HCFC1

Summary

HCFC1 (host cell factor C1, HGNC:4839) is a protein-coding gene on chromosome Xq28, encoding Host cell factor 1 (P51610). Transcriptional coregulator. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

This gene is a member of the host cell factor family and encodes a protein with five Kelch repeats, a fibronectin-like motif, and six HCF repeats, each of which contains a highly specific cleavage signal. This nuclear coactivator is proteolytically cleaved at one of the six possible sites, resulting in the creation of an N-terminal chain and the corresponding C-terminal chain. The final form of this protein consists of noncovalently bound N- and C-terminal chains. The protein is involved in control of the cell cycle and transcriptional regulation during herpes simplex virus infection. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.

Source: NCBI Gene 3054 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 1,716 total — 10 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 22
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_005334

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4839
Approved symbol	HCFC1
Name	host cell factor C1
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	HCF-1, HCF1, CFF, VCAF, MGC70925, PPP1R89
Ensembl gene	ENSG00000172534
Ensembl biotype	protein_coding
OMIM	300019
Entrez	3054

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000310441, ENST00000369984, ENST00000444191, ENST00000461098, ENST00000925197, ENST00000925198, ENST00000925199, ENST00000925200, ENST00000925201, ENST00000925202, ENST00000925203, ENST00000925204, ENST00000925205, ENST00000960407

RefSeq mRNA: 2 — MANE Select: NM_005334 NM_001410705, NM_005334

CCDS: CCDS44020, CCDS94699

Canonical transcript exons

ENST00000310441 — 26 exons

Exon	Start	End
ENSE00001201536	153949553	153949616
ENSE00001201544	153950243	153950543
ENSE00001201554	153950813	153950998
ENSE00001201563	153951350	153951487
ENSE00001201571	153951589	153951707
ENSE00001201580	153951841	153952158
ENSE00001201585	153952514	153952958
ENSE00001201593	153953607	153953770
ENSE00001201597	153954066	153955542
ENSE00001201602	153956191	153956411
ENSE00001201607	153956625	153956763
ENSE00001201612	153956918	153957060
ENSE00001201618	153957314	153957533
ENSE00001201626	153957782	153957886
ENSE00001201635	153958025	153958249
ENSE00001201643	153959331	153959491
ENSE00001201648	153959802	153960161
ENSE00001201657	153961542	153961648
ENSE00001201661	153962222	153962306
ENSE00001201666	153963225	153963433
ENSE00001201671	153964124	153964284
ENSE00001201673	153964578	153964726
ENSE00001201680	153947557	153949386
ENSE00001376480	153958569	153958766
ENSE00001958936	153970648	153971818
ENSE00003607414	153960235	153960414

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 93.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 38.4426 / max 289.5386, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200941	33.5922	1815
200938	4.8504	1637

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	93.21	gold quality
parotid gland	UBERON:0001831	92.60	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.60	silver quality
triceps brachii	UBERON:0001509	90.97	gold quality
ganglionic eminence	UBERON:0004023	90.79	gold quality
endometrium epithelium	UBERON:0004811	90.31	gold quality
adenohypophysis	UBERON:0002196	90.16	gold quality
gluteal muscle	UBERON:0002000	89.99	gold quality
nipple	UBERON:0002030	89.98	gold quality
ventricular zone	UBERON:0003053	89.89	gold quality
body of uterus	UBERON:0009853	89.52	gold quality
pituitary gland	UBERON:0000007	89.50	gold quality
pylorus	UBERON:0001166	89.50	gold quality
apex of heart	UBERON:0002098	89.50	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.43	gold quality
granulocyte	CL:0000094	89.33	gold quality
thymus	UBERON:0002370	89.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.10	silver quality
mucosa of transverse colon	UBERON:0004991	89.07	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.06	gold quality
bone marrow cell	CL:0002092	88.86	gold quality
saphenous vein	UBERON:0007318	88.82	gold quality
left uterine tube	UBERON:0001303	88.74	gold quality
lower esophagus	UBERON:0013473	88.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.62	gold quality
right adrenal gland cortex	UBERON:0035827	88.57	gold quality
right adrenal gland	UBERON:0001233	88.41	gold quality
embryo	UBERON:0000922	88.36	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.34	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
CCNA2	Activation
CDC6	Activation
CDK1	Activation
COX7C
E2F1	Activation
E2F4	Repression
MMACHC	Unknown
PDX1	Activation

Upstream regulators (CollecTRI, top): CREB3, CREBZF, E2F4, EGR2, NFE2L2, SREBF1, STAT1, THAP11, YY1, ZBTB17, ZBTB7A

miRNA regulators (miRDB)

134 targeting HCFC1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
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-6845-3P	99.94	66.88	1439
HSA-MIR-218-5P	99.93	72.22	2103
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-6768-5P	99.92	67.36	1942

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• HCF-1 activity is regulated by HPIP by modulating its subcellular localization (PMID:12235138)
• HCF-1 contains an activation domain (HCF-1(AD)) required for maximal transactivation by VP16 and its cellular counterpart LZIP. (PMID:12271126)
• The results presented in this paper suggest that HCF-1 can broadly regulate transcription, both positively and negatively, through selective modulation of chromatin structure. (PMID:12670868)
• These results suggest that host cell factor-1 (HCF-1) links the regulation of exit from mitosis and the G(1) phase of cell growth, possibly to coordinate the reactivation of gene expression after mitosis. (PMID:12743030)
• Three proteins found to contain the HCF-binding motif were further analyzed for their ability to use HCF-1 as a coactivator. Krox20 and E2F4 showed a strong requirement for HCF-1 to activate activation transcription, while estrogen receptor-alpha did not. (PMID:14532282)
• Altered expression is associated with therapy failure and death in patients with multiple types of cancer. (PMID:15931389)
• The fibronectin domain of HCF interacts with HCF in the herpes simplex virus VP16-induced transcriptional activating complex, an association requiring a region outside the putative HCF beta-propeller fold (PMID:16042417)
• HCF-1 was required for recruitment of the histone methyltransferases Set1 and MLL1, leading to histone H3K4 trimethylation and transcriptional activation. (PMID:17578910)
• During the G1-to-S phase transition, HCF-1 recruits the mixed-lineage leukemia (MLL) and Set-1 histone H3 lysine 4 methyltransferases to E2F-responsive promoters and induces histone methylation and transcriptional activation. (PMID:17612494)
• The results are consistent with a pathway whereby PRC regulates NRF-2-dependent genes through a multiprotein complex involving HCF-1. (PMID:18343819)
• A viable hypothesis for disease development is presented based on the known interaction between HCFC1 and the herpes simplex viral protein VP16 (PMID:18520591)
• The identified components revealed factors involved in histone methylation and cell cycle control and include Ash2L, RbBP5, WDR5, HCF-1, DBC-1, and EMSY. (PMID:19131338)
• The most interesting biological findings were the binding sites for SREBP-1 in genes for host cell factor C1 (HCFC1), involved in cell cycle regulation (PMID:19292868)
• Sequence changes in the E2F1 HCF-1-binding site can modulate both up and down the ability of E2F1 to induce apoptosis indicating that HCF-1 association with E2F1 is a regulator of E2F1-induced apoptosis. (PMID:19763085)
• BAP1 regulates cell proliferation by deubiquitinating HCF-1 (PMID:19815555)
• NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes. (PMID:20018852)
• Data show that the HCF-1 Basic region displays striking structural flexibility for controlling cell proliferation. (PMID:20126307)
• Data show that Asf1b localizes with HCF-1 in viral replication foci and depletion of Asf1b results in significantly reduced viral DNA accumulation. (PMID:20133788)
• THAP1 mediates the recruitment of HCF-1 to the RRM1 promoter during endothelial cell proliferation and that HCF-1 is essential for transcriptional activation of RRM1. (PMID:20200153)
• HCF-1 interacts with the middle region of YY1 encompassing the glycine-lysine-rich domain and is essential for the formation of a ternary complex with YY1 and BAP1 in vivo. (PMID:20805357)
• These results reveal an unexpected role of OGT in HCF-1 proteolytic maturation and an unforeseen nexus between OGT-directed O-GlcNAcylation and proteolytic maturation in HCF-1 cell-cycle regulation. (PMID:21295698)
• Studies suggest that BAP1 influences cell proliferation at G1/S by co-regulating transcription from HCF-1/E2F-governed promoters. (PMID:21484256)
• THAP11 was found to associate physically with the transcriptional coregulator HCF-1 (host cell factor 1) and recruit HCF-1 to target promoters (PMID:22371484)
• Host cell factor C1 recruits O-GlcNAc transferase to O-GlcNAcylate PGC-1alpha, and O-GlcNAcylation facilitates the binding of the deubiquitinase BAP1, thus protecting PGC-1alpha from degradation and promoting gluconeogenesis. (PMID:22883232)
• A noncoding, regulatory mutation was identified in the binding site of transcription factor YY1 in the HCFC1 gene in patients with nonsyndromic intellectual disability. (PMID:23000143)
• HCF-1(N)-HCF-1(C) association via an integrated Fn3 structure permits an NLS to facilitate formation of a transcriptional regulatory complex (PMID:23045687)
• HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy. (PMID:23539139)
• MLL5 can associate with HCF-1 and then be recruited to E2F1-responsive promoters to stimulate H3K4 trimethylation and transcriptional activation. (PMID:23629655)
• A missense mutation in a global transcriptional coregulator, HCFC1, was identified as the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia. (PMID:24011988)
• study reports the tetratricopeptide-repeat domain of O-GlcNAc transferase binds the carboxyl-terminal portion of an HCF-1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate-GlcNAc; protein glycosylation and HCF-1 cleavage occur in the same active site (PMID:24311690)
• THAP11, ZNF143, and HCF-1 form a mutually dependent complex on chromatin, which is independent of E2F occupancy. (PMID:25437553)
• We report here two brothers with dysmorphic features and complex malformations resulting from an X-linked inherited cobalamin deficiency due to HCFC1 gene mutation. (PMID:25595573)
• our work identifies plausible cellular consequences of missense HCFC1 variants and identifies likely and relevant disease mechanisms that converge on embryonic stages of brain development. (PMID:25740848)
• O-GlcNAcylation of the transcription regulators Host Cell Factor-1 (HCF-1) and Ten-Eleven Translocation protein 2 (TET2) could be readily observed. Our study raises questions on the occurrence and abundance of O-GlcNAcylation as a histone modification (PMID:26075789)
• These results demonstrate that distinct OGT-binding sites in HCF-1 promote proteolysis, and provide novel insights into the mechanism of this unusual protease activity. (PMID:26305326)
• Data show that Myc boxes (MbIV) is required for the association of MYC with the abundant transcriptional coregulator host cell factor-1 (HCF-1). (PMID:26522729)
• findings show that cellular factors OCT2 and HCF1 bind OriP in association with Epstein-Barr virus nuclear antigen 1 to maintain elevated histone H3K4me3 and transcriptional enhancer function (PMID:27009953)
• Beyond its well-known role in adding beta-O-GlcNAc to serine and threonine residues of nuclear and cytoplasmic proteins, OGT also acts as a protease in the maturation of the cell cycle regulator, HCF-1, and serves as an integral member of several protein complexes, many of them linked to gene expression. (Review) (PMID:27294441)
• The M4 motif (ACTAYRNNNCCCR) is a functional regulatory bipartite cis-element, which engages a THAP11/HCF-1 complex via binding to the ACTAYR module, while the CCCRRNRNRC subsequence part constitutes a binding platform for Ikaros and NFKB1 (PMID:27576892)
• The HCF-1PRO repeat possesses an important extended threonine-rich region that is tightly bound by the OGT tetratricopeptide-repeat region. This region confers both glycosylation and proteolytic activities to HCF-1. (PMID:30224358)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcfc1	ENSMUSG00000031386
rattus_norvegicus	Hcfc1	ENSRNOG00000051948

Paralogs (10): FBXO42 (ENSG00000037637), LZTR1 (ENSG00000099949), KLHDC4 (ENSG00000104731), HCFC2 (ENSG00000111727), KLHDC3 (ENSG00000124702), KLHDC10 (ENSG00000128607), RABEPK (ENSG00000136933), KLHDC9 (ENSG00000162755), KLHDC2 (ENSG00000165516), KLHDC1 (ENSG00000197776)

Protein

Protein identifiers

Host cell factor 1 — P51610 (reviewed: P51610)

Alternative names: C1 factor, CFF, VCAF, VP16 accessory protein

All UniProt accessions (3): P51610, A6NEM2, H7C1C4

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coregulator. Serves as a scaffold protein, bridging interactions between transcription factors, including THAP11 and ZNF143, and transcriptional coregulators. Involved in control of the cell cycle. Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300. Coactivator for EGR2 and GABP2. Tethers the chromatin modifying Set1/Ash2 histone H3 ‘Lys-4’ methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition. Modulates expression of homeobox protein PDX1, perhaps acting in concert with transcription factor E2F1, thereby regulating pancreatic beta-cell growth and glucose-stimulated insulin secretion. May negatively modulate transcriptional activity of FOXO3. (Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes.

Subunit / interactions. Composed predominantly of six polypeptides ranging from 110 to 150 kDa and a minor 300 kDa polypeptide. The majority of N- and C-terminal cleavage products remain tightly, albeit non-covalently, associated. Interacts with POU2F1, CREB3, ZBTB17, EGR2, E2F4, CREBZF, SP1, GABP2, Sin3 HDAC complex (SIN3A, HDAC1, HDAC2, SUDS3), SAP30, SIN3B and FHL2. Component of a MLL1 complex, composed of at least the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BACC1, CHD8, DPY30, E2F6, HCFC2, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8, PELP1, PHF20, PRP31, RING2, RUVBL1, RUVBL2, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. Interacts directly with THAP3 (via its HBM). Interacts (via the Kelch-repeat domain) with THAP1 (via the HBM); the interaction recruits HCHC1 to the RRM1. Interacts with THAP7 and THAP11 (via the HMB). Interacts directly with OGT; the interaction, which requires the HCFC1 cleavage site domain, glycosylates and promotes the proteolytic processing of HCFC1, retains OGT in the nucleus and impacts the expression of herpes simplex virus immediate early viral genes. Component of the SET1 complex, at least composed of the catalytic subunit (SETD1A or SETD1B), WDR5, WDR82, RBBP5, ASH2L, CXXC1, HCFC1 and DPY30. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1. Component of a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5; the complex is formed as a result of interactions between components of a nuclear receptor-mediated transcription complex and a histone methylation complex. Within the complex interacts with ZNF335. Interacts with TET2 and TET3. Interacts with HCFC1R1. Interacts with THAP11. Interacts (via Kelch domain) with KMT2E/MLL5 isoform 3 (via HBM motif). Interacts with E2F1. Accessory scaffold component of the polycomb repressive deubiquitinase (PR-DUB) complex, at least composed of BAP1, one of ASXL1, ASXL2 or (probably) ASXL3 and one of MBD5 or MBD6; the PR-DUB core associates with a number of accessory proteins, including FOXK1, FOXK2, KDM1B, HCFC1, YY1 and OGT. Interacts with YY1 (via Gly-rich region); the interaction is direct. Interacts with BAP1 (via HBM-like motif). (Microbial infection) Associates with the VP16-induced complex; binding to HCFC1 activates the viral transcriptional activator VP16 for association with POU2F1, to form a multiprotein-DNA complex responsible for activating transcription of the viral immediate early genes. Interacts with the viral transactivator protein VP16.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in fetal tissues and the adult kidney. Present in all tissues tested.

Post-translational modifications. Proteolytically cleaved at one or several PPCE–THET sites within the HCF repeats. Further cleavage of the primary N- and C-terminal chains results in a ’trimming’ and accumulation of the smaller chains. Cleavage is promoted by O-glycosylation. O-glycosylated. GlcNAcylation by OGT promotes proteolytic processing. Ubiquitinated. Lys-1807 and Lys-1808 are ubiquitinated both via ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains. BAP1 mediated deubiquitination of ‘Lys-48’-linked polyubiquitin chains; deubiquitination by BAP1 does not seem to stabilize the protein.

Disease relevance. Methylmalonic aciduria and homocystinuria, cblX type (MAHCX) [MIM:309541] An X-linked recessive metabolic disorder characterized by severely delayed psychomotor development apparent in infancy, failure to thrive, impaired intellectual development, and intractable epilepsy. Additional features may include microcephaly and choreoathetosis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The HCF repeat is a highly specific proteolytic cleavage signal. The kelch repeats fold into a 6-bladed kelch beta-propeller called the beta-propeller domain which mediates interaction with HCFC1R1.

Miscellaneous. The N- and the C-terminal fragments fail to associate.

Isoforms (4)

UniProt ID	Names	Canonical?
P51610-1	1	yes
P51610-2	2
P51610-3	3
P51610-4	4

RefSeq proteins (2): NP_001397634, NP_005325* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR043536	HCF1/2	Family
IPR059124	Kelch_HCF	Domain

Pfam: PF13854

UniProt features (152 total): mutagenesis site 45, modified residue 19, strand 16, repeat 13, chain 12, region of interest 9, cross-link 8, sequence conflict 7, site 6, compositionally biased region 5, splice variant 4, domain 3, sequence variant 3, initiator methionine 1, helix 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
4N39	X-RAY DIFFRACTION	1.76
4N3A	X-RAY DIFFRACTION	1.88
5LWV	X-RAY DIFFRACTION	1.9
6MA3	X-RAY DIFFRACTION	2
6MA4	X-RAY DIFFRACTION	2
6MA5	X-RAY DIFFRACTION	2
6MA2	X-RAY DIFFRACTION	2.1
4N3B	X-RAY DIFFRACTION	2.17
4N3C	X-RAY DIFFRACTION	2.55
4GO6	X-RAY DIFFRACTION	2.7
6MA1	X-RAY DIFFRACTION	2.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51610-F1	47.89	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (6): 1019–1020 (cleavage; by autolysis); 1081–1082 (cleavage; by autolysis); 1110–1111 (cleavage; by autolysis); 1295–1296 (cleavage; by autolysis); 1323–1324 (cleavage; by autolysis); 1423–1424 (cleavage; by autolysis)

Post-translational modifications (27): 2, 6, 288, 411, 504, 524, 598, 666, 669, 813, 1205, 1219, 1224, 1491, 1497, 1507, 1771, 1838, 2005, 105 …

Mutagenesis-validated functional residues (45):

Position	Phenotype
1072	no effect on cleavage at hcf repeat.
1073	no effect on cleavage at hcf repeat.
1074	no effect on cleavage at hcf repeat.
1075	no effect on cleavage at hcf repeat.
1076	no effect on cleavage at hcf repeat.
1077	no effect on cleavage at hcf repeat.
1078	inactivates cleavage at hcf repeat.
1079–1083	reduces and disrupts cleavage at hcf repeat.
1079	inactivates cleavage at hcf repeat.
1080	inactivates cleavage at hcf repeat.
1081	inactivates cleavage at hcf repeat.
1082	inactivates cleavage at hcf repeat.
1082	reduces cleavage at hcf repeat.
1083	reduces cleavage at hcf repeat.
1084	no effect on cleavage at hcf repeat.
1085	inactivates cleavage at hcf repeat.
1086	no effect on cleavage at hcf repeat.
1087	inactivates cleavage at hcf repeat.
1088	inactivates cleavage at hcf repeat.
1089	reduces cleavage at hcf repeat.
1090	inactivates cleavage at hcf repeat.
1092	inactivates cleavage at hcf repeat.
1093	inactivates cleavage at hcf repeat.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-3214847	HATs acetylate histones
R-HSA-5689603	UCH proteinases
R-HSA-9772755	Formation of WDR5-containing histone-modifying complexes

MSigDB gene sets: 297 (showing top): AGGAAGC_MIR5163P, MORF_DNMT1, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, MORF_ESPL1, MORF_RRM1, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, MORF_HDAC2, MODULE_453, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, NFKB_Q6, PATIL_LIVER_CANCER, KRASNOSELSKAYA_ILF3_TARGETS_DN, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (12): negative regulation of transcription by RNA polymerase II (GO:0000122), blastocyst hatching (GO:0001835), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), positive regulation of gene expression (GO:0010628), release from viral latency (GO:0019046), regulation of protein-containing complex assembly (GO:0043254), positive regulation of cell cycle (GO:0045787), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), protein stabilization (GO:0050821), chromatin organization (GO:0006325)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), protein-macromolecule adaptor activity (GO:0030674), chromatin DNA binding (GO:0031490), identical protein binding (GO:0042802), cadherin binding (GO:0045296), DNA-binding transcription factor binding (GO:0140297), protein binding (GO:0005515)

GO Cellular Component (12): histone acetyltransferase complex (GO:0000123), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), membrane (GO:0016020), protein-containing complex (GO:0032991), histone methyltransferase complex (GO:0035097), neuronal cell body (GO:0043025), NSL complex (GO:0044545), MLL1/2 complex (GO:0044665), Set1C/COMPASS complex (GO:0048188), MLL1 complex (GO:0071339)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Chromatin modifying enzymes	1
Deubiquitination	1
Epigenetic regulation by WDR5-containing histone modifying complexes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of gene expression	2
positive regulation of DNA-templated transcription	2
binding	2
protein binding	2
histone methyltransferase complex	2
negative regulation of DNA-templated transcription	1
blastocyst development	1
hatching	1
chromatin organization	1
regulation of RNA biosynthetic process	1
gene expression	1
positive regulation of macromolecule biosynthetic process	1
viral process	1
latent virus replication	1
regulation of cellular component biogenesis	1
regulation of cellular component organization	1
protein-containing complex assembly	1
cell cycle	1
positive regulation of cellular process	1
regulation of cell cycle	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of protein stability	1
cellular component organization	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
transcription coregulator activity	1
molecular adaptor activity	1
DNA binding	1
chromatin binding	1
cell adhesion molecule binding	1
transcription factor binding	1
chromatin	1
protein acetyltransferase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1855 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCFC1	WDR5	P61964	991
HCFC1	SETD1A	O15047	990
HCFC1	RBBP5	Q15291	988
HCFC1	CREBZF	Q9NS37	985
HCFC1	ASH2L	Q9UBL3	983
HCFC1	OGT	O15294	982
HCFC1	POU2F1	P14859	982
HCFC1	PHF8	Q9UPP1	955
HCFC1	DPY30	Q9C005	943
HCFC1	CREB3	O43889	928
HCFC1	E2F1	Q01094	919
HCFC1	FOXK1	P85037	883
HCFC1	CREB3L4	Q8TEY5	882
HCFC1	KDM1A	O60341	869
HCFC1	BAP1	Q92560	846

IntAct

247 interactions, top by confidence:

A	B	Type	Score
ASH2L	KMT2D	psi-mi:“MI:0914”(association)	0.890
RBBP5	KMT2D	psi-mi:“MI:0914”(association)	0.840
HCFC1	ASH2L	psi-mi:“MI:0915”(physical association)	0.800
NFE2L3	MAFG	psi-mi:“MI:0914”(association)	0.780
WDR5	HCFC1	psi-mi:“MI:0915”(physical association)	0.770
CREBZF	HCFC1	psi-mi:“MI:0915”(physical association)	0.770
OGT	HCFC1	psi-mi:“MI:0915”(physical association)	0.760
HCFC1	OGT	psi-mi:“MI:0570”(protein cleavage)	0.760
OGT	HCFC1	psi-mi:“MI:0570”(protein cleavage)	0.760
HCFC1	OGT	psi-mi:“MI:0915”(physical association)	0.760
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
BAP1	OGT	psi-mi:“MI:0914”(association)	0.730
FOXN2	RFX1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
WDR5	MEN1	psi-mi:“MI:0914”(association)	0.710
SP1	HCFC1	psi-mi:“MI:0915”(physical association)	0.680
DIDO1	OGT	psi-mi:“MI:0914”(association)	0.670
HCFC1	CREB3	psi-mi:“MI:0915”(physical association)	0.660
DDAH2	EPB41L2	psi-mi:“MI:0914”(association)	0.640
KMT2A	MEN1	psi-mi:“MI:0914”(association)	0.640

BioGRID (535): HCFC1 (Affinity Capture-MS), HCFC1 (Affinity Capture-Western), HCFC1 (Affinity Capture-Western), HCFC1 (Affinity Capture-Western), HCFC1 (Affinity Capture-Western), HCFC1 (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), HCFC1 (Co-fractionation), HCFC1 (Co-fractionation), HCFC1 (Co-fractionation), HCFC1 (Co-fractionation)

ESM2 similar proteins: A1Z9E2, B0R0I6, B5DE69, D3ZN95, E9Q7E2, P14859, P15143, P16143, P25425, P27699, P47825, P49848, P51610, P51611, Q02086, Q02446, Q03061, Q08CM4, Q09XV5, Q0IHV2, Q0P5K4, Q28BL7, Q29076, Q3TUF7, Q571G4, Q5E9U0, Q5F3U0, Q5R6A9, Q5RBN8, Q61191, Q62445, Q641Z1, Q68CP9, Q6MZP7, Q6P4L9, Q6ZPK0, Q7Z589, Q7ZUV7, Q7ZX03, Q86NP2

Diamond homologs: A8JAM0, D3ZN95, P38853, P51610, P51611, Q2R2W1, Q39610, Q4V516, Q5E9A7, Q5RKG2, Q61191, Q6PDJ6, Q7M3S9, Q86L99, Q8N7A1, Q8RWD9, Q9D968, Q9MA55, Q9V4C8, Q9Y5Z7, G5EC23, Q10AZ7, Q4V8F4, Q53EP0, Q5RDA9, Q6AYI2, Q6NWW9, Q6P3S6, Q8H4D4, Q8VEM9, Q93XW5, Q9BQ90, G5EF96, P16621, Q9V410, P50090, P87061, Q67UX0, Q6A051, Q94BT6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
GABPB2	“down-regulates activity”	HCFC1	binding
GABPB1	“down-regulates activity”	HCFC1	binding
HCFC1	“up-regulates activity”	“Set1-Ash2 HMT complex”	binding
HCFC1	“form complex”	“NSL histone acetyltransferase”	binding
HCFC1	“down-regulates activity”	ZBTB17	binding
HCFC1	“up-regulates activity”	CREB3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 185 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
Formation of WDR5-containing histone-modifying complexes	12	26.1×	1e-11
MECP2 regulates neuronal receptors and channels	5	24.6×	8e-05
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	11	13.2×	2e-07
Deactivation of the beta-catenin transactivating complex	6	11.5×	5e-04
mRNA 3’-end processing	7	11.3×	1e-04
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	11	10.8×	1e-06
Epigenetic regulation by WDR5-containing histone modifying complexes	8	10.1×	8e-05
Formation of the beta-catenin:TCF transactivating complex	9	8.9×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of stem cell population maintenance	5	23.5×	3e-04
negative regulation of type I interferon production	5	15.2×	2e-03
heterochromatin formation	9	14.1×	5e-06
transcription initiation-coupled chromatin remodeling	6	14.1×	6e-04
positive regulation of stem cell population maintenance	6	12.7×	9e-04
circadian regulation of gene expression	6	8.6×	5e-03
mRNA splicing, via spliceosome	12	6.7×	4e-05
negative regulation of cell migration	9	6.2×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1716 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	6
Uncertain significance	396
Likely benign	747
Benign	204

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1299214	NM_005334.3(HCFC1):c.6046C>T (p.Arg2016Trp)	Pathogenic
208691	NM_005334.3(HCFC1):c.5860G>A (p.Gly1954Arg)	Pathogenic
224121	NM_005334.3(HCFC1):c.5048C>G (p.Pro1683Arg)	Pathogenic
39694	NM_005334.3(HCFC1):c.-970T>C	Pathogenic
39695	NM_005334.3(HCFC1):c.674G>A (p.Ser225Asn)	Pathogenic
4033929	NM_005334.3(HCFC1):c.1367dup (p.Thr457fs)	Pathogenic
4796314	GRCh38/hg38 Xq28(chrX:153958631-154171022)x2	Pathogenic
584394	NC_000023.10:g.(?153184286)(153409869_?)dup	Pathogenic
66984	NM_005334.3(HCFC1):c.344C>T (p.Ala115Val)	Pathogenic
66986	NM_005334.3(HCFC1):c.217G>A (p.Ala73Thr)	Pathogenic
3062162	NM_005334.3(HCFC1):c.5705G>A (p.Ser1902Asn)	Likely pathogenic
3773823	NM_005334.3(HCFC1):c.4094C>T (p.Thr1365Ile)	Likely pathogenic
3893250	NM_005334.3(HCFC1):c.97C>T (p.Arg33Cys)	Likely pathogenic
424161	NM_005334.3(HCFC1):c.1781_1803+3delinsCA	Likely pathogenic
429997	NM_005334.3(HCFC1):c.5491C>T (p.Pro1831Ser)	Likely pathogenic
4823492	NM_005334.3(HCFC1):c.214C>A (p.Pro72Thr)	Likely pathogenic

SpliceAI

3755 predictions. Top by Δscore:

Variant	Effect	Δscore
X:153949386:CCT:C	acceptor_gain	1.0000
X:153949388:T:C	acceptor_gain	1.0000
X:153949388:T:TC	acceptor_gain	1.0000
X:153949396:C:CT	acceptor_gain	1.0000
X:153949397:A:T	acceptor_gain	1.0000
X:153949543:T:TA	donor_gain	1.0000
X:153949547:GCTTA:G	donor_loss	1.0000
X:153949548:CTTA:C	donor_loss	1.0000
X:153949549:TTA:T	donor_loss	1.0000
X:153949550:TAC:T	donor_loss	1.0000
X:153949551:A:AC	donor_gain	1.0000
X:153949551:ACAT:A	donor_loss	1.0000
X:153949552:C:CA	donor_gain	1.0000
X:153949552:CA:C	donor_gain	1.0000
X:153949552:CATTT:C	donor_gain	1.0000
X:153949614:TTTC:T	acceptor_loss	1.0000
X:153949615:TTC:T	acceptor_loss	1.0000
X:153949616:TCTGG:T	acceptor_loss	1.0000
X:153949617:C:A	acceptor_loss	1.0000
X:153949617:C:CC	acceptor_gain	1.0000
X:153949618:T:A	acceptor_loss	1.0000
X:153950239:TCAC:T	donor_loss	1.0000
X:153950241:AC:A	donor_gain	1.0000
X:153950242:C:A	donor_loss	1.0000
X:153950242:CC:C	donor_gain	1.0000
X:153950242:CCCTG:C	donor_gain	1.0000
X:153950257:A:AC	donor_gain	1.0000
X:153950258:C:CC	donor_gain	1.0000
X:153950276:AGC:A	donor_gain	1.0000
X:153950542:CT:C	acceptor_gain	1.0000

AlphaMissense

13015 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:153950250:C:A	W1999C	1.000
X:153950250:C:G	W1999C	1.000
X:153950252:A:G	W1999R	1.000
X:153950252:A:T	W1999R	1.000
X:153950272:C:T	G1992D	1.000
X:153950290:C:G	R1986P	1.000
X:153950293:G:T	A1985D	1.000
X:153950296:G:T	A1984D	1.000
X:153950299:A:C	I1983S	1.000
X:153950299:A:T	I1983N	1.000
X:153950302:C:G	R1982P	1.000
X:153950304:G:C	F1981L	1.000
X:153950304:G:T	F1981L	1.000
X:153950305:A:G	F1981S	1.000
X:153950306:A:G	F1981L	1.000
X:153950370:G:C	C1959W	1.000
X:153950372:A:G	C1959R	1.000
X:153950403:G:C	F1948L	1.000
X:153950403:G:T	F1948L	1.000
X:153950405:A:G	F1948L	1.000
X:153950467:A:G	L1927P	1.000
X:153950473:A:T	V1925E	1.000
X:153950477:A:G	S1924P	1.000
X:153950517:C:A	W1910C	1.000
X:153950517:C:G	W1910C	1.000
X:153950518:C:G	W1910S	1.000
X:153950519:A:G	W1910R	1.000
X:153950519:A:T	W1910R	1.000
X:153950524:A:G	L1908P	1.000
X:153950524:A:T	L1908H	1.000

dbSNP variants (sampled 300 via entrez): RS1000024340 (X:153960717 G>A), RS1000069168 (X:153950424 G>A,C), RS1000177621 (X:153957289 C>T), RS1000352259 (X:153964798 G>T), RS1000463445 (X:153964361 A>T), RS1000646328 (X:153971661 C>G), RS1000933507 (X:153971902 C>A,G,T), RS1001068985 (X:153952251 C>T), RS1001314634 (X:153968155 C>T), RS1001600478 (X:153968480 G>A), RS1001732609 (X:153948956 G>T), RS1002021490 (X:153963091 G>A), RS1002203457 (X:153970134 G>A,C), RS1002620023 (X:153952546 G>A), RS1002679 (X:153959311 C>A)

Disease associations

OMIM: gene MIM:300019 | disease phenotypes: MIM:309541, MIM:300049, MIM:304120, MIM:309350, MIM:305620, MIM:308350, MIM:147920, MIM:300673, MIM:277400

GenCC curated gene-disease

Disease	Classification	Inheritance
methylmalonic acidemia with homocystinuria, type cblX	Definitive	X-linked
X-linked intellectual disability	Definitive	X-linked
non-syndromic X-linked intellectual disability	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked intellectual disability	Definitive	XL

Mondo (13): methylmalonic acidemia with homocystinuria, type cblX (MONDO:0010657), X-linked intellectual disability (MONDO:0100284), autosomal recessive disease (MONDO:0006025), heterotopia, periventricular, X-linked dominant (MONDO:0010233), otopalatodigital syndrome type 2 (MONDO:0010571), Melnick-Needles syndrome (MONDO:0010650), frontometaphyseal dysplasia (MONDO:0015942), genetic developmental and epileptic encephalopathy (MONDO:0100062), intellectual disability (MONDO:0001071), Kabuki syndrome 1 (MONDO:0007843), severe neonatal-onset encephalopathy with microcephaly (MONDO:0010397), methylmalonic aciduria and homocystinuria type cblC (MONDO:0010184), non-syndromic X-linked intellectual disability (MONDO:0019181)

Orphanet (12): Methylmalonic acidemia with homocystinuria, type cblX (Orphanet:369962), Frontometaphyseal dysplasia (Orphanet:1826), Nodular neuronal heterotopia (Orphanet:2149), Melnick-Needles syndrome (Orphanet:2484), OBSOLETE: Otopalatodigital syndrome (Orphanet:669), Ehlers-Danlos syndrome with periventricular heterotopia (Orphanet:82004), Otopalatodigital syndrome type 2 (Orphanet:90652), Kabuki syndrome (Orphanet:2322), MECP2-related severe neonatal encephalopathy (Orphanet:209370), Methylmalonic acidemia with homocystinuria (Orphanet:26), Methylmalonic acidemia with homocystinuria, type cblC (Orphanet:79282), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

22 total (22 of 22 shown, HPO-id order):

HPO	Term
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0002072	Chorea
HP:0002156	Homocystinuria
HP:0002160	Hyperhomocystinemia
HP:0002188	Delayed CNS myelination
HP:0002305	Athetosis
HP:0002521	Hypsarrhythmia
HP:0002912	Methylmalonic acidemia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004322	Short stature
HP:0012120	Methylmalonic aciduria
HP:0012469	Infantile spasms
HP:0030674	Antenatal onset

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003155_27	Systemic lupus erythematosus	2.000000e-15
GCST005523_40	Celiac disease	3.000000e-08
GCST005568_10	Rheumatoid arthritis (ACPA-positive)	1.000000e-12
GCST005569_32	Rheumatoid arthritis	3.000000e-12

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C566878	Encephalopathy, Neonatal Severe, Due To Mecp2 Mutations (supp.)
C538064	Frontometaphyseal dysplasia (supp.)
C563136	Mental Retardation, X-Linked 3 (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)
C538089	Oto-palato-digital syndrome, type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724666 (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

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

pChembl	Type	Value	Unit	Molecule
7.28	Kd	52.29	nM	CHEMBL5653589
7.28	ED50	52.29	nM	CHEMBL5653589
7.17	Kd	68	nM	MOLIBRESIB
6.89	IC50	130	nM	MOLIBRESIB
5.85	Kd	1414	nM	CHEMBL3752910
5.85	ED50	1414	nM	CHEMBL3752910

PubChem BioAssay actives

4 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148492: Binding affinity to human HCFC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0523	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	2179210: Binding affinity against HCFC1 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0680	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148492: Binding affinity to human HCFC1 incubated for 45 mins by Kinobead based pull down assay	kd	1.4143	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, increases abundance	5
Arsenic	increases expression, affects methylation, increases abundance	2
Valproic Acid	affects expression, increases methylation	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
lead acetate	increases expression	1
trichostatin A	affects expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
abrine	decreases expression	1
Irinotecan	decreases expression	1
Arsenic Trioxide	affects cotreatment, increases expression	1
Ascorbic Acid	affects cotreatment, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Benztropine	affects cotreatment, increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Carmustine	decreases expression	1
Catechin	increases expression	1
Cisplatin	decreases expression	1
Cuprizone	affects cotreatment, increases 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
CHEMBL5651534	Binding	Binding affinity to human HCFC1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2L4	SEES3-1V human HCFC1, clone1	Embryonic stem cell	Male
CVCL_A2L5	SEES3-1V human HCFC1, clone2	Embryonic stem cell	Male
CVCL_A2L6	SEES3-1V human HCFC1, clone3	Embryonic stem cell	Male
CVCL_B3Z7	WG3023	Finite cell line	Female
CVCL_B3ZA	WG3357	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05857085	PHASE4	COMPLETED	Novel Therapeutics and Endothelial Dysfunction in T1DM Patients
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06500260	Not specified	RECRUITING	CNKSR2 Natural History Study
NCT03013777	Not specified	COMPLETED	A Trial of Cognitive Behavioral Therapy in Familial Dysautonomia
NCT05747924	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT01862146	Not specified	COMPLETED	Arterial Remodeling in Smokers
NCT02127333	Not specified	COMPLETED	Role of Oxygen for Vascular Dysfunction
NCT04199949	Not specified	COMPLETED	Effects of Five Days of Physical Inactivity on Endothelial Function in Healthy Humans
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills