SMC4

Summary

SMC4 (structural maintenance of chromosomes 4, HGNC:14013) is a protein-coding gene on chromosome 3q25.33, encoding Structural maintenance of chromosomes protein 4 (Q9NTJ3). Central component of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. It is a common-essential gene (DepMap: required in 99.4% of cancer cell lines).

This gene belongs to the ‘structural maintenance of chromosomes’ (SMC) gene family. Members of this gene family play a role in two changes in chromosome structure during mitotic segregation of chromosomes- chromosome condensation and sister chromatid cohesion. The protein encoded by this gene is likely a subunit of the 13S condensin complex, which is involved in chromosome condensation. A pseudogene related to this gene is located on chromosome 2.

Source: NCBI Gene 10051 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 170 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_001002800

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14013
Approved symbol	SMC4
Name	structural maintenance of chromosomes 4
Location	3q25.33
Locus type	gene with protein product
Status	Approved
Aliases	hCAP-C, CAP-C
Ensembl gene	ENSG00000113810
Ensembl biotype	protein_coding
OMIM	605575
Entrez	10051

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 16 protein_coding, 9 retained_intron, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000344722, ENST00000357388, ENST00000462668, ENST00000462787, ENST00000465563, ENST00000465903, ENST00000467263, ENST00000467468, ENST00000468653, ENST00000469762, ENST00000469858, ENST00000470240, ENST00000472282, ENST00000472991, ENST00000484799, ENST00000485645, ENST00000485867, ENST00000486711, ENST00000487747, ENST00000488017, ENST00000489573, ENST00000490207, ENST00000493695, ENST00000494612, ENST00000497203, ENST00000497311, ENST00000497984, ENST00000937685, ENST00000937686, ENST00000937687, ENST00000937688

RefSeq mRNA: 3 — MANE Select: NM_001002800 NM_001002800, NM_001288753, NM_005496

CCDS: CCDS3189, CCDS75046

Canonical transcript exons

ENST00000357388 — 24 exons

Exon	Start	End
ENSE00001860968	160433657	160434953
ENSE00001903917	160399650	160399749
ENSE00003467954	160426074	160426200
ENSE00003469344	160430599	160430743
ENSE00003484125	160416251	160416415
ENSE00003492279	160431032	160431205
ENSE00003498711	160400822	160400965
ENSE00003509821	160420740	160420901
ENSE00003509918	160411920	160412084
ENSE00003518573	160428753	160428942
ENSE00003527231	160401915	160402093
ENSE00003551775	160419358	160419543
ENSE00003565103	160412326	160412453
ENSE00003575633	160413473	160413613
ENSE00003582862	160424867	160425019
ENSE00003605730	160431643	160431825
ENSE00003632193	160423425	160423650
ENSE00003638493	160433026	160433209
ENSE00003641104	160414367	160414517
ENSE00003647077	160432283	160432515
ENSE00003656132	160417723	160417956
ENSE00003671742	160423761	160423840
ENSE00003786876	160404328	160404504
ENSE00003789809	160402676	160402867

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.1794 / max 576.1547, expressed in 1804 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39579	28.8612	1791
39580	1.0875	555
39586	0.7373	345
39583	0.6931	354
39578	0.5804	316
39581	0.5392	287
39582	0.4994	271
39577	0.4733	283
39584	0.3594	161
39585	0.3485	176

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.28	gold quality
ganglionic eminence	UBERON:0004023	98.12	gold quality
embryo	UBERON:0000922	97.59	gold quality
trabecular bone tissue	UBERON:0002483	96.89	gold quality
lower esophagus mucosa	UBERON:0035834	96.81	gold quality
adrenal tissue	UBERON:0018303	96.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.37	gold quality
bone marrow cell	CL:0002092	96.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.09	gold quality
bone marrow	UBERON:0002371	95.82	gold quality
right testis	UBERON:0004534	94.77	gold quality
calcaneal tendon	UBERON:0003701	94.76	gold quality
esophagus mucosa	UBERON:0002469	94.59	gold quality
testis	UBERON:0000473	94.50	gold quality
esophagus squamous epithelium	UBERON:0006920	94.37	gold quality
left testis	UBERON:0004533	94.35	gold quality
right coronary artery	UBERON:0001625	94.00	gold quality
vermiform appendix	UBERON:0001154	93.95	gold quality
colonic epithelium	UBERON:0000397	93.94	gold quality
rectum	UBERON:0001052	93.45	gold quality
secondary oocyte	CL:0000655	93.39	gold quality
oral cavity	UBERON:0000167	93.31	gold quality
visceral pleura	UBERON:0002401	93.22	gold quality
epithelium of esophagus	UBERON:0001976	92.56	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.46	gold quality
oocyte	CL:0000023	92.23	gold quality
tonsil	UBERON:0002372	92.11	gold quality
pleura	UBERON:0000977	92.08	gold quality
colonic mucosa	UBERON:0000317	91.90	gold quality
sperm	CL:0000019	91.89	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	1849.33
E-MTAB-10485	yes	1214.35
E-CURD-112	yes	1179.91
E-GEOD-124472	yes	942.17
E-MTAB-8559	yes	752.13
E-HCAD-31	yes	731.70
E-HCAD-56	yes	533.97
E-HCAD-32	yes	503.37
E-MTAB-7052	yes	353.52
E-MTAB-6108	yes	351.90
E-HCAD-13	yes	340.43
E-MTAB-9154	yes	272.91
E-HCAD-1	yes	45.02
E-HCAD-10	yes	44.56
E-HCAD-5	yes	40.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

56 targeting SMC4, 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-433-3P	99.98	69.37	1203
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-7154-5P	99.69	70.52	1900
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-6807-3P	99.15	69.23	1275
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-4738-3P	98.98	67.98	1846

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• mutation analysis of hCAP-C & hCAP-E in leukemia-lymphoma cell lines including 8 pyothorax-associated lymphoma (PAL); 3 of 8 PAL cell lines have hCAP-C or hCAP-E heterozygous mutations, indicating condensin mutations are relatively frequent in PAL (PMID:17488335)
• SMC4 expression was significantly associated with tumor size, de-differentiation, advanced stages and vascular invasion of the primary liver cancers. (PMID:22842912)
• Results indicate that miR-124-5p may target the tumorigenesis gene, SMC4, which suggests that expression levels of miR-124-5p in plasma and FFPE samples. (PMID:25081869)
• Knockdown of SMC-4 expression significantly suppressed the proliferation. (PMID:25422241)
• analysis of functional differences of SMC2 and SMC4 hinge domain between condensins and cohesin in DNA recognition (PMID:26491021)
• Study examined the expression of SMC4 in acute myeloid leukemia (AML) pediatric patients cells and normal cells and revealed that SMC4 was significantly higher than control. Utilizing SMC4 gene knockdown in the established MLL-AF9 AML mouse model study found that SMC4 knockdown inhibited AML progression by maintaining leukemia stem cells. (PMID:29043883)
• this paper shows that condensin Smc4 promotes inflammatory innate immune response by epigenetically enhancing NEMO transcription (PMID:29803706)
• Study found that mRNA expression of SMC4 was upregulated in invasive breast cancer cells. Patients with high mRNA level of SMC4 suffered different survival with triple negative breast cancer (TNBC) and non-TNBC. These results suggest that SMC4 could be a good biomarker for predicting the prognosis. (PMID:31871499)
• MiR-433-3p restrains the proliferation, migration and invasion of glioma cells via targeting SMC4. (PMID:34147470)
• SMC4 knockdown inhibits malignant biological behaviors of endometrial cancer cells by regulation of FoxO1 activity. (PMID:34506757)
• Screening Differential CircRNAs Expression Profiles Reveals the Regulatory Role of the has_circTPT1_003-has-miR-218-5p-CCNE2/SMC4 Signaling Axis in Bladder Carcinoma Progression. (PMID:35005988)
• TREM-1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway. (PMID:36181338)
• Structural Maintenance of Chromosome Protein 4 Promotes the Progression of Cardia Adenocarcinoma via Regulation of the Wnt/beta-catenin Signaling Pathway. (PMID:37170988)
• FoxO1 promotes ovarian cancer by increasing transcription and METTL14-mediated m[6]A modification of SMC4. (PMID:38403332)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	smc4	ENSDARG00000038882
mus_musculus	Smc4	ENSMUSG00000034349
rattus_norvegicus	Smc4	ENSRNOG00000010274
drosophila_melanogaster	glu	FBGN0015391
caenorhabditis_elegans		WBGENE00001086
caenorhabditis_elegans		WBGENE00004874

Paralogs (7): SMC1A (ENSG00000072501), SMC1B (ENSG00000077935), SMC3 (ENSG00000108055), CKAP4 (ENSG00000136026), SMC2 (ENSG00000136824), CCDC122 (ENSG00000151773), CCDC157 (ENSG00000187860)

Protein

Protein identifiers

Structural maintenance of chromosomes protein 4 — Q9NTJ3 (reviewed: Q9NTJ3)

Alternative names: Chromosome-associated polypeptide C, XCAP-C homolog

All UniProt accessions (10): Q9NTJ3, C9IYK2, C9J578, C9J9E4, C9JJ64, C9JR83, C9JVD8, C9JWF0, E9PD53, F8WCB7

UniProt curated annotations — full annotation on UniProt →

Function. Central component of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases.

Subunit / interactions. Forms a heterodimer with SMC2. Component of the condensin complex, which contains the SMC2 and SMC4 heterodimer, and three non SMC subunits that probably regulate the complex: BRRN1/CAPH, CNAP1/CAPD2 and CAPG.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Tissue specificity. Widely expressed. Higher expression in testis, colon, thymus.

Domain organisation. The SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterodimerization with SMC2, forming a V-shaped heterodimer.

Similarity. Belongs to the SMC family. SMC4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NTJ3-1	1	yes
Q9NTJ3-2	2

RefSeq proteins (3): NP_001002800, NP_001275682, NP_005487 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003395	RecF/RecN/SMC_N	Domain
IPR010935	SMC_hinge	Domain
IPR024704	SMC	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036277	SMC_hinge_sf	Homologous_superfamily

Pfam: PF02463, PF06470

UniProt features (47 total): helix 11, modified residue 10, strand 8, sequence conflict 5, sequence variant 3, coiled-coil region 3, compositionally biased region 2, chain 1, domain 1, splice variant 1, region of interest 1, binding site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4U4P	X-RAY DIFFRACTION	1.89
9F5W	ELECTRON MICROSCOPY	7.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NTJ3-F1	81.93	0.20

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 (1): 113–120

Post-translational modifications (10): 28, 39, 41, 50, 143, 381, 679, 982, 1056, 22

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2514853	Condensation of Prometaphase Chromosomes
R-HSA-1640170	Cell Cycle
R-HSA-68875	Mitotic Prophase
R-HSA-68877	Mitotic Prometaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic

MSigDB gene sets: 456 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, VALK_AML_WITH_FLT3_ITD, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GNF2_MSH2, MULLIGHAN_NPM1_SIGNATURE_3_UP, TAATAAT_MIR126, WANG_CLIM2_TARGETS_UP, GNF2_CENPF, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCACTT_MIR519C_MIR519B_MIR519A, CROONQUIST_NRAS_SIGNALING_DN, GNF2_H2AFX

GO Biological Process (13): mitotic sister chromatid segregation (GO:0000070), mitotic chromosome condensation (GO:0007076), meiotic chromosome condensation (GO:0010032), meiotic chromosome segregation (GO:0045132), cell division (GO:0051301), kinetochore organization (GO:0051383), positive regulation of chromosome segregation (GO:0051984), positive regulation of chromosome separation (GO:1905820), positive regulation of chromosome condensation (GO:1905821), nuclear division (GO:0000280), chromosome condensation (GO:0030261), chromosome organization (GO:0051276), nuclear chromosome segregation (GO:0098813)

GO Molecular Function (6): chromatin binding (GO:0003682), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, centromeric region (GO:0000775), condensed nuclear chromosome (GO:0000794), condensin complex (GO:0000796), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), nuclear speck (GO:0016607), chromosome (GO:0005694), cytoplasm (GO:0005737), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
M Phase	2
Mitotic Prophase	1
Mitotic Prometaphase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromosome condensation	3
cellular anatomical structure	3
mitotic cell cycle process	2
chromosome organization	2
chromosome segregation	2
positive regulation of cell cycle process	2
binding	2
nucleus	2
sister chromatid segregation	1
mitotic nuclear division	1
mitotic sister chromatid segregation	1
mitotic cell cycle	1
meiotic cell cycle	1
chromosome organization involved in meiotic cell cycle	1
nuclear chromosome segregation	1
meiotic nuclear division	1
meiotic cell cycle process	1
cellular process	1
regulation of chromosome segregation	1
chromosome separation	1
regulation of chromosome separation	1
regulation of chromosome condensation	1
positive regulation of chromosome organization	1
organelle fission	1
organelle organization	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
chromosomal region	1
nuclear chromosome	1
condensed chromosome	1
chromosome	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

3560 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMC4	NCAPD2	Q15021	998
SMC4	NCAPH	Q15003	996
SMC4	NCAPG	Q9BPX3	996
SMC4	NCAPD3	P42695	993
SMC4	NCAPG2	Q86XI2	990
SMC4	SMC2	O95347	978
SMC4	NCAPH2	Q6IBW4	978
SMC4	RAD21	O60216	903
SMC4	POU3F3	P20264	811
SMC4	SMC6	Q96SB8	758
SMC4	AURKB	Q96GD4	755
SMC4	SMC5	Q8IY18	744
SMC4	SMC3	Q9UQE7	705
SMC4	CENPE	Q02224	694
SMC4	TOP2A	P11388	653

IntAct

160 interactions, top by confidence:

A	B	Type	Score
NCAPH	NCAPG	psi-mi:“MI:0915”(physical association)	0.780
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PKMYT1	CCNB2	psi-mi:“MI:0914”(association)	0.730
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
NCAPH	SMC4	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SMC4	SMC2	psi-mi:“MI:0915”(physical association)	0.690
SMC2	SMC4	psi-mi:“MI:0915”(physical association)	0.690
NCAPH2	NCAPG2	psi-mi:“MI:0915”(physical association)	0.640
IFT22	IFT56	psi-mi:“MI:0914”(association)	0.640
SMC4	NCAPH2	psi-mi:“MI:0915”(physical association)	0.640
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
DPEP1	ILVBL	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
VAV1	SMC4	psi-mi:“MI:0915”(physical association)	0.400
MGAM2	SMC4	psi-mi:“MI:0915”(physical association)	0.400
SMC4	SPTAN1	psi-mi:“MI:0915”(physical association)	0.400
NCAPH	SCAMP2	psi-mi:“MI:0914”(association)	0.350
Ncaph	ATP5MF-PTCD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (400): SMC4 (Affinity Capture-MS), SMC4 (Affinity Capture-MS), SMC4 (Affinity Capture-MS), SMC4 (Affinity Capture-MS), SMC4 (Affinity Capture-MS), KIF2C (Co-fractionation), NCAPH (Co-fractionation), SMC1A (Co-fractionation), SMC2 (Co-fractionation), SMC4 (Co-fractionation), SMC4 (Co-fractionation), SMC4 (Co-fractionation), SMC4 (Co-fractionation), SMC4 (Affinity Capture-MS), SMC4 (Affinity Capture-MS)

ESM2 similar proteins: E7F0W1, F1LVW7, J9VL63, O42649, O93308, O93309, O97593, O97594, P0C928, P24785, P42285, P50532, P50533, P97690, Q00737, Q0IIM3, Q14683, Q56YN8, Q5R4K5, Q5R606, Q5ZJY5, Q60446, Q61699, Q66HA8, Q7PKQ5, Q802R8, Q802R9, Q805A1, Q8CG46, Q8CG47, Q8IY18, Q8NDV3, Q8UUU2, Q90ZA1, Q920F6, Q924W5, Q92598, Q96MR6, Q96SB8, Q9CU62

Diamond homologs: A3PMS2, A9II65, B8CW13, B8GZ28, B9E1H0, C4ZJU1, D4GUK1, E1X022, O66878, O95347, P15016, P32908, P41508, P47540, P48996, P50532, P50533, P75361, Q12267, Q1INB1, Q20060, Q24U48, Q54PK4, Q59037, Q5H054, Q5N0D2, Q604U6, Q69GZ5, Q6N1B7, Q6Q1P4, Q7NG51, Q7ZAK1, Q81ZL2, Q8CG47, Q8CG48, Q8KBS6, Q8NDV3, Q8REH4, Q8TZY2, Q90988

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SMC4	“form complex”	“Condensin I”	binding
SMC4	“form complex”	“Condensin II”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
mitotic chromosome condensation	5	36.2×	4e-05
cell division	12	4.0×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	135
Likely benign	6
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3943 predictions. Top by Δscore:

Variant	Effect	Δscore
3:160401905:A:AG	acceptor_gain	1.0000
3:160401905:ACT:A	acceptor_gain	1.0000
3:160401906:C:G	acceptor_gain	1.0000
3:160401907:T:A	acceptor_gain	1.0000
3:160401914:GA:G	acceptor_gain	1.0000
3:160402669:A:AG	acceptor_gain	1.0000
3:160402674:A:AG	acceptor_gain	1.0000
3:160402675:G:GG	acceptor_gain	1.0000
3:160402675:GC:G	acceptor_gain	1.0000
3:160402675:GCGCT:G	acceptor_gain	1.0000
3:160404321:A:AG	acceptor_gain	1.0000
3:160404327:GGAA:G	acceptor_gain	1.0000
3:160404505:G:GG	donor_gain	1.0000
3:160404506:T:G	donor_loss	1.0000
3:160406412:A:G	acceptor_gain	1.0000
3:160412081:GAAGG:G	donor_loss	1.0000
3:160412083:AG:A	donor_loss	1.0000
3:160412085:G:A	donor_loss	1.0000
3:160412086:T:A	donor_loss	1.0000
3:160412454:G:GG	donor_gain	1.0000
3:160413470:TA:T	acceptor_loss	1.0000
3:160413471:A:AG	acceptor_gain	1.0000
3:160413471:AGT:A	acceptor_loss	1.0000
3:160413472:G:GC	acceptor_gain	1.0000
3:160413472:GT:G	acceptor_gain	1.0000
3:160413472:GTT:G	acceptor_gain	1.0000
3:160413472:GTTAT:G	acceptor_gain	1.0000
3:160413551:G:GT	donor_gain	1.0000
3:160413579:A:T	donor_gain	1.0000
3:160413583:C:G	donor_gain	1.0000

AlphaMissense

8632 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:160402053:A:T	K93I	1.000
3:160402054:A:C	K93N	1.000
3:160402054:A:T	K93N	1.000
3:160402694:G:A	G113R	1.000
3:160402694:G:C	G113R	1.000
3:160402694:G:T	G113W	1.000
3:160402695:G:A	G113E	1.000
3:160402702:T:A	N115K	1.000
3:160402702:T:G	N115K	1.000
3:160402704:G:A	G116D	1.000
3:160402710:G:A	G118D	1.000
3:160402716:C:T	S120F	1.000
3:160402720:T:A	N121K	1.000
3:160402720:T:G	N121K	1.000
3:160404377:G:C	R187T	1.000
3:160404378:A:C	R187S	1.000
3:160404378:A:T	R187S	1.000
3:160404490:T:C	F225L	1.000
3:160404492:T:A	F225L	1.000
3:160404492:T:G	F225L	1.000
3:160404497:T:A	I227N	1.000
3:160404504:G:C	Q229H	1.000
3:160404504:G:T	Q229H	1.000
3:160411920:G:C	G230R	1.000
3:160411939:C:A	A236D	1.000
3:160411977:G:C	G249R	1.000
3:160432443:T:C	L1153P	1.000
3:160432455:G:A	G1157E	1.000
3:160432461:C:A	A1159D	1.000
3:160432502:G:A	G1173R	1.000

dbSNP variants (sampled 300 via entrez): RS1000135707 (3:160410529 C>T), RS1000190911 (3:160420395 G>A), RS1000237155 (3:160430496 A>G), RS1000373210 (3:160413988 C>T), RS1000647381 (3:160419983 C>G), RS1000715202 (3:160408015 A>G), RS1000815436 (3:160425952 T>C,G), RS1000824269 (3:160413957 C>T), RS1000906306 (3:160431432 C>T), RS1000907503 (3:160420203 A>G), RS1001008535 (3:160401546 A>G), RS1001206646 (3:160418116 G>A), RS1001213230 (3:160429129 A>C), RS1001256601 (3:160413794 C>G,T), RS1001336878 (3:160409597 A>C)

Disease associations

OMIM: gene MIM:605575 | disease phenotypes: MIM:614675

GenCC curated gene-disease

Mondo (1): bone marrow failure syndrome (MONDO:0000159)

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006716_3	Alcohol use disorder (total score)	2.000000e-08
GCST008103_105	Bipolar disorder	4.000000e-06
GCST010725_1	Malaria	3.000000e-09
GCST010725_57	Malaria	2.000000e-08
GCST010725_87	Malaria	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009458	alcohol use disorder measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725092 (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

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

pChembl	Type	Value	Unit	Molecule
6.02	IC50	960	nM	MOLIBRESIB
5.14	Kd	7294	nM	CHEMBL5653589
5.14	ED50	7294	nM	CHEMBL5653589
5.13	Kd	7321	nM	CHEMBL3752910
5.13	ED50	7321	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 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	2178750: Inhibition of SMC4 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.9600	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149447: Binding affinity to human SMC4 incubated for 45 mins by Kinobead based pull down assay	kd	7.2937	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149447: Binding affinity to human SMC4 incubated for 45 mins by Kinobead based pull down assay	kd	7.3213	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	4
Cyclosporine	decreases expression	4
Resveratrol	affects cotreatment, increases expression, decreases expression	3
Estradiol	affects binding, increases reaction, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
2,3-dimethoxy-1,4-naphthoquinone	increases expression	2
Air Pollutants	increases abundance, decreases expression	2
Testosterone	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
tert-Butylhydroperoxide	affects expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
geraniol	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
deguelin	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
bisphenol B	decreases expression	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
CHEMBL5652489	Binding	Binding affinity to human SMC4 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00774527	PHASE3	COMPLETED	Comparison of Cy-Atg Vs Cy-Flu-Atg for the Conditioning Therapy in Allo-HCT
NCT02393508	PHASE3	UNKNOWN	The Impact of Red Cell Age on Product Utilization in the Chronically Transfused Outpatient Population
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT01050439	PHASE2	TERMINATED	Unrelated Donor Transplant for Malignant and Non-Malignant Disorders
NCT01596699	PHASE2	TERMINATED	Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
NCT01757145	PHASE2	UNKNOWN	Eltrombopag for Enhancing Platelet Engraftment in Adult Patients Undergoing Cord Blood Transplantation
NCT02224872	PHASE2	COMPLETED	Transplantation of Partially Mismatched Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia
NCT02277639	PHASE2	COMPLETED	Reduced Intensity Conditioning Using CD3+/CD19+ Depletion for Non Malignant Transplantable Diseases
NCT02349906	PHASE2	COMPLETED	Treosulfan-based Versus Busulfan-based Conditioning in Paediatric Patients With Non-malignant Diseases
NCT02722668	PHASE2	COMPLETED	UCB Transplant for Hematological Diseases Using a Non Myeloablative Prep
NCT04356469	PHASE2	RECRUITING	TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Non-Malignant Hematological Disorders in Children
NCT04558736	PHASE2	RECRUITING	Haploidentical HCT for Severe Aplastic Anemia
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT07585136	PHASE1	NOT_YET_RECRUITING	Stem Cell Mobilization and Apheresis for Life-threatening Blood Disorders
NCT01419704	PHASE1/PHASE2	WITHDRAWN	Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT02055456	PHASE1/PHASE2	COMPLETED	Nandrolone Decanoate in the Treatment of Telomeropathies
NCT02337595	PHASE1/PHASE2	COMPLETED	Memory T-cell Infusion to Improve Immunity After TCR-alpha/Beta Depleted Hematopoietic Stem Cell Transplantation
NCT03128996	PHASE1/PHASE2	RECRUITING	Reduced Intensity Conditioning and Familial HLA-Mismatched BMT for Non-Malignant Disorders
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT02356653	EARLY_PHASE1	RECRUITING	Expanded Access Protocol Using CD3+/CD19+ Depleted PBSC
NCT02928991	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Fludarabine Based RIC for Bone Marrow Failure Syndromes
NCT06787560	EARLY_PHASE1	RECRUITING	CD7 CAR-T Cell Sequential Allo-HSCT for Non-malignant Blood and Immune System Diseases
NCT00315419	Not specified	UNKNOWN	Identifying Characteristics of Bone Marrow Failure Syndromes
NCT00897260	Not specified	COMPLETED	Umbilical Cord Blood Transplantation As Treatment Of Adult Patients With Hematologic Disorders
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03145545	Not specified	AVAILABLE	Expanded Access Protocol Using Alpha/Beta T and CD19+ Depleted PBSC
NCT04781790	Not specified	RECRUITING	French National Registry of Bone Marrow Failures
NCT04819607	Not specified	UNKNOWN	The Evaluating Multidisciplinary Bone Marrow Failure Care in Bone Marrow Failure and Related Disorders.
NCT05236764	Not specified	ACTIVE_NOT_RECRUITING	Haploidentical Hematopoietic Cell Transplantation Using TCR Alpha/Beta and CD19 Depletion