ZCCHC8

Summary

ZCCHC8 (zinc finger CCHC-type containing 8, HGNC:25265) is a protein-coding gene on chromosome 12q24.31, encoding Zinc finger CCHC domain-containing protein 8 (Q6NZY4). Scaffolding subunit of the trimeric nuclear exosome targeting (NEXT) complex that is involved in the surveillance and turnover of aberrant transcripts and non-coding RNAs.

This gene encodes a scaffold protein which serves as an assessory factor to the nuclear RNA exosome complex. The encoded protein forms a trimeric human nuclear exosome targeting (NEXT) complex, together with hMTR4 and the RNA-binding factor RBM7 which promotes the exosomal degradation of non-coding promoter-upstream transcripts, enhancer RNAs and 3’-extended products of histone- and small nuclear RNA transcription. This complex is also thought to recruit the exosome to degrade intronic RNAs via its interaction with both the exosome and the spliceosome. It contains both an N-terminal zinc-knuckle domain and a C-terminal proline-rich domain.

Source: NCBI Gene 55596 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pulmonary fibrosis and/or bone marrow failure, telomere-related (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 505 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• MANE Select transcript: NM_017612

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25265
Approved symbol	ZCCHC8
Name	zinc finger CCHC-type containing 8
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp434E2220
Ensembl gene	ENSG00000033030
Ensembl biotype	protein_coding
OMIM	616381
Entrez	55596

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 4 retained_intron

ENST00000536306, ENST00000536663, ENST00000538116, ENST00000538493, ENST00000540586, ENST00000542892, ENST00000543897, ENST00000544054, ENST00000546149, ENST00000633063, ENST00000851764

RefSeq mRNA: 5 — MANE Select: NM_017612 NM_001350935, NM_001350936, NM_001350937, NM_001350938, NM_017612

CCDS: CCDS86340, CCDS91763

Canonical transcript exons

ENST00000633063 — 14 exons

Exon	Start	End
ENSE00001037362	122477841	122477958
ENSE00001037365	122480190	122480311
ENSE00001301076	122481945	122482087
ENSE00003562680	122478206	122478292
ENSE00003638995	122481522	122481664
ENSE00003711766	122471600	122474275
ENSE00003775556	122492715	122492789
ENSE00003778620	122489386	122489463
ENSE00003781647	122482635	122482695
ENSE00003782355	122490462	122490567
ENSE00003783412	122483279	122483344
ENSE00003783618	122483460	122483563
ENSE00003889798	122498827	122498869
ENSE00003894057	122500642	122500932

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 97.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2586 / max 101.0143, expressed in 1786 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133828	6.1152	1710
133827	5.0891	1462
133825	0.0543	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	97.67	gold quality
sperm	CL:0000019	94.62	gold quality
endothelial cell	CL:0000115	94.44	gold quality
oocyte	CL:0000023	94.41	gold quality
squamous epithelium	UBERON:0006914	93.74	gold quality
gingival epithelium	UBERON:0001949	93.71	gold quality
secondary oocyte	CL:0000655	93.47	gold quality
amniotic fluid	UBERON:0000173	93.18	gold quality
tibia	UBERON:0000979	93.12	gold quality
upper leg skin	UBERON:0004262	92.88	gold quality
visceral pleura	UBERON:0002401	92.84	gold quality
esophagus squamous epithelium	UBERON:0006920	92.72	gold quality
germinal epithelium of ovary	UBERON:0001304	92.37	gold quality
trabecular bone tissue	UBERON:0002483	92.21	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.79	gold quality
parietal pleura	UBERON:0002400	91.64	gold quality
pleura	UBERON:0000977	91.55	gold quality
gingiva	UBERON:0001828	91.51	gold quality
skin of hip	UBERON:0001554	91.27	gold quality
choroid plexus epithelium	UBERON:0003911	91.11	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.94	gold quality
cerebellar hemisphere	UBERON:0002245	90.85	gold quality
colonic mucosa	UBERON:0000317	90.80	gold quality
male germ cell	CL:0000015	90.75	gold quality
cerebellar cortex	UBERON:0002129	90.66	gold quality
palpebral conjunctiva	UBERON:0001812	90.52	gold quality
skin of abdomen	UBERON:0001416	90.49	gold quality
left ovary	UBERON:0002119	90.45	gold quality
bone marrow	UBERON:0002371	90.37	gold quality
epithelium of esophagus	UBERON:0001976	90.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

94 targeting ZCCHC8, 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-3924	100.00	72.09	2394
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
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-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426

Literature-anchored findings (GeneRIF, showing 6)

• Zcchc8 is a glycogen synthase kinase-3 substrate with a role in RNA metabolism (PMID:16263084)
• ZCCHC8-ROS1 fusion is associated with congenital glioblastoma multiforme. (PMID:27121553)
• a proline-rich segment of ZCCHC8 as the interaction site for the RNA-recognition motif (RRM) of RBM7 and present the crystal structure of the corresponding complex at 2.0 A resolution. (PMID:27905398)
• 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)
• ZCCHC8 associated with telomerase RNA and was required for telomerase function (PMID:31488579)
• Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC. (PMID:38606545)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	zcchc8	ENSDARG00000034982
mus_musculus	Zcchc8	ENSMUSG00000029427
rattus_norvegicus	Zcchc8	ENSRNOG00000001243
drosophila_melanogaster	CG4622	FBGN0035021
caenorhabditis_elegans		WBGENE00014018
caenorhabditis_elegans	Y34D9A.7	WBGENE00021332

Protein

Protein identifiers

Zinc finger CCHC domain-containing protein 8 — Q6NZY4 (reviewed: Q6NZY4)

Alternative names: TRAMP-like complex RNA-binding factor ZCCHC8

All UniProt accessions (4): F5GX80, F5GYI9, Q6NZY4, F5H6J5

UniProt curated annotations — full annotation on UniProt →

Function. Scaffolding subunit of the trimeric nuclear exosome targeting (NEXT) complex that is involved in the surveillance and turnover of aberrant transcripts and non-coding RNAs. NEXT functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation. May be involved in pre-mRNA splicing. It is required for 3’-end maturation of telomerase RNA component (TERC), TERC 3’-end targeting to the nuclear RNA exosome, and for telomerase function.

Subunit / interactions. Component of a nuclear TRAMP-like complex, an ATP-dependent exosome regulatory complex consisting of a helicase (MTREX), an oligadenylate polymerase (TENT4B or TENT4A), and a substrate specific RNA-binding factor (ZCCHC7 or ZCCHC8). Several TRAMP-like complexes exist with specific compositions and are associated with nuclear, or nucleolar RNA exosomes. Identified in the spliceosome C complex. Component of the nuclear exosome targeting (NEXT) complex composed of MTREX, ZCCHC8, and RBM7 that directs a subset of non-coding short-lived RNAs for exosomal degradation. Interacts with proteins involved in RNA processing and degradation such as MTREX and RBM7; interaction with MTREX enhances MTREX RNA helicase activity and bridges between RBM7 and MTREX. Interacts with TERC, the telomerase RNA component.

Subcellular location. Nucleus. Nucleoplasm.

Post-translational modifications. Phosphorylation at Thr-492 by GSK3 is triggered in cells entering mitosis; this phosphorylation is greatly enhanced by nocodazole treatment, but reduced by lithium.

Disease relevance. Pulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 5 (PFBMFT5) [MIM:618674] A disease associated with shortened telomeres. Pulmonary fibrosis is the most common manifestation. Other manifestations include aplastic anemia due to bone marrow failure, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome and acute myeloid leukemia. Phenotype, age at onset, and severity are determined by telomere length. PFBMFT5 inheritance is autosomal dominant. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal part (659-707) contributes to MTREX RNA helicase activity, in part, by enhancing its RNA-dependent ATPase activity.

Induction. Slight accumulation in cells entering S phase of the cell cycle.

Similarity. Belongs to the ZCCHC8 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6NZY4-1	1	yes
Q6NZY4-2	2

RefSeq proteins (5): NP_001337864, NP_001337865, NP_001337866, NP_001337867, NP_060082* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001878	Znf_CCHC	Domain
IPR006568	PSP_pro-rich	Domain
IPR052115	NEXT_complex_subunit_ZCCHC8	Family

Pfam: PF00098, PF04046

UniProt features (58 total): mutagenesis site 13, modified residue 12, region of interest 7, sequence conflict 6, helix 6, compositionally biased region 5, coiled-coil region 2, sequence variant 2, initiator methionine 1, chain 1, zinc finger region 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5LXR	X-RAY DIFFRACTION	2
6C90	X-RAY DIFFRACTION	2.2
5LXY	X-RAY DIFFRACTION	2.85
7Z52	ELECTRON MICROSCOPY	3.4
7S7C	ELECTRON MICROSCOPY	3.62
7Z4Z	ELECTRON MICROSCOPY	4
7S7B	ELECTRON MICROSCOPY	4.06
7Z4Y	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6NZY4-F1	62.25	0.12

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 (13): 2, 342, 472, 479, 485, 492, 577, 598, 648, 649, 658, 695, 413

Mutagenesis-validated functional residues (13):

Position	Phenotype
295	impaired interaction with zcchc8; when associated with e-299.
299	impaired interaction with zcchc8; when associated with e-295.
309	reduced interaction with zcchc8; when associated with e-313.
313	reduced interaction with zcchc8; when associated with a-309.
492	impaired phosphorylation by gsk3.
662	does not alter rna helicase activity of next complex; when associated with k-666.
666	does not alter rna helicase activity of next complex; when associated with a-662.
673	does not affect rna helicase activity of next complex; when associated with a-675.
674	does not affect rna helicase activity of next complex; when associated with a-676.
675	does not affect rna helicase activity of next complex; when associated with a-673.
676	does not affect rna helicase activity of next complex; when associated with a-674.
688	loss of rna helicase activity of next complex; when associated with e-692.
692	loss of rna helicase activity of next complex; when associated with e-688.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9843970	Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex
R-HSA-9930044	Nuclear RNA decay

MSigDB gene sets: 189 (showing top): E2F_Q4, E2F_Q4_01, WANG_CLIM2_TARGETS_UP, E2F4DP1_01, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, E2F1DP1_01, E2F_Q3, E2F1DP2_01, GOBP_MRNA_3_END_PROCESSING, GOBP_RNA_SPLICING, GNF2_TDG, E2F1_Q3

GO Biological Process (7): mRNA splicing, via spliceosome (GO:0000398), RNA processing (GO:0006396), snRNA catabolic process (GO:0016076), mRNA 3’-end processing (GO:0031124), co-transcriptional lncRNA 3’ end processing, cleavage and polyadenylation pathway (GO:0180034), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (5): RNA binding (GO:0003723), zinc ion binding (GO:0008270), nucleic acid binding (GO:0003676), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), nuclear body (GO:0016604), TRAMP complex (GO:0031499), catalytic step 2 spliceosome (GO:0071013), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Regulation of endogenous retroelements	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA processing	2
RNA processing	2
binding	2
nuclear protein-containing complex	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA catabolic process	1
snRNA metabolic process	1
RNA 3’-end processing	1
co-transcriptional RNA 3’-end processing, cleavage and polyadenylation pathway	1
lncRNA processing	1
mRNA metabolic process	1
nucleic acid binding	1
transition metal ion binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
ribonucleoprotein complex	1

Protein interactions and networks

STRING

1502 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZCCHC8	RBM7	Q9Y580	998
ZCCHC8	MTREX	P42285	997
ZCCHC8	ZFC3H1	O60293	812
ZCCHC8	ZCCHC7	Q8N3Z6	793
ZCCHC8	PABPN1	Q86U42	707
ZCCHC8	TENT4B	Q8NDF8	678
ZCCHC8	PHAX	Q9H814	653
ZCCHC8	EXOSC3	Q9NQT5	643
ZCCHC8	EXOSC10	Q01780	642
ZCCHC8	SRRT	Q9BXP5	633
ZCCHC8	NRDE2	Q9H7Z3	619
ZCCHC8	TENT4A	Q5XG87	612
ZCCHC8	DIS3	Q9Y2L1	611
ZCCHC8	GOPC	Q9HD26	608
ZCCHC8	EXOSC6	Q5RKV6	580

IntAct

178 interactions, top by confidence:

A	B	Type	Score
PPP2R2A	PPP2R1A	psi-mi:“MI:2364”(proximity)	0.970
ZCCHC8	RBM7	psi-mi:“MI:0915”(physical association)	0.890
ZCCHC8	RBM7	psi-mi:“MI:0407”(direct interaction)	0.890
RBM7	ZCCHC8	psi-mi:“MI:0915”(physical association)	0.890
RBM7	ZCCHC8	psi-mi:“MI:0914”(association)	0.890
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
EXOSC1	EXOSC10	psi-mi:“MI:0914”(association)	0.810
RBM7	SF3B2	psi-mi:“MI:0914”(association)	0.780
RBM11	ZCCHC8	psi-mi:“MI:0914”(association)	0.740
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
RBM7	MTREX	psi-mi:“MI:0914”(association)	0.730
RBM7	PPP2R1A	psi-mi:“MI:0914”(association)	0.730
MPHOSPH6	MTREX	psi-mi:“MI:0914”(association)	0.690
C1D	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640

BioGRID (223): ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), INPPL1 (Co-fractionation), RBM7 (Co-fractionation), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS), ZCCHC8 (Affinity Capture-MS)

ESM2 similar proteins: A0JMK9, A0JMT0, A0JMZ1, A1L3I5, A2BIL7, A6QLA6, A8DZJ1, A8PUI7, B0BLU1, B7ZD04, O13024, Q0IHP2, Q12495, Q12830, Q13111, Q1MTN9, Q1W1G1, Q24595, Q2YDJ0, Q32N93, Q3T8J9, Q4FZB7, Q535K8, Q5BKG8, Q5R1T0, Q5R789, Q65Z40, Q68F53, Q6DD45, Q6INS5, Q6NZY4, Q76FK4, Q7Z5K2, Q801E2, Q86BP6, Q8IYH5, Q8K298, Q8RWK8, Q8WML3, Q98TA5

Diamond homologs: P34656, Q2PE14, Q5F3D1, Q5R789, Q6DD45, Q6NZY4, Q9CYA6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 159 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
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	8	44.1×	2e-10
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	8	44.1×	2e-10
mRNA decay by 3’ to 5’ exoribonuclease	7	43.5×	6e-09
Nuclear RNA decay	16	42.9×	1e-20
KSRP (KHSRP) binds and destabilizes mRNA	7	38.6×	1e-08
ATF4 activates genes in response to endoplasmic reticulum stress	7	24.8×	4e-07
FGFR2 alternative splicing	5	18.4×	2e-04
mRNA 3’-end processing	10	17.1×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
maturation of 5.8S rRNA	5	37.6×	1e-05
RNA catabolic process	10	32.5×	1e-10
alternative mRNA splicing, via spliceosome	5	24.1×	9e-05
RNA processing	12	18.8×	5e-10
mRNA splicing, via spliceosome	20	13.1×	5e-14
translational initiation	5	12.8×	1e-03
regulation of alternative mRNA splicing, via spliceosome	7	12.2×	9e-05
negative regulation of translation	8	11.2×	4e-05

Disease & clinical

Cancer significance

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

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	287
Likely benign	175
Benign	11

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
3244353	NC_000012.11:g.(?121416034)(122985387_?)del	Pathogenic
694674	NM_017612.5(ZCCHC8):c.557C>T (p.Pro186Leu)	Pathogenic
2626809	NM_017612.5(ZCCHC8):c.337G>A (p.Glu113Lys)	Likely pathogenic
2626811	NM_017612.5(ZCCHC8):c.508G>C (p.Gly170Arg)	Likely pathogenic
2626812	NM_017612.5(ZCCHC8):c.551G>A (p.Gly184Glu)	Likely pathogenic

SpliceAI

1886 predictions. Top by Δscore:

Variant	Effect	Δscore
12:122477836:CCTA:C	donor_loss	1.0000
12:122477955:CTGG:C	acceptor_gain	1.0000
12:122477956:TGG:T	acceptor_gain	1.0000
12:122477957:GG:G	acceptor_gain	1.0000
12:122477959:C:CC	acceptor_gain	1.0000
12:122477959:C:T	acceptor_loss	1.0000
12:122477960:T:C	acceptor_loss	1.0000
12:122478205:CCG:C	donor_gain	1.0000
12:122480184:ACTT:A	donor_loss	1.0000
12:122480186:TTACG:T	donor_loss	1.0000
12:122480187:TA:T	donor_loss	1.0000
12:122480188:A:AC	donor_gain	1.0000
12:122480188:A:C	donor_loss	1.0000
12:122480188:ACGT:A	donor_gain	1.0000
12:122480189:C:CG	donor_gain	1.0000
12:122480189:CG:C	donor_gain	1.0000
12:122480189:CGT:C	donor_gain	1.0000
12:122480189:CGTC:C	donor_gain	1.0000
12:122480189:CGTCT:C	donor_gain	1.0000
12:122480307:GCCAT:G	acceptor_gain	1.0000
12:122480308:CCAT:C	acceptor_gain	1.0000
12:122480308:CCATC:C	acceptor_gain	1.0000
12:122480309:CAT:C	acceptor_gain	1.0000
12:122480309:CATC:C	acceptor_gain	1.0000
12:122480311:TC:T	acceptor_loss	1.0000
12:122480312:C:CC	acceptor_gain	1.0000
12:122480312:C:CG	acceptor_loss	1.0000
12:122480313:T:C	acceptor_loss	1.0000
12:122480315:T:C	acceptor_gain	1.0000
12:122480315:T:TC	acceptor_gain	1.0000

AlphaMissense

4688 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:122481600:G:T	R314S	1.000
12:122481656:A:G	L295P	1.000
12:122480217:A:C	N371K	0.999
12:122480217:A:T	N371K	0.999
12:122480220:A:C	F370L	0.999
12:122480220:A:T	F370L	0.999
12:122480221:A:G	F370S	0.999
12:122480222:A:G	F370L	0.999
12:122480224:C:T	G369D	0.999
12:122480231:A:C	Y367D	0.999
12:122481572:A:G	L323P	0.999
12:122481576:A:G	W322R	0.999
12:122481576:A:T	W322R	0.999
12:122481599:C:G	R314P	0.999
12:122481602:A:C	M313R	0.999
12:122481602:A:G	M313T	0.999
12:122481644:A:G	L299P	0.999
12:122481648:C:G	A298P	0.999
12:122482055:T:A	R255S	0.999
12:122482055:T:G	R255S	0.999
12:122482056:C:G	R255T	0.999
12:122482642:C:G	C242S	0.999
12:122482643:A:G	C242R	0.999
12:122482643:A:T	C242S	0.999
12:122482674:A:C	N231K	0.999
12:122482674:A:T	N231K	0.999
12:122482677:G:C	F230L	0.999
12:122482677:G:T	F230L	0.999
12:122482679:A:G	F230L	0.999
12:122482680:A:C	C229W	0.999

dbSNP variants (sampled 300 via entrez): RS1000032012 (12:122478462 A>C), RS1000244126 (12:122490788 C>A,T), RS1000520311 (12:122497430 T>G), RS1000882888 (12:122493165 C>G), RS1001161611 (12:122499894 C>A), RS1001217756 (12:122492964 G>A), RS1001401369 (12:122496948 C>T), RS1001671414 (12:122474719 G>A), RS1001727264 (12:122471764 T>C), RS1001822149 (12:122482863 A>G), RS1001831413 (12:122496588 C>T), RS1001868640 (12:122491443 C>A,T), RS1001874718 (12:122484335 C>T), RS1001960660 (12:122472203 A>T), RS1002074908 (12:122472047 T>C)

Disease associations

OMIM: gene MIM:616381 | disease phenotypes: MIM:127550, MIM:618674

GenCC curated gene-disease

Disease	Classification	Inheritance
pulmonary fibrosis and/or bone marrow failure, telomere-related	Strong	Autosomal dominant
intellectual disability	Limited	Autosomal recessive
pulmonary fibrosis and/or bone marrow failure, telomere-related, 5	Limited	Unknown
neurodevelopmental disorder	Refuted Evidence	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
pulmonary fibrosis and/or bone marrow failure, telomere-related, 5	Moderate	AD

Mondo (7): dyskeratosis congenita (MONDO:0015780), pulmonary fibrosis and/or bone marrow failure, telomere-related, 5 (MONDO:0032865), inherited aplastic anemia (MONDO:0001713), inherited acute myeloid leukemia (MONDO:0017893), intellectual disability (MONDO:0001071), pulmonary fibrosis and/or bone marrow failure, telomere-related (MONDO:0000148), neurodevelopmental disorder (MONDO:0700092)

Orphanet (4): Dyskeratosis congenita (Orphanet:1775), Rare constitutional aplastic anemia (Orphanet:68383), Inherited acute myeloid leukemia (Orphanet:319465), Hereditary isolated aplastic anemia (Orphanet:397692)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0002206	Pulmonary fibrosis
HP:0005528	Bone marrow hypocellularity
HP:0031413	Short telomere length

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST007576_396	Chronotype	7.000000e-08
GCST012227_562	Hip circumference adjusted for BMI	3.000000e-09
GCST90020024_241	A body shape index	5.000000e-19
GCST90020024_242	A body shape index	3.000000e-10
GCST90020025_116	Waist-to-hip ratio adjusted for BMI	7.000000e-30
GCST90020027_1194	Waist-hip index	3.000000e-29
GCST90020027_1195	Waist-hip index	7.000000e-12
GCST90020029_469	Waist circumference adjusted for body mass index	6.000000e-11
GCST90020029_470	Waist circumference adjusted for body mass index	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D029502	Anemia, Hypoplastic, Congenital	C15.378.050.085.080; C15.378.190.223.500.500; C16.320.077
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
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067358 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
bisphenol A	increases methylation	1
trichostatin A	affects expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
abrine	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Diuron	decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Naphthoquinones	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5653010	Binding	Binding affinity to human ZCCHC8 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9VZ	Ubigene HEK293 ZCCHC8 KO	Transformed cell line	Female
CVCL_TY61	HAP1 ZCCHC8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills