractionation), NHP2 (Co-fractionation), NHP2 (Affinity Capture-MS), NHP2 (Two-hybrid), NHP2 (Affinity Capture-MS)

ESM2 similar proteins: A8N0V8, B7F845, B8B9K6, O14023, O74690, O82569, P0CQ52, P0CQ53, P35602, P39990, P42678, P59230, P59231, P78371, P80314, Q09130, Q16HW7, Q1ZXC6, Q21568, Q23651, Q24208, Q29NT9, Q3ZBH0, Q4P0K3, Q4R6F8, Q54XD8, Q5ANL6, Q5E950, Q5RC65, Q5TNH5, Q5XIM9, Q60LW7, Q6BLQ3, Q6C0I0, Q6CM69, Q6FQV5, Q6P8E9, Q6PC69, Q757T2, Q8VZB9

Diamond homologs: A0A1D8PF11, A0B601, A0RUB4, A2BK92, A3DMR6, A3MTA9, A4YIL9, A5UJN3, A6UT51, A8A912, A9A2Z3, B0R4Z9, B1Y9V4, B6YWH9, B8D6E8, B9LPY2, C3MJN1, C3MYY9, C3N038, C3N8Q2, C3NMR6, C4KJ77, C5A1V9, O13672, O26355, O29494, O74690, O76732, P0CQ52, P0CQ53, P0DJ14, P0DKK7, P12743, P17076, P32429, P32495, P35685, P39990, P46223, P49692

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NHP2	“up-regulates activity”	TERT	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 77 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.

GO biological processes:

GO term	Partners	Fold	FDR
telomere maintenance via telomerase	5	59.1×	7e-06
rRNA processing	5	11.4×	6e-03
mRNA processing	7	8.9×	3e-03
RNA splicing	6	8.5×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	106
Likely benign	76
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4280	NM_017838.4(NHP2):c.415T>C (p.Tyr139His)	Pathogenic
4281	NM_017838.4(NHP2):c.376G>A (p.Val126Met)	Pathogenic
4282	NM_017838.4(NHP2):c.460T>A (p.Ter154Arg)	Pathogenic

SpliceAI

339 predictions. Top by Δscore:

Variant	Effect	Δscore
5:178153485:TCTTA:T	donor_loss	1.0000
5:178153486:CTTA:C	donor_loss	1.0000
5:178153487:TTAC:T	donor_loss	1.0000
5:178153488:TACCC:T	donor_loss	1.0000
5:178153489:A:AC	donor_gain	1.0000
5:178153489:AC:A	donor_gain	1.0000
5:178153489:ACCC:A	donor_loss	1.0000
5:178153490:C:CA	donor_loss	1.0000
5:178153490:C:CC	donor_gain	1.0000
5:178153490:CC:C	donor_gain	1.0000
5:178153556:CACCG:C	acceptor_gain	1.0000
5:178153558:CCG:C	acceptor_gain	1.0000
5:178153559:CG:C	acceptor_gain	1.0000
5:178153559:CGC:C	acceptor_gain	1.0000
5:178153561:C:CC	acceptor_gain	1.0000
5:178153654:TCA:T	donor_loss	1.0000
5:178153655:CACC:C	donor_loss	1.0000
5:178153656:A:AC	donor_gain	1.0000
5:178153657:C:CC	donor_gain	1.0000
5:178153657:CCTTT:C	donor_gain	1.0000
5:178149834:AGGTC:A	acceptor_gain	0.9900
5:178149835:GGTC:G	acceptor_gain	0.9900
5:178149837:TC:T	acceptor_gain	0.9900
5:178149838:CC:C	acceptor_gain	0.9900
5:178149839:C:CC	acceptor_gain	0.9900
5:178149839:CTACA:C	acceptor_loss	0.9900
5:178150887:CCGT:C	donor_gain	0.9900
5:178153489:ACC:A	donor_gain	0.9900
5:178153490:CCC:C	donor_gain	0.9900
5:178153490:CCCT:C	donor_gain	0.9900

AlphaMissense

984 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:178149801:C:T	C125Y	0.999
5:178149802:A:G	C125R	0.999
5:178149831:C:T	G115D	0.999
5:178153533:C:T	G63E	0.999
5:178149789:A:T	V129D	0.998
5:178149795:A:T	I127K	0.998
5:178149800:A:C	C125W	0.998
5:178149831:C:A	G115V	0.998
5:178149832:C:G	G115R	0.998
5:178150891:C:A	K111N	0.998
5:178150891:C:G	K111N	0.998
5:178150965:G:A	P87S	0.998
5:178150979:G:T	A82E	0.998
5:178150985:A:T	V80D	0.998
5:178153492:C:G	G77R	0.998
5:178153492:C:T	G77R	0.998
5:178153525:C:T	E66K	0.998
5:178153534:C:G	G63R	0.998
5:178153534:C:T	G63R	0.998
5:178153539:C:G	R61P	0.998
5:178149798:A:T	V126E	0.997
5:178149811:G:T	R122S	0.997
5:178149834:A:G	L114P	0.997
5:178150932:A:G	C98R	0.997
5:178150947:G:C	H93D	0.997
5:178150964:G:C	P87R	0.997
5:178150964:G:T	P87H	0.997
5:178150965:G:T	P87T	0.997
5:178153491:C:T	G77E	0.997
5:178153509:A:T	V71D	0.997

dbSNP variants (sampled 300 via entrez): RS1000188177 (5:178150382 CTATT>C), RS1000516916 (5:178154530 G>C), RS1000974207 (5:178154322 T>C), RS1001155880 (5:178151350 A>C), RS1001191830 (5:178152125 T>C), RS1001252810 (5:178151306 G>A,C,T), RS1003258164 (5:178154332 A>G), RS1003584899 (5:178150634 T>C,G), RS1003617061 (5:178154583 G>A,C,T), RS1004048449 (5:178149794 T>C), RS1004185681 (5:178149614 G>A), RS1004416605 (5:178153609 A>C,G), RS1004740449 (5:178155738 A>C), RS1004750604 (5:178154631 G>C), RS1005365343 (5:178152496 A>G)

Disease associations

OMIM: gene MIM:606470 | disease phenotypes: MIM:127550, MIM:613987, MIM:224230

GenCC curated gene-disease

Disease	Classification	Inheritance
dyskeratosis congenita, autosomal recessive 2	Strong	Autosomal recessive
dyskeratosis congenita	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
dyskeratosis congenita, autosomal recessive 2	Limited	AR

Mondo (3): dyskeratosis congenita (MONDO:0015780), dyskeratosis congenita, autosomal recessive 2 (MONDO:0013519), dyskeratosis congenita, autosomal recessive 1 (MONDO:0009136)

Orphanet (1): Dyskeratosis congenita (Orphanet:1775)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000029	Testicular atrophy
HP:0000035	Abnormal testis morphology
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000498	Blepharitis
HP:0000499	Abnormal eyelash morphology
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000579	Nasolacrimal duct obstruction
HP:0000600	Abnormality of the pharynx
HP:0000653	Sparse eyelashes
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000691	Microdontia
HP:0000704	Periodontitis
HP:0000819	Diabetes mellitus
HP:0000939	Osteoporosis
HP:0000953	Hyperpigmentation of the skin
HP:0000972	Palmoplantar hyperkeratosis
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0001034	Hypermelanotic macule
HP:0001053	Hypopigmented skin patches
HP:0001059	Pterygium
HP:0001231	Abnormal fingernail morphology

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005991_13	Platelet count	1.000000e-08
GCST009391_632	Metabolite levels	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0010503	inosine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235
C565611	Dyskeratosis Congenita, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724611 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.14	Kd	72	nM	MOLIBRESIB
6.92	IC50	120	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 7 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179150: Binding affinity against NHP2 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0720	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
TAK-243	decreases sumoylation	1
TL8-506	increases expression, affects cotreatment	1
alpha phellandrene	decreases expression	1
bisphenol A	affects expression	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
arsenite	affects binding, increases reaction	1
nivalenol	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
chloropicrin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
picoxystrobin	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Poly I-C	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697212	Binding	Inhibition of NHP2 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04638517	PHASE2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT06477614	PHASE1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT00455312	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02162420	Not specified	COMPLETED	Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT04959188	Not specified	COMPLETED	Needs Assessment for Individuals and Families Affected by Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders (TBD)
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts