SUPT16H

Summary

SUPT16H (SPT16 homolog, facilitates chromatin remodeling subunit, HGNC:11465) is a protein-coding gene on chromosome 14q11.2, encoding FACT complex subunit SPT16 (Q9Y5B9). Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Transcription of protein-coding genes can be reconstituted on naked DNA with only the general transcription factors and RNA polymerase II. However, this minimal system cannot transcribe DNA packaged into chromatin, indicating that accessory factors may facilitate access to DNA. One such factor, FACT (facilitates chromatin transcription), interacts specifically with histones H2A/H2B to effect nucleosome disassembly and transcription elongation. FACT is composed of an 80 kDa subunit and a 140 kDa subunit; this gene encodes the 140 kDa subunit.

Source: NCBI Gene 11198 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with dysmorphic facies and thin corpus callosum (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 202 total — 5 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 63
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_007192

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11465
Approved symbol	SUPT16H
Name	SPT16 homolog, facilitates chromatin remodeling subunit
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FACT, FACTP140, SPT16/CDC68, FLJ14010, FLJ10857, CDC68
Ensembl gene	ENSG00000092201
Ensembl biotype	protein_coding
OMIM	605012
Entrez	11198

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000216297, ENST00000552829, ENST00000555752, ENST00000555943, ENST00000556217, ENST00000556309, ENST00000557394, ENST00000557652, ENST00000894929, ENST00000894930, ENST00000924162, ENST00000924163, ENST00000924164, ENST00000924165

RefSeq mRNA: 1 — MANE Select: NM_007192 NM_007192

CCDS: CCDS9569

Canonical transcript exons

ENST00000216297 — 26 exons

Exon	Start	End
ENSE00000585083	21366439	21366529
ENSE00000585086	21363438	21363503
ENSE00000585088	21363034	21363149
ENSE00000585094	21359484	21359609
ENSE00000585095	21358315	21358427
ENSE00000585096	21357927	21358002
ENSE00000653170	21360415	21360533
ENSE00000653171	21360846	21360972
ENSE00000653178	21361078	21361213
ENSE00000653179	21362197	21362324
ENSE00000653187	21362794	21362947
ENSE00000653189	21363233	21363328
ENSE00000653191	21364827	21364939
ENSE00000653193	21365070	21365143
ENSE00000653195	21368269	21368441
ENSE00000653196	21369204	21369355
ENSE00000889083	21351476	21352818
ENSE00001123842	21383862	21384019
ENSE00003509850	21373338	21373430
ENSE00003539434	21353703	21353832
ENSE00003552566	21369750	21369896
ENSE00003638600	21353488	21353565
ENSE00003645848	21354411	21354540
ENSE00003650438	21357197	21357366
ENSE00003651370	21371874	21372044
ENSE00003658551	21370336	21370488

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 98.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.8068 / max 458.7072, expressed in 1809 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142164	26.6827	1804
142163	4.2552	1434
142165	2.8688	1297

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.07	gold quality
embryo	UBERON:0000922	97.52	gold quality
ganglionic eminence	UBERON:0004023	97.52	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.23	gold quality
cortical plate	UBERON:0005343	96.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.26	gold quality
calcaneal tendon	UBERON:0003701	96.14	gold quality
colonic epithelium	UBERON:0000397	95.39	gold quality
cerebellar hemisphere	UBERON:0002245	95.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.93	gold quality
cerebellar cortex	UBERON:0002129	94.89	gold quality
body of uterus	UBERON:0009853	94.69	gold quality
smooth muscle tissue	UBERON:0001135	94.62	gold quality
islet of Langerhans	UBERON:0000006	94.58	gold quality
right testis	UBERON:0004534	94.49	gold quality
left testis	UBERON:0004533	94.38	gold quality
right ovary	UBERON:0002118	94.36	gold quality
sural nerve	UBERON:0015488	94.34	gold quality
right uterine tube	UBERON:0001302	94.27	gold quality
rectum	UBERON:0001052	94.26	gold quality
stromal cell of endometrium	CL:0002255	94.24	gold quality
left ovary	UBERON:0002119	94.18	gold quality
vermiform appendix	UBERON:0001154	94.17	gold quality
endocervix	UBERON:0000458	94.16	gold quality
ectocervix	UBERON:0012249	94.16	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.10	gold quality
left uterine tube	UBERON:0001303	93.84	gold quality
popliteal artery	UBERON:0002250	93.74	gold quality
tibial artery	UBERON:0007610	93.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.70	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	285.19
E-ANND-3	yes	9.61
E-MTAB-6379	no	2418.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

64 targeting SUPT16H, 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-196A-1-3P	99.99	72.15	2772
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-488-5P	99.28	68.12	821

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 22)

• facilitates RNA polymerase II driven transcription by destabilizing nucleosomal structure so that one histone H2A-H2B dimer is removed during enzyme passage; possesses intrinsic histone chaperone activity and can deposit core histones onto DNA (PMID:12934006)
• Results demonstrate that elongation by RNA polymerase II through the nucleosomal barrier is minimally dependent upon (1) FACT and (2) the recruitment of PAF and the H2B monoubiquitination machinery. (PMID:16713563)
• FACT is an integral and conserved component of the endogenous replication machinery, and support a model in which the concerted action of helicase and chromatin-modifying activities promotes chromosome replication. (PMID:16902406)
• yFACT and Set2 oppose one another during transcriptional initiation at a step involving DNA binding by TBP and TFIIA. (PMID:16977311)
• SSRP1 has Spt16-dependent and -independent roles in regulating gene transcription in human cells. (PMID:17209051)
• Data establish FACT as the major regulator involved in H2AX exchange process that is modulated by H2AX phosphorylation and Spt16 ADP-ribosylation. (PMID:18406329)
• SUPT16H and RNF40 are required for proper DNA end resection and timely DNA repair after double-strand breaks. (PMID:22031019)
• In the absence of FACT complex, SSRP1 and SPT16 mRNAs are unstable and inefficiently translated, making reactivation of FACT function unlikely in normal cells. (PMID:23839038)
• present observation and published data suggest that phenotype present in patients with duplication of 14q11.2 region, encompassing the SUPT16H and CHD8 genes, resemble in some extend features described in cases carrying microdeletion of that genomic region (PMID:26834018)
• FACT is required for TOP1 binding to H3K4me3 at non-B DNA containing chromatin for the site-specific cleavage. (PMID:26842758)
• Spt16 N-terminal domain is a histone H3-H4-specific binding domain with a distinct mechanism of interaction between histones and histone chaperones. (PMID:30528735)
• We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H..The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8. (PMID:30670789)
• FACT subunit Spt16 controls UVSSA recruitment to lesion-stalled RNA Pol II and stimulates transcription-coupled nucleotide excision repair. (PMID:30715484)
• suggest a compelling mechanism for how FACT maintains chromatin integrity during polymerase passage, by facilitating removal of the H2A-H2B dimer, stabilizing intermediate subnucleosomal states and promoting nucleosome reassembly (PMID:31775157)
• Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication. (PMID:31823155)
• De novo variants in SUPT16H cause neurodevelopmental disorders associated with corpus callosum abnormalities. (PMID:31924697)
• Proteasomal Regulation of Mammalian SPT16 in Controlling Transcription. (PMID:33526453)
• FACT subunit SUPT16H associates with BRD4 and contributes to silencing of interferon signaling. (PMID:35904816)
• The fly homolog of SUPT16H, a gene associated with neurodevelopmental disorders, is required in a cell-autonomous fashion for cell survival. (PMID:36255738)
• Human FACT subunits coordinate to catalyze both disassembly and reassembly of nucleosomes. (PMID:36577379)
• Supt16 Haploinsufficiency Impairs PI3K/AKT/mTOR/Autophagy Pathway in Human Pluripotent Stem Cells Derived Neural Stem Cells. (PMID:36769360)
• Structural basis for H2A-H2B recognitions by human Spt16. (PMID:36801613)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	supt16h	ENSDARG00000079949
mus_musculus	Supt16	ENSMUSG00000035726
rattus_norvegicus	Supt16h	ENSRNOG00000011953
drosophila_melanogaster	dre4	FBGN0002183
caenorhabditis_elegans	spt-16	WBGENE00018849

Protein

Protein identifiers

FACT complex subunit SPT16 — Q9Y5B9 (reviewed: Q9Y5B9)

Alternative names: Chromatin-specific transcription elongation factor 140 kDa subunit, FACT 140 kDa subunit, FACTp140, Facilitates chromatin transcription complex subunit SPT16

All UniProt accessions (4): Q9Y5B9, G3V2X0, G3V401, G3V5A4

UniProt curated annotations — full annotation on UniProt →

Function. Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II. The FACT complex is probably also involved in phosphorylation of ‘Ser-392’ of p53/TP53 via its association with CK2 (casein kinase II).

Subunit / interactions. Interacts with MYOG (via C-terminal region). Component of the FACT complex, a stable heterodimer of SSRP1 and SUPT16H. Also a component of a CK2-SPT16-SSRP1 complex which forms following UV irradiation, composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B. Interacts with NEK9. Binds to histone H2A-H2B. Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1. Interacts with GTF2E2. (Microbial infection) Interacts with Herpes simplex virus 1 (HHV-1) protein ICP22; this interaction relocalizes the FACT complex to viral genomes in infected cells.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Ubiquitous.

Post-translational modifications. ADP-ribosylated. ADP-ribosylation by PARP1 is induced by genotoxic stress and correlates with dissociation of FACT from chromatin.

Disease relevance. Neurodevelopmental disorder with dysmorphic facies and thin corpus callosum (NEDDFAC) [MIM:619480] An autosomal dominant disorder characterized by global developmental delay, impaired intellectual development with poor or absent speech and language, and autistic-like behaviors. Corpus callosum anomalies are visible on brain imaging. Most patients have dysmorphic features including tall forehead, down-slanting palpebral fissures, ear anomalies and broad nasal bridge. Other variably present clinical features include seizures, sleeping difficulties and precocious puberty. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal Glu-rich acidic region is essential for FACT activity.

Similarity. Belongs to the peptidase M24 family. SPT16 subfamily.

RefSeq proteins (1): NP_009123* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000994	Pept_M24	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013719	RTT106/SPT16-like_middle_dom	Domain
IPR013953	FACT_SPT16_M	Domain
IPR029148	FACT-SPT16_Nlobe	Domain
IPR029149	Creatin/AminoP/Spt16_N	Homologous_superfamily
IPR033825	Spt16_M24	Domain
IPR036005	Creatinase/aminopeptidase-like	Homologous_superfamily
IPR040258	Spt16	Family
IPR048969	FACT_SPT16_C	Domain
IPR056595	Fact-SPT16_PH	Domain

Pfam: PF00557, PF08512, PF08644, PF14826, PF21091, PF24824

UniProt features (106 total): strand 40, helix 28, modified residue 18, sequence variant 4, turn 4, compositionally biased region 4, cross-link 3, region of interest 2, initiator methionine 1, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
5E5B	X-RAY DIFFRACTION	1.84
5UMU	X-RAY DIFFRACTION	1.9
4Z2N	X-RAY DIFFRACTION	1.92
8I17	X-RAY DIFFRACTION	1.98
5UMT	X-RAY DIFFRACTION	2.09
5XM2	X-RAY DIFFRACTION	2.19
4Z2M	X-RAY DIFFRACTION	2.98
9EH2	ELECTRON MICROSCOPY	3.1
9RZC	ELECTRON MICROSCOPY	3.66
8YJM	X-RAY DIFFRACTION	4.15
8YJF	X-RAY DIFFRACTION	4.4
9GW2	ELECTRON MICROSCOPY	4.84
6UPK	ELECTRON MICROSCOPY	4.9
9S3G	ELECTRON MICROSCOPY	6.4
9S0U	ELECTRON MICROSCOPY	6.72
6UPL	ELECTRON MICROSCOPY	7.4
9RZE	ELECTRON MICROSCOPY	8.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5B9-F1	80.07	0.48

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 (21): 139, 188, 196, 223, 455, 508, 513, 650, 658, 732, 786, 903, 904, 979, 982, 986, 1015, 497, 513, 647 …

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-167152	Formation of HIV elongation complex in the absence of HIV Tat
R-HSA-167200	Formation of HIV-1 elongation complex containing HIV-1 Tat
R-HSA-167238	Pausing and recovery of Tat-mediated HIV elongation
R-HSA-167243	Tat-mediated HIV elongation arrest and recovery
R-HSA-167246	Tat-mediated elongation of the HIV-1 transcript
R-HSA-167287	HIV elongation arrest and recovery
R-HSA-167290	Pausing and recovery of HIV elongation
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-9943411	CHD1 and CHD2 subfamily
R-HSA-162587	HIV Life Cycle
R-HSA-162599	Late Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-1643685	Disease
R-HSA-167169	HIV Transcription Elongation
R-HSA-167172	Transcription of the HIV genome
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5633007	Regulation of TP53 Activity
R-HSA-5663205	Infectious disease
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 375 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, RNGTGGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GNF2_MSH2, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GCANCTGNY_MYOD_Q6, MITSIADES_RESPONSE_TO_APLIDIN_DN, RACCACAR_AML_Q6, KAUFFMANN_DNA_REPAIR_GENES, CAGCTG_AP4_Q5, PATIL_LIVER_CANCER, PAX8_B, REACTOME_HIV_INFECTION, ONKEN_UVEAL_MELANOMA_UP

GO Biological Process (8): DNA replication (GO:0006260), DNA repair (GO:0006281), nucleosome assembly (GO:0006334), nucleosome disassembly (GO:0006337), transcription by RNA polymerase II (GO:0006366), transcription elongation by RNA polymerase II (GO:0006368), positive regulation of DNA-templated transcription, elongation (GO:0032786), DNA damage response (GO:0006974)

GO Molecular Function (3): RNA binding (GO:0003723), nucleosome binding (GO:0031491), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), FACT complex (GO:0035101), chromosome (GO:0005694), transcription elongation factor complex (GO:0008023)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Transcription of the HIV genome	6
RNA Polymerase II Transcription	3
RNA Polymerase II Transcription Elongation	1
Tat-mediated elongation of the HIV-1 transcript	1
HIV Transcription Elongation	1
Transcriptional Regulation by TP53	1
Regulation of TP53 Activity	1
CHD chromatin remodelers	1
HIV Infection	1
HIV Life Cycle	1
Viral Infection Pathways	1
Late Phase of HIV Life Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
nucleosome organization	2
DNA-templated transcription elongation	2
DNA biosynthetic process	1
DNA damage response	1
chromatin organization	1
protein-DNA complex assembly	1
protein-DNA complex disassembly	1
DNA-templated transcription	1
transcription by RNA polymerase II	1
regulation of DNA-templated transcription elongation	1
positive regulation of DNA-templated transcription	1
cellular response to stress	1
nucleic acid binding	1
chromatin binding	1
protein-containing complex binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
chromatin	1
transcription elongation factor complex	1
intracellular membraneless organelle	1
nucleoplasm	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

3414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SUPT16H	SSRP1	Q08945	999
SUPT16H	H2BC21	Q16778	962
SUPT16H	H2AC20	Q16777	949
SUPT16H	H2AC19	P20670	947
SUPT16H	SUPT6H	Q7KZ85	944
SUPT16H	SUPT5H	O00267	893
SUPT16H	POLR2A	P24928	806
SUPT16H	H3C1	P02295	802
SUPT16H	POLR2C	P19387	800
SUPT16H	H3-3A	P06351	790
SUPT16H	H3-4	Q16695	789
SUPT16H	H3-7	Q5TEC6	789
SUPT16H	H3-5	Q6NXT2	789
SUPT16H	H3C14	Q71DI3	789
SUPT16H	CDC45	O75419	759

IntAct

308 interactions, top by confidence:

A	B	Type	Score
CDKN2A	CDK4	psi-mi:“MI:0914”(association)	0.960
CEP97	CCP110	psi-mi:“MI:2364”(proximity)	0.950
PRKAA1	PRKAB2	psi-mi:“MI:0914”(association)	0.950
SUPT16H	SSRP1	psi-mi:“MI:0915”(physical association)	0.910
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
PRKDC	XRCC6	psi-mi:“MI:0914”(association)	0.900
XRCC5	PARP1	psi-mi:“MI:0915”(physical association)	0.880
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730
COMMD1	VPS26C	psi-mi:“MI:0914”(association)	0.730
COMMD4	VPS26C	psi-mi:“MI:0914”(association)	0.730
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
COMMD6	VPS26C	psi-mi:“MI:0914”(association)	0.640
APP	SUPT16H	psi-mi:“MI:0915”(physical association)	0.560
H2AC11	PARP1	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
MACROH2A2	PPM1G	psi-mi:“MI:0914”(association)	0.530

BioGRID (694): HIST1H2AB (Affinity Capture-Western), SUPT16H (Affinity Capture-RNA), SUPT16H (Affinity Capture-RNA), TONSL (Co-localization), SUPT16H (Synthetic Growth Defect), SUPT16H (Co-localization), SUPT16H (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), SUPT16H (Reconstituted Complex), SUPT16H (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), SUPT16H (Affinity Capture-MS)

ESM2 similar proteins: A2XKU9, A7RHL5, A9NK39, B4YYA9, B5X8A5, O13907, O42130, O42131, O46374, P0C0A1, P11388, P17248, P23612, P41515, P41516, Q01320, Q02880, Q1JQD4, Q27128, Q498C5, Q498D9, Q4HYB8, Q558Y7, Q5E9A6, Q5E9R3, Q5R4J1, Q5RBP4, Q641Z6, Q64399, Q64511, Q6AVK1, Q6NWF4, Q6P7B0, Q6TGV7, Q6Z9U7, Q7X923, Q8K224, Q8LBN7, Q8T9B6, Q8VZC9

Diamond homologs: O82491, O94267, P0CQ22, P0CQ23, P32558, Q00976, Q2UBF1, Q4HYB8, Q4P2U5, Q4WJ02, Q54S43, Q5A1D5, Q5B2X8, Q61E63, Q6BXE5, Q6C931, Q6FWT4, Q756A7, Q7X923, Q8H6B1, Q8IRG6, Q8X0X6, Q920B9, Q9N5R9, Q9W603, Q9Y5B9, Q49YD7, Q58216

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 240 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
Signaling by FGFR2 IIIa TM	5	16.9×	1e-04
Abortive elongation of HIV-1 transcript in the absence of Tat	5	13.9×	2e-04
Deposition of new CENPA-containing nucleosomes at the centromere	15	13.4×	2e-10
Nucleosome assembly	5	13.4×	3e-04
HIV Transcription Elongation	7	13.2×	1e-05
Pausing and recovery of Tat-mediated HIV elongation	6	12.4×	8e-05
Tat-mediated HIV elongation arrest and recovery	6	12.4×	8e-05
Inhibition of DNA recombination at telomere	13	12.3×	9e-09

GO biological processes:

GO term	Partners	Fold	FDR
NLS-bearing protein import into nucleus	5	19.0×	7e-04
heterochromatin formation	13	15.7×	2e-09
base-excision repair	7	15.5×	7e-05
amyloid fibril formation	5	14.3×	1e-03
double-strand break repair via nonhomologous end joining	7	14.0×	1e-04
response to gamma radiation	5	13.8×	2e-03
nucleotide-excision repair	7	12.7×	2e-04
replication fork processing	6	12.0×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	4
Uncertain significance	135
Likely benign	12
Benign	8

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1199250	NM_007192.4(SUPT16H):c.1712A>G (p.Asn571Ser)	Pathogenic
1199251	NM_007192.4(SUPT16H):c.1295T>C (p.Leu432Pro)	Pathogenic
1691274	NM_007192.4(SUPT16H):c.2539C>T (p.Arg847Trp)	Pathogenic
1700349	NM_007192.4(SUPT16H):c.2078G>A (p.Arg693Gln)	Pathogenic
4845369	NM_007192.4(SUPT16H):c.1475_1481del (p.Arg492fs)	Pathogenic
1199249	NM_007192.4(SUPT16H):c.2200C>T (p.Arg734Trp)	Likely pathogenic
2692480	NM_007192.4(SUPT16H):c.2077C>T (p.Arg693Ter)	Likely pathogenic
4293064	NM_007192.4(SUPT16H):c.1161_1164del (p.Asn388fs)	Likely pathogenic
4540024	NM_007192.4(SUPT16H):c.512C>T (p.Thr171Ile)	Likely pathogenic

SpliceAI

2663 predictions. Top by Δscore:

Variant	Effect	Δscore
14:21352814:GTCCG:G	acceptor_gain	1.0000
14:21352815:TCCG:T	acceptor_gain	1.0000
14:21352816:CCG:C	acceptor_gain	1.0000
14:21352816:CCGC:C	acceptor_gain	1.0000
14:21352817:C:CT	acceptor_gain	1.0000
14:21352817:C:T	acceptor_gain	1.0000
14:21352817:CG:C	acceptor_gain	1.0000
14:21352817:CGCTA:C	acceptor_loss	1.0000
14:21352818:GC:G	acceptor_loss	1.0000
14:21352819:C:CC	acceptor_gain	1.0000
14:21352819:C:T	acceptor_loss	1.0000
14:21352823:A:AC	acceptor_gain	1.0000
14:21352823:A:C	acceptor_gain	1.0000
14:21353484:AAAC:A	donor_loss	1.0000
14:21353485:AAC:A	donor_loss	1.0000
14:21353486:A:AT	donor_loss	1.0000
14:21353487:C:CT	donor_loss	1.0000
14:21353502:T:TA	donor_gain	1.0000
14:21353562:TAGT:T	acceptor_gain	1.0000
14:21353564:GT:G	acceptor_gain	1.0000
14:21353565:TC:T	acceptor_loss	1.0000
14:21353566:C:CC	acceptor_gain	1.0000
14:21353566:CTGGA:C	acceptor_loss	1.0000
14:21353699:TAAC:T	donor_gain	1.0000
14:21353700:AAC:A	donor_loss	1.0000
14:21353700:AACCT:A	donor_gain	1.0000
14:21353701:A:AC	donor_gain	1.0000
14:21353701:A:AT	donor_gain	1.0000
14:21353701:A:C	donor_loss	1.0000
14:21353702:C:CA	donor_loss	1.0000

AlphaMissense

7023 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:21353496:G:T	A997D	1.000
14:21353497:C:G	A997P	1.000
14:21353508:A:G	L993P	1.000
14:21353516:C:A	W990C	1.000
14:21353516:C:G	W990C	1.000
14:21353518:A:G	W990R	1.000
14:21353518:A:T	W990R	1.000
14:21354427:A:G	L925P	1.000
14:21354435:C:A	W922C	1.000
14:21354435:C:G	W922C	1.000
14:21354436:C:G	W922S	1.000
14:21354437:A:G	W922R	1.000
14:21354437:A:T	W922R	1.000
14:21354439:C:T	G921D	1.000
14:21354453:G:C	F916L	1.000
14:21354453:G:T	F916L	1.000
14:21354455:A:G	F916L	1.000
14:21354475:A:T	I909N	1.000
14:21354487:A:C	I905S	1.000
14:21354487:A:T	I905N	1.000
14:21354495:C:A	W902C	1.000
14:21354495:C:G	W902C	1.000
14:21354496:C:G	W902S	1.000
14:21354497:A:G	W902R	1.000
14:21354497:A:T	W902R	1.000
14:21354502:A:G	L900P	1.000
14:21354502:A:T	L900H	1.000
14:21354515:C:G	G896R	1.000
14:21354515:C:T	G896R	1.000
14:21357202:C:A	W885C	1.000

dbSNP variants (sampled 300 via entrez): RS1000265099 (14:21363901 A>G), RS1000374133 (14:21357845 A>T), RS1000397548 (14:21359046 C>G,T), RS1000575702 (14:21370771 G>A), RS1000589799 (14:21376994 A>G), RS1000683368 (14:21377194 T>C), RS1000826102 (14:21379660 C>G), RS1000841851 (14:21353298 A>G), RS1001267736 (14:21365545 G>C), RS1001319973 (14:21365821 G>A,C), RS1001431211 (14:21384315 C>G), RS1001678738 (14:21378663 A>T), RS1001728206 (14:21378589 A>C,G,T), RS1001843199 (14:21367173 C>T), RS1001941994 (14:21355180 C>T)

Disease associations

OMIM: gene MIM:605012 | disease phenotypes: MIM:619480

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with dysmorphic facies and thin corpus callosum	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant

Mondo (4): neurodevelopmental disorder with dysmorphic facies and thin corpus callosum (MONDO:0859179), neurodevelopmental disorder (MONDO:0700092), dextrocardia (MONDO:0015661), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Li-Fraumeni syndrome (Orphanet:524), Dextrocardia (Orphanet:1666)

HPO phenotypes

63 total (30 of 63 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000160	Narrow mouth
HP:0000193	Bifid uvula
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000391	Thickened helices
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000473	Torticollis
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000666	Horizontal nystagmus
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000821	Hypothyroidism
HP:0000956	Acanthosis nigricans
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010796_1841	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003914	Dextrocardia	C14.240.400.280; C14.280.400.280; C16.131.240.400.280; C16.131.810.250
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465367 (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
8.34	Kd	4.602	nM	CHEMBL3752910
8.34	ED50	4.602	nM	CHEMBL3752910
6.92	IC50	120	nM	MOLIBRESIB
6.83	Kd	148.7	nM	CHEMBL5653589
6.83	ED50	148.7	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 11 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149529: Binding affinity to human SUPT16H incubated for 45 mins by Kinobead based pull down assay	kd	0.0046	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178621: Inhibition of SUPT16H (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.1200	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149529: Binding affinity to human SUPT16H incubated for 45 mins by Kinobead based pull down assay	kd	0.1487	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
trichostatin A	affects cotreatment, decreases expression	2
perfluorooctanoic acid	decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
geldanamycin	increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
geraniol	decreases expression	1
titanium dioxide	increases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
chloropicrin	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5338473	Binding	Binding affinity to Supt16h (unknown origin) assessed as fold change in protein upregulation at 200 uM preincubated for 2 hrs followed by pronase addition and measured after 30 mins by coomassie blue staining based SDS-PAGE gel analysis	Structurally Diverse Alkaloids with Anti-Renal-Fibrosis Activity from the Centipede Scolopendra subspinipes mutilans. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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,
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
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
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
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
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism