NUF2

Summary

NUF2 (NUF2 component of NDC80 kinetochore complex, HGNC:14621) is a protein-coding gene on chromosome 1q23.3, encoding Kinetochore protein Nuf2 (Q9BZD4). Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity. It is a common-essential gene (DepMap: required in 99.0% of cancer cell lines).

This gene encodes a protein that is highly similar to yeast Nuf2, a component of a conserved protein complex associated with the centromere. Yeast Nuf2 disappears from the centromere during meiotic prophase when centromeres lose their connection to the spindle pole body, and plays a regulatory role in chromosome segregation. The encoded protein is found to be associated with centromeres of mitotic HeLa cells, which suggests that this protein is a functional homolog of yeast Nuf2. Alternatively spliced transcript variants that encode the same protein have been described.

Source: NCBI Gene 83540 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 84 total — 1 pathogenic
• Phenotypes (HPO): 1
• Cancer dependency (DepMap): dependent in 99.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_145697

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14621
Approved symbol	NUF2
Name	NUF2 component of NDC80 kinetochore complex
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	NUF2R, CT106
Ensembl gene	ENSG00000143228
Ensembl biotype	protein_coding
OMIM	611772
Entrez	83540

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000271452, ENST00000367900, ENST00000442820, ENST00000450453, ENST00000487578, ENST00000490881, ENST00000497990, ENST00000524800, ENST00000527120, ENST00000527439, ENST00000531529, ENST00000534289, ENST00000911837, ENST00000911838, ENST00000911839, ENST00000911840, ENST00000911841

RefSeq mRNA: 2 — MANE Select: NM_145697 NM_031423, NM_145697

CCDS: CCDS1245

Canonical transcript exons

ENST00000271452 — 14 exons

Exon	Start	End
ENSE00000958767	163345678	163345818
ENSE00000958768	163347763	163347938
ENSE00000958769	163348945	163349080
ENSE00001289121	163321954	163322212
ENSE00003465053	163328846	163328907
ENSE00003483337	163326032	163326174
ENSE00003520402	163328228	163328304
ENSE00003529499	163340364	163340426
ENSE00003611410	163327488	163327562
ENSE00003637453	163338020	163338093
ENSE00003689272	163343733	163343870
ENSE00003784955	163339381	163339477
ENSE00003791595	163336751	163336848
ENSE00003843838	163355335	163355759

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 97.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.9970 / max 319.1302, expressed in 1393 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6344	11.2814	1272
6345	5.3224	1076
6343	0.3932	248

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.10	gold quality
ganglionic eminence	UBERON:0004023	93.35	gold quality
embryo	UBERON:0000922	93.34	gold quality
thymus	UBERON:0002370	90.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.95	gold quality
right testis	UBERON:0004534	90.72	gold quality
left testis	UBERON:0004533	90.63	gold quality
testis	UBERON:0000473	89.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.39	gold quality
sperm	CL:0000019	89.20	gold quality
bone marrow	UBERON:0002371	86.01	gold quality
trabecular bone tissue	UBERON:0002483	84.97	gold quality
secondary oocyte	CL:0000655	82.27	gold quality
adrenal tissue	UBERON:0018303	81.30	gold quality
rectum	UBERON:0001052	80.18	gold quality
bone marrow cell	CL:0002092	79.90	gold quality
vermiform appendix	UBERON:0001154	79.43	gold quality
esophagus mucosa	UBERON:0002469	78.76	gold quality
mucosa of transverse colon	UBERON:0004991	78.07	gold quality
lower esophagus mucosa	UBERON:0035834	77.66	gold quality
stromal cell of endometrium	CL:0002255	77.62	gold quality
lymph node	UBERON:0000029	77.03	gold quality
gingival epithelium	UBERON:0001949	73.33	silver quality
epithelium of nasopharynx	UBERON:0001951	72.95	gold quality
tonsil	UBERON:0002372	72.63	gold quality
oral cavity	UBERON:0000167	72.46	gold quality
duodenum	UBERON:0002114	72.33	gold quality
caecum	UBERON:0001153	72.24	gold quality
oocyte	CL:0000023	72.12	gold quality
spleen	UBERON:0002106	71.39	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-79	yes	522.66
E-MTAB-6819	yes	254.51
E-HCAD-10	yes	36.91
E-MTAB-6678	yes	8.41
E-ANND-3	yes	4.28

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CDR2

miRNA regulators (miRDB)

24 targeting NUF2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-606	98.72	67.34	960
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-7843-3P	98.31	67.94	803
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-4693-3P	95.23	65.92	735

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 34)

• Data highlight a specific role for hNuf2 in kinetochore-microtubule attachment and suggest that hNuf2 is part of a molecular linker between the kinetochore attachment site and tubulin subunits within the lattice of attached plus ends. (PMID:12438418)
• NUF2 is a core component of the kinetochore outer plate essential for organizing microtubule attachment sites. (PMID:15548592)
• the Spc24, Spc25, Nuf2, and Ndc80/Hec1 complex is a faithful copy of the endogenous Ndc80 complex (PMID:15961401)
• HsNUF2 and CENP-E are required for organization of stable microtubule-kinetochore attachment that is essential for faithful chromosome segregation in mitosis (PMID:17535814)
• CDCA1 may therefore be an ideal tumor-associated antigen useful for the diagnosis and immunotherapy of these cancer (PMID:18770861)
• alternative splicing variants, M-RIP, HYAL2, CDCA1, and MSMB genes showed differential expressions between cancer cells and corresponding normal tissues. (PMID:19081476)
• Chromosome congression in HSET + hNuf2 co-depleted cells required the plus-end directed motor CENP-E , which has been implicated in the gliding of mono-oriented kinetochores alongside adjacent K-fibres. (PMID:19525938)
• cell growths of colorectal and gastric cancers after the siRNA-mediated knockdown of either CDCA1 or KNTC2 were significantly suppressed. (PMID:19878654)
• These data suggest that the CH and tail domains of Hec1 generate essential contacts between kinetochores and microtubules in cells, whereas the Nuf2 CH domain does not. (PMID:21270439)
• NDC80, NUF2 and PTN were significantly aberrantly overexpressed in serous adenocarcinomas. (PMID:23056589)
• these findings demonstrated that three buried glutamic acid-lysine pairs, in concert with hydrophobic interactions of core residues, provide the major specificity and stability requirements for Hec1-Nuf2 dimerization (PMID:24129578)
• These results suggest that CDCA1 could be a prognostic biomarker and a potential therapeutic target for colorectal cancers . (PMID:24247253)
• NUF2 plays a critical role in the regulation of HCC cell proliferation and apoptosis. (PMID:25374179)
• NUF2 was overexpressed in glioma tissues and differentially expressed in a series of glioma cell lines. Depletion of NUF2 by short-hairpin RNA inhibited cell growth in vitro and in vivo. (PMID:25481014)
• hnRNP K binds to the promoter region of NUF2 and activates its transcription. (PMID:25701787)
• found LncRNA AF339813 was positively regulated by NUF2 (PMID:26045769)
• NUF2 modulates cell proliferation via cell cycle control in osteosarcoma Saos-2 cells. (PMID:27049259)
• CDCA1 could be a prognostic marker in malignant melanoma patients. (PMID:27237743)
• Results provide evidence that CDCA1 plays a significant role in oral cavity carcinoma (OCC) tumorigenesis. Importantly, CDCA1 is associated with growth and survival of OCC cells where its elevated expression issignificantly associated with poor prognosis . (PMID:27499128)
• NUF2 was identified to be the minimal biomarker sufficient to discriminate ER tumors from LR tumors. NUF2 in combination with liver cirrhosis could significantly improve the detection of ER tumors with an AUROC of 0.82 and 0.85 in the test and validation cohort, respectively. (PMID:30653265)
• NUF2 gene is overexpressed in breast cancer, and its expression level is important in predicting the prognosis of breast cancer. (PMID:31140425)
• A Gene Set Enrichment Analysis indicated that NUF2 may regulate breast carcinogenesis and progression via cell cyclerelated pathways. (PMID:31198978)
• NUF2 as an anticancer therapeutic target and prognostic factor in breast cancer. (PMID:33173994)
• Correlation of NUF2 Overexpression with Poorer Patient Survival in Multiple Cancers. (PMID:33421974)
• Poly-SUMO-2/3 chain modification of Nuf2 facilitates CENP-E kinetochore localization and chromosome congression during mitosis. (PMID:33910471)
• NUF2 Is a Potential Immunological and Prognostic Marker for Non-Small-Cell Lung Cancer. (PMID:35600043)
• ANP32E contributes to gastric cancer progression via NUF2 upregulation. (PMID:35795988)
• NUF2 Drives Clear Cell Renal Cell Carcinoma by Activating HMGA2 Transcription through KDM2A-mediated H3K36me2 Demethylation. (PMID:35813477)
• NUF2 promotes tumorigenesis by interacting with HNRNPA2B1 via PI3K/AKT/mTOR pathway in ovarian cancer. (PMID:36670423)
• NUF2 Promotes Breast Cancer Development as a New Tumor Stem Cell Indicator. (PMID:36835637)
• NUF2 Drives Cholangiocarcinoma Progression and Migration via Inhibiting Autophagic Degradation of TFR1. (PMID:37056930)
• NUF2 is correlated with a poor prognosis and immune infiltration in clear cell renal cell carcinoma. (PMID:37138262)
• FOXM1 promotes neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor progression in a NUF2-dependent manner. (PMID:37488294)
• Maintenance of magnesium homeostasis by NUF2 promotes protein synthesis and anaplastic thyroid cancer progression. (PMID:39242581)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nuf2	ENSDARG00000034624
mus_musculus	Nuf2	ENSMUSG00000026683
rattus_norvegicus	Nuf2	ENSRNOG00000002711

Paralogs (1): TMEM259 (ENSG00000182087)

Protein

Protein identifiers

Kinetochore protein Nuf2 — Q9BZD4 (reviewed: Q9BZD4)

Alternative names: Cell division cycle-associated protein 1

All UniProt accessions (6): Q9BZD4, B1AQT3, B1AQT4, E9PKH1, E9PP32, E9PQC4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity. Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore. The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules.

Subunit / interactions. Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end. May interact with AURKB/Aurora-B. Directly interacts with CENPE; this interaction determines CENPE kinetochore localization.

Subcellular location. Nucleus. Chromosome. Centromere. Kinetochore.

Post-translational modifications. Can be phosphorylated by AURKA and AURKB.

Similarity. Belongs to the NUF2 family.

RefSeq proteins (2): NP_113611, NP_663735* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005549	Kinetochore_Nuf2_N	Domain
IPR038275	Nuf2_N_sf	Homologous_superfamily

Pfam: PF03800

UniProt features (23 total): helix 11, modified residue 3, region of interest 2, coiled-coil region 2, sequence variant 2, chain 1, strand 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8G0P	X-RAY DIFFRACTION	2
2VE7	X-RAY DIFFRACTION	2.88
9N9G	ELECTRON MICROSCOPY	3
3IZ0	ELECTRON MICROSCOPY	8.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZD4-F1	89.67	0.73

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 (3): 1, 171, 247

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation

MSigDB gene sets: 340 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_CHROMOSOME_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DARWICHE_SKIN_TUMOR_PROMOTER_UP, GOBP_CHROMOSOME_SEPARATION, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN

GO Biological Process (8): mitotic spindle organization (GO:0007052), chromosome segregation (GO:0007059), mitotic spindle assembly checkpoint signaling (GO:0007094), attachment of spindle microtubules to kinetochore (GO:0008608), meiotic chromosome segregation (GO:0045132), cell division (GO:0051301), attachment of mitotic spindle microtubules to kinetochore (GO:0051315), kinetochore organization (GO:0051383)

GO Molecular Function (3): microtubule binding (GO:0008017), protein-containing complex binding (GO:0044877), protein binding (GO:0005515)

GO Cellular Component (9): kinetochore (GO:0000776), outer kinetochore (GO:0000940), nucleoplasm (GO:0005654), cytosol (GO:0005829), membrane (GO:0016020), Ndc80 complex (GO:0031262), chromosome, centromeric region (GO:0000775), nucleus (GO:0005634), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Mitotic Prometaphase	2
Amplification of signal from the kinetochores	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
M Phase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
mitotic cell cycle	2
cell cycle process	2
binding	2
intracellular membraneless organelle	2
protein-containing complex	2
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
microtubule binding	1
metaphase chromosome alignment	1
nuclear chromosome segregation	1
meiotic nuclear division	1
meiotic cell cycle process	1
cellular process	1
mitotic metaphase chromosome alignment	1
attachment of spindle microtubules to kinetochore	1
mitotic cell cycle process	1
chromosome organization	1
tubulin binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
kinetochore	1
nuclear lumen	1
cytoplasm	1
outer kinetochore	1
chromosomal region	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUF2	SPC24	Q8NBT2	999
NUF2	NDC80	O14777	998
NUF2	CENPE	Q02224	958
NUF2	SPC25	Q9HBM1	947
NUF2	CENPH	Q9H3R5	932
NUF2	CENPA	P49450	837
NUF2	AURKB	Q96GD4	835
NUF2	KNL1	Q8NG31	823
NUF2	CENPC	Q03188	819
NUF2	DSN1	Q9H410	806
NUF2	CENPI	Q92674	788
NUF2	MIS12	Q9H081	767
NUF2	BUB1	O43683	758
NUF2	CDC20	Q12834	752
NUF2	SKA1	Q96BD8	741

IntAct

138 interactions, top by confidence:

A	B	Type	Score
NDC80	NUF2	psi-mi:“MI:0915”(physical association)	0.950
NUF2	NDC80	psi-mi:“MI:0915”(physical association)	0.950
NUF2	NDC80	psi-mi:“MI:0914”(association)	0.950
ZWINT	NDC80	psi-mi:“MI:0914”(association)	0.940
SPC25	NDC80	psi-mi:“MI:0914”(association)	0.940
NDC80	SPC24	psi-mi:“MI:0915”(physical association)	0.920
NDC80	SPC24	psi-mi:“MI:0914”(association)	0.920
SPC24	NDC80	psi-mi:“MI:0914”(association)	0.920
MIS12	NDC80	psi-mi:“MI:0914”(association)	0.850
DSN1	NDC80	psi-mi:“MI:0914”(association)	0.790
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740

BioGRID (199): NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Affinity Capture-MS), NUF2 (Proximity Label-MS), INPP5B (Affinity Capture-MS), MYBL2 (Affinity Capture-MS), SP100 (Affinity Capture-MS), CTDP1 (Affinity Capture-MS), PPIG (Affinity Capture-MS), NDC80 (Affinity Capture-MS)

ESM2 similar proteins: A7RNG8, A7RX34, A7SK48, A9ULY7, B0WTU5, B6MFW3, F1QRC1, M1V4Y8, O14777, O35594, P83829, Q16VW9, Q17QH9, Q28G12, Q28HX4, Q4R630, Q4R6Y7, Q4R8Y5, Q4V909, Q4WVA0, Q567U6, Q5BH14, Q5BJT7, Q5TZ80, Q5U4X5, Q5ZJ27, Q5ZKI4, Q640U7, Q68RJ5, Q6AYJ5, Q6DRJ7, Q6GQI5, Q6IVW0, Q6NRB0, Q6PA15, Q76I89, Q76I90, Q7TQK5, Q7ZVC2, Q8BIL5

Diamond homologs: Q6AYL9, Q6FNH8, Q6GQ71, Q76I90, Q7ZW63, Q8AWF4, Q99P69, Q9BZD4, Q5BH14, Q4WVA0, Q7S9H0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CDR2	“up-regulates quantity by expression”	NUF2	“transcriptional regulation”
NUF2	“form complex”	“Ndc80 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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
Amplification of signal from the kinetochores	9	26.9×	2e-09
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	14	24.7×	4e-14
Mitotic Spindle Checkpoint	9	21.6×	1e-08
Resolution of Sister Chromatid Cohesion	16	21.0×	7e-15
EML4 and NUDC in mitotic spindle formation	14	19.7×	6e-13
RHO GTPases Activate Formins	14	16.5×	5e-12
Mitotic Prometaphase	15	15.7×	1e-12
Separation of Sister Chromatids	16	14.7×	6e-13

GO biological processes:

GO term	Partners	Fold	FDR
attachment of spindle microtubules to kinetochore	8	80.5×	8e-12
attachment of mitotic spindle microtubules to kinetochore	5	56.6×	2e-06
mitotic spindle assembly checkpoint signaling	7	42.3×	3e-08
mitotic sister chromatid segregation	7	36.2×	9e-08
chromosome segregation	10	18.7×	3e-08
mitotic spindle organization	5	14.6×	2e-03
cell division	21	10.4×	3e-13

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
992629	NM_145697.3(NUF2):c.371T>G (p.Ile124Ser)	Pathogenic

SpliceAI

2189 predictions. Top by Δscore:

Variant	Effect	Δscore
1:163324803:TGTCA:T	donor_gain	1.0000
1:163324804:GTCAG:G	donor_gain	1.0000
1:163326030:A:AG	acceptor_gain	1.0000
1:163326031:G:GG	acceptor_gain	1.0000
1:163326172:AAG:A	donor_loss	1.0000
1:163326175:G:GA	donor_loss	1.0000
1:163326176:T:G	donor_loss	1.0000
1:163327486:A:AG	acceptor_gain	1.0000
1:163327487:G:GG	acceptor_gain	1.0000
1:163328305:G:GG	donor_gain	1.0000
1:163336842:GCAA:G	donor_gain	1.0000
1:163336849:G:GG	donor_gain	1.0000
1:163338094:G:GG	donor_gain	1.0000
1:163340360:TTA:T	acceptor_loss	1.0000
1:163340362:A:AG	acceptor_gain	1.0000
1:163340362:A:AT	acceptor_loss	1.0000
1:163340363:G:A	acceptor_loss	1.0000
1:163340363:G:GG	acceptor_gain	1.0000
1:163340363:GAT:G	acceptor_gain	1.0000
1:163340363:GATA:G	acceptor_gain	1.0000
1:163343729:ACAG:A	acceptor_loss	1.0000
1:163343730:CA:C	acceptor_loss	1.0000
1:163343731:A:AG	acceptor_gain	1.0000
1:163343731:AGAAT:A	acceptor_gain	1.0000
1:163343732:G:GC	acceptor_gain	1.0000
1:163343732:GA:G	acceptor_gain	1.0000
1:163343732:GAA:G	acceptor_gain	1.0000
1:163343732:GAAT:G	acceptor_gain	1.0000
1:163343732:GAATG:G	acceptor_gain	1.0000
1:163343848:TCCAG:T	donor_gain	1.0000

AlphaMissense

3091 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:163336777:A:C	S122R	0.993
1:163336779:T:A	S122R	0.993
1:163336779:T:G	S122R	0.993
1:163336791:C:A	N126K	0.990
1:163336791:C:G	N126K	0.990
1:163326067:T:C	F6L	0.989
1:163326069:C:A	F6L	0.989
1:163326069:C:G	F6L	0.989
1:163328865:T:C	C99R	0.989
1:163336801:T:C	F130L	0.985
1:163336803:C:A	F130L	0.985
1:163336803:C:G	F130L	0.985
1:163336781:G:A	G123D	0.982
1:163328867:C:G	C99W	0.976
1:163336792:T:C	F127L	0.976
1:163336794:T:A	F127L	0.976
1:163336794:T:G	F127L	0.976
1:163328866:G:A	C99Y	0.974
1:163336793:T:C	F127S	0.970
1:163336802:T:C	F130S	0.964
1:163326068:T:C	F6S	0.963
1:163336780:G:C	G123R	0.963
1:163336775:T:C	L121S	0.962
1:163336778:G:T	S122I	0.962
1:163326119:T:C	L23S	0.960
1:163328304:T:C	L92P	0.958
1:163326107:G:C	R19P	0.957
1:163336760:G:C	R116P	0.957
1:163328854:T:C	F95S	0.956
1:163327509:T:G	Y49D	0.953

dbSNP variants (sampled 300 via entrez): RS1000005992 (1:163351337 A>G), RS1000035427 (1:163351635 A>T), RS1000082276 (1:163350839 G>C), RS1000150982 (1:163350079 A>G), RS1000173011 (1:163322079 G>A), RS1000265040 (1:163324537 A>G), RS1000423177 (1:163331188 T>C), RS1000497986 (1:163325532 A>G,T), RS1000498184 (1:163356180 C>A), RS1000817141 (1:163340017 G>A), RS1000858928 (1:163331433 G>A,T), RS1000992799 (1:163346883 A>G), RS1001037481 (1:163350172 G>A), RS1001234996 (1:163322693 C>A,G,T), RS1001257499 (1:163350455 A>T)

Disease associations

OMIM: gene MIM:611772 | disease phenotypes: MIM:194190

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (3): Wolf-Hirschhorn syndrome (MONDO:0008684), microcephaly (MONDO:0001149), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (1): Wolf-Hirschhorn syndrome (Orphanet:280)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002351_7	Chronic obstructive pulmonary disease (moderate to severe)	5.000000e-07
GCST003997_32	Myopia	3.000000e-19
GCST005212_19	Asthma	9.000000e-06
GCST007538_1	Cellular nuclear factor (erythroid-derived 2)-like 2 levels	3.000000e-07
GCST007637_6	Diffusing capacity of carbon monoxide	3.000000e-06
GCST008163_553	Height	4.000000e-08
GCST012465_58	Bipolar disorder	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009794	NRF2 measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D054877	Wolf-Hirschhorn Syndrome	C16.131.077.944; C16.131.260.985; C16.320.180.985

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	3
Aflatoxin B1	affects expression, decreases expression, decreases methylation	3
propionaldehyde	decreases expression, increases methylation	2
Acetaminophen	increases expression, decreases expression	2
Estradiol	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
nonanal	increases methylation	1
n-hexanal	increases methylation	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases methylation	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
cupric oxide	decreases expression	1
caprylic aldehyde	increases methylation	1
diallyl trisulfide	decreases expression	1
M-VAC protocol	increases response to substance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
pentanal	increases methylation	1
heptanal	increases methylation	1
CGP 52608	affects binding, increases reaction	1
deguelin	increases expression	1
2-palmitoylglycerol	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.