H1-2

Summary

H1-2 (H1.2 linker histone, cluster member, HGNC:4716) is a protein-coding gene on chromosome 6p22.2, encoding Histone H1.2 (P16403). Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. It is a selective cancer dependency (DepMap: 12.4% of cell lines).

Histones are basic nuclear proteins responsible for nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H1 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.

Source: NCBI Gene 3006 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 127 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 12.4% of screened cell lines
• MANE Select transcript: NM_005319

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4716
Approved symbol	H1-2
Name	H1.2 linker histone, cluster member
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	H1.2, H1s-1, H1c
Ensembl gene	ENSG00000187837
Ensembl biotype	protein_coding
OMIM	142710
Entrez	3006

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000343677, ENST00000718281

RefSeq mRNA: 1 — MANE Select: NM_005319 NM_005319

CCDS: CCDS4577

Canonical transcript exons

ENST00000343677 — 1 exons

Exon	Start	End
ENSE00004034618	26055740	26056470

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1915.1820 / max 61459.6126, expressed in 1824 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72304	1915.1820	1824

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.41	gold quality
adrenal tissue	UBERON:0018303	98.77	gold quality
mucosa of transverse colon	UBERON:0004991	98.53	gold quality
colonic epithelium	UBERON:0000397	98.27	gold quality
apex of heart	UBERON:0002098	98.07	gold quality
gastrocnemius	UBERON:0001388	97.57	gold quality
muscle of leg	UBERON:0001383	97.50	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.10	gold quality
metanephros cortex	UBERON:0010533	96.94	gold quality
right uterine tube	UBERON:0001302	96.79	gold quality
heart left ventricle	UBERON:0002084	96.73	gold quality
cardiac ventricle	UBERON:0002082	96.36	gold quality
lower esophagus mucosa	UBERON:0035834	96.12	gold quality
muscle organ	UBERON:0001630	95.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.75	gold quality
right lobe of liver	UBERON:0001114	95.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.52	gold quality
right atrium auricular region	UBERON:0006631	95.46	gold quality
right lung	UBERON:0002167	95.33	gold quality
prostate gland	UBERON:0002367	94.93	gold quality
islet of Langerhans	UBERON:0000006	94.88	gold quality
right adrenal gland	UBERON:0001233	94.88	gold quality
right lobe of thyroid gland	UBERON:0001119	94.83	gold quality
heart	UBERON:0000948	94.53	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.51	gold quality
gluteal muscle	UBERON:0002000	94.46	gold quality
sural nerve	UBERON:0015488	94.37	gold quality
right adrenal gland cortex	UBERON:0035827	94.35	gold quality
monocyte	CL:0000576	94.07	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	6575.33
E-MTAB-6911	yes	257.41
E-HCAD-4	yes	100.32
E-CURD-122	yes	38.93
E-CURD-46	yes	38.35
E-MTAB-9467	yes	33.10
E-HCAD-1	yes	26.39
E-MTAB-6701	yes	19.64
E-HCAD-10	yes	16.48
E-MTAB-9067	yes	12.91
E-MTAB-9689	no	195.03
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA1, HBP1, JUN, NR3C1, PARP1, PGR, TBP, TBPL1, TFCP2, TP53, ZBED1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 12.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• confirmed N-terminal acetylation on all isoforms plus a single internal acetylation site; phosphorylation sites were located on peptides containing the cyclin dependent kinase (CDK) consensus motif (PMID:15595731)
• The binding of histone H1 to a general amyloid-like motif indicates that histone H1 may play an important common role in diseases associated with amyloid-like fibrils. (PMID:16854430)
• Histone H1.2 was translocated from the nucleus to the mitochondria after treatment with bleomycin and co-localized with Bak in mitochondria. (PMID:17879944)
• that the recruitment of YB1, PURalpha, and H1.2 to the p53 target gene Bax is required for repression of p53-induced transcription. (PMID:18258596)
• These data suggest that p53 acetylation-H1.2 phosphorylation cascade serves as a unique mechanism for triggering p53-dependent DNA damage response pathways. (PMID:22249259)
• H1.2 interacts with Cul4A and PAF1 to activate developmental regulatory genes. (PMID:24360965)
• Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. (PMID:24435047)
• H1.2 is less abundant than other histone H1 variants at the transcription start sites of inactive genes, and promoters enriched in H1.2 are different from those enriched in other histone H1 variants and tend to be repressed. (PMID:24476918)
• Integration with apoptotic intermediates (via C-terminal tail interactions) may constitute a more generalized function of linker histone isoforms in apoptotic cascades. (PMID:24525734)
• Histone H1.2-T165 post translational modifications are dispensable for chromatin binding and cell proliferation while the H1.4-K26 modifications are essential for proper cell cycle progression. (PMID:24873882)
• Results show that histones H1.2 and H1.4 were observed in MDA-MB-231 metastatic breast cancer cells. The phosphorylation at S173 of histone H1.2 and S172, S187, T18, T146, and T154 of H1.4 significantly increases during M phase suggesting that these events are cell cycle-dependent. Also, the study reports the observation of the H1.2 SNP variant A18V in MCF-10A cells. (PMID:26209608)
• BRG1 participates in gene repression by interacting with H1.2, facilitating its deposition and stabilizing nucleosome positioning around the transcription start site. (PMID:27390128)
• results define a network of E2F target genes as susceptible to the regulatory influence of H1.2, where H1.2 augments global association of pRb with chromatin, enhances transcriptional repression by pRb, and facilitates pRb-dependent cell-cycle arrest (PMID:28614707)
• The linker histone H1.2 is a novel component of nucleolar organizer regions. (PMID:29301938)
• these findings suggest that linker histone H1.2 functions as a physiological barrier for ATM to target the chromatin, and PARylation-mediated active H1.2 turnover is required for robust ATM activation and DNA damage repair. (PMID:29844578)
• Taken together, these data provide important insights into a surprisingly complex hTR-RNA interaction network and define an unexpected non-coding RNA role for HIST1H1C in regulating telomere length homeostasis. (PMID:30355447)
• Site-specific ubiquitylation acts as a regulator of linker histone H1. (PMID:34108453)
• Interactome of intact chromatosome variants with site-specifically ubiquitylated and acetylated linker histone H1.2. (PMID:37994785)
• Histone H1.2 Inhibited EMCV Replication through Enhancing MDA5-Mediated IFN-beta Signaling Pathway. (PMID:38399950)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
mus_musculus	H1f2	ENSMUSG00000036181
rattus_norvegicus	H1f2	ENSRNOG00000067441
caenorhabditis_elegans		WBGENE00001853
caenorhabditis_elegans		WBGENE00001854
caenorhabditis_elegans		WBGENE00001855
caenorhabditis_elegans	hil-5	WBGENE00001856
caenorhabditis_elegans		WBGENE00001857

Paralogs (9): H1-3 (ENSG00000124575), H1-1 (ENSG00000124610), H1-4 (ENSG00000168298), H1-8 (ENSG00000178804), H1-5 (ENSG00000184357), H1-10 (ENSG00000184897), H1-7 (ENSG00000187166), H1-6 (ENSG00000187475), H1-0 (ENSG00000189060)

Protein

Protein identifiers

Histone H1.2 — P16403 (reviewed: P16403)

Alternative names: Histone H1c, Histone H1d, Histone H1s-1

All UniProt accessions (1): P16403

UniProt curated annotations — full annotation on UniProt →

Function. Histone H1 protein binds to linker DNA between nucleosomes forming the macromolecular structure known as the chromatin fiber. Histone H1-2 is required for the condensation of nucleosome chains into higher-order structured fibers. Compared to other histone H1 variants, H1-2 plays an essnetial role in nucleosome condensation: its absence leads to global chromatin decompaction, which is not observed when depleting other histone H1 variants. Histone H1-2 also acts as a histone reader: specifically recognizes and binds histone H3 trimethylated at ’lys-27’ (H3K27me3). Histones H1 also promote formation of the H3K27me3 mark by the PRC2/EED-EZH2 complex, possibly by facilitating restoration of H3K27me3 post-replication. Together with histone H1-3, histone H1-2 acts as a regulator of splicing, most specifically exon skipping and intron retention events: histone H1-2 has a high affinity for exons and regulates splicing by affecting RNA polymerase II (RNAPII) elongation. Also acts as a regulator of individual gene transcription through chromatin remodeling, nucleosome spacing and DNA methylation.

Subunit / interactions. Associates with nucleosomes, promoting condensation into higher-order structured chromatin. Interacts with TSC22D1 isoforms 2 and 5.

Subcellular location. Nucleus. Nucleolus. Chromosome.

Post-translational modifications. Deamidation of Asn-76 and Asn-77 by CTPS1 in response to DNA damage promotes subsequent acetylation of histo75 (H1K75ac). Acetylated at Lys-75 (H1K75ac) by EP300 following deamidation of Asn-76 and Asn-77 by CTPS1 in response to DNA damage, thereby increasing chromatin accessibility to facilitate the recruitment of DNA repair proteins. H1 histones are progressively phosphorylated during the cell cycle, becoming maximally phosphorylated during late G2 phase and M phase, and being dephosphorylated sharply thereafter. Phosphorylation at Thr-165 is associated with condensed chromosomes, with maximum levels occurring at metaphase and drastically dropping down at later mitotic phases. During interphase, phosphorylation at Thr-165 is enriched within nucleoli. Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes. Citrullination at Arg-54 (H1R54ci) by PADI4 takes place within the DNA-binding site of H1 and results in its displacement from chromatin and global chromatin decondensation, thereby promoting pluripotency and stem cell maintenance. ADP-ribosylated on Ser-188 in response to DNA damage.

Domain organisation. The C-terminal domain is required for high-affinity binding to chromatin.

Induction. Expression is activated by transcription factor CRAMP1, in collaboration with NPAT and GON4L.

Similarity. Belongs to the histone H1/H5 family.

RefSeq proteins (1): NP_005310* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005818	Histone_H1/H5_H15	Domain
IPR005819	H1/H5	Family
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily

Pfam: PF00538

UniProt features (78 total): modified residue 63, compositionally biased region 5, sequence variant 3, region of interest 2, mutagenesis site 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8H0V	ELECTRON MICROSCOPY	3.8
8KE0	ELECTRON MICROSCOPY	4
8H0W	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16403-F1	65.22	0.32

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 (63): 2, 2, 17, 23, 26, 26, 27, 34, 34, 34, 34, 46, 46, 52, 52, 52, 54, 63, 63, 64 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
120–132	impared ability to recognize and bind histone h3 trimethylated at ’lys-27’ (h3k27me3).
187	abolishes methylation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-140342	Apoptosis induced DNA fragmentation
R-HSA-2559584	Formation of Senescence-Associated Heterochromatin Foci (SAHF)

MSigDB gene sets: 319 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, MODULE_52, GOBP_REGULATION_OF_DNA_RECOMBINATION, KOBAYASHI_EGFR_SIGNALING_24HR_UP, MODULE_169, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, SATO_SILENCED_BY_DEACETYLATION_IN_PANCREATIC_CANCER, GOBP_CHROMOSOME_CONDENSATION, GOLDRATH_ANTIGEN_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, MODULE_75

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), nucleosome assembly (GO:0006334), chromosome condensation (GO:0030261), negative regulation of DNA recombination (GO:0045910), regulation of mRNA splicing, via spliceosome (GO:0048024), facultative heterochromatin formation (GO:0140718), chromatin organization (GO:0006325), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (8): double-stranded DNA binding (GO:0003690), RNA binding (GO:0003723), structural constituent of chromatin (GO:0030527), chromatin DNA binding (GO:0031490), nucleosomal DNA binding (GO:0031492), histone H3K27me3 reader activity (GO:0061628), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): nucleosome (GO:0000786), euchromatin (GO:0000791), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleolus (GO:0005730), chromatin (GO:0000785), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Apoptotic execution phase	1
DNA Damage/Telomere Stress Induced Senescence	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromatin	4
transcription by RNA polymerase II	2
DNA binding	2
nucleic acid binding	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
chromosome organization	1
regulation of DNA recombination	1
DNA recombination	1
negative regulation of DNA metabolic process	1
mRNA splicing, via spliceosome	1
regulation of RNA splicing	1
regulation of mRNA processing	1
heterochromatin formation	1
cellular component organization	1
regulation of DNA-templated transcription	1
structural molecule activity	1
chromatin binding	1
chromatin DNA binding	1
nucleosome binding	1
histone H3 reader activity	1
binding	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
chromosome	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1436 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H1-2	H2AC19	P20670	773
H1-2	H2AC20	Q16777	772
H1-2	H2BC21	Q16778	732
H1-2	H1-7	Q75WM6	730
H1-2	STH	Q8IWL8	723
H1-2	H1-8	Q8IZA3	711
H1-2	MAPT	P10636	661
H1-2	WNT3	P56703	639
H1-2	H1-3	P16402	622
H1-2	H1-4	P10412	586
H1-2	KANSL1	Q7Z3B3	580
H1-2	CRHR1	P34998	577
H1-2	CUL4A	Q13619	533
H1-2	PTMA	P06454	527
H1-2	H1-6	P22492	526

IntAct

360 interactions, top by confidence:

A	B	Type	Score
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
H1-2	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H1-2	H2AC21	psi-mi:“MI:0915”(physical association)	0.560
BAZ1B	H1-2	psi-mi:“MI:0915”(physical association)	0.560
FTSJ3	H1-2	psi-mi:“MI:0915”(physical association)	0.560
DDX21	H1-2	psi-mi:“MI:0915”(physical association)	0.560
RPL30	RRP8	psi-mi:“MI:0914”(association)	0.530
ZBTB48	ZBTB24	psi-mi:“MI:0914”(association)	0.530
BHLHA15	RPLP0	psi-mi:“MI:0914”(association)	0.530
RNF168	H1-2	psi-mi:“MI:0915”(physical association)	0.400
SSPN	H1-2	psi-mi:“MI:0915”(physical association)	0.400
H1-2	H1-4	psi-mi:“MI:0915”(physical association)	0.400
H1-2	H3-4	psi-mi:“MI:0915”(physical association)	0.400
H1-2	H1-1	psi-mi:“MI:0915”(physical association)	0.400
H1-2	BICD2	psi-mi:“MI:0915”(physical association)	0.400
H1-2	H3C13	psi-mi:“MI:0915”(physical association)	0.400
SPATA24	H1-2	psi-mi:“MI:0915”(physical association)	0.400
CCDC91	H1-2	psi-mi:“MI:0915”(physical association)	0.400
CALY	H1-2	psi-mi:“MI:0915”(physical association)	0.400
RGS11	H1-2	psi-mi:“MI:0915”(physical association)	0.400
ASCL5	H1-2	psi-mi:“MI:0915”(physical association)	0.400
H1-2	GBP3	psi-mi:“MI:0915”(physical association)	0.400
H1-2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
PHF3	H1-2	psi-mi:“MI:0915”(physical association)	0.400
REV1	H1-2	psi-mi:“MI:0915”(physical association)	0.400
EHBP1	H1-2	psi-mi:“MI:0915”(physical association)	0.400
UTRN	H1-2	psi-mi:“MI:0915”(physical association)	0.400
FMNL1	H1-2	psi-mi:“MI:0915”(physical association)	0.400
H1-5	H1-2	psi-mi:“MI:0915”(physical association)	0.400
PCP4L1	H1-2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (943): HIST1H1C (Biochemical Activity), HIST1H1C (Affinity Capture-MS), CTR9 (Affinity Capture-MS), LEO1 (Affinity Capture-MS), PAF1 (Affinity Capture-MS), CDC73 (Affinity Capture-MS), WDR61 (Affinity Capture-MS), CUL4A (Affinity Capture-MS), DDB1 (Affinity Capture-MS), RBX1 (Affinity Capture-MS), WDR5 (Affinity Capture-MS), VPRBP (Affinity Capture-MS), CTR9 (Affinity Capture-Western), LEO1 (Affinity Capture-Western), CDC73 (Affinity Capture-Western)

ESM2 similar proteins: A7MAZ5, D3ZBN0, D4A3K5, G3N131, P02251, P02252, P02253, P02254, P06350, P06893, P07305, P08284, P08285, P08286, P08287, P08288, P09426, P09987, P10412, P15796, P15864, P15865, P15866, P15867, P15870, P16401, P16402, P16403, P21895, P22844, P22845, P23444, P27806, P35060, P40262, P40263, P40264, P40265, P40266, P40275

Diamond homologs: A7MAZ5, D3ZBN0, D3ZZW6, D4A3K5, G3N131, O01833, O16277, P02251, P02252, P02253, P02254, P02255, P02256, P02257, P02258, P02259, P06144, P06348, P06349, P06350, P06513, P06892, P06893, P06894, P07305, P07796, P08284, P08285, P08286, P08287, P08288, P09426, P09987, P10412, P10922, P15796, P15864, P15865, P15866, P15867

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ITCH	“up-regulates activity”	H1-2	polyubiquitination
RNF168	down-regulates	H1-2	polyubiquitination
RNF8	down-regulates	H1-2	polyubiquitination
H1-2	“down-regulates activity”	TP53BP1	binding
PRKDC	“down-regulates activity”	H1-2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 219 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 Senescence-Associated Heterochromatin Foci (SAHF)	5	23.3×	3e-04
Packaging Of Telomere Ends	7	10.7×	3e-04
Metalloprotease DUBs	5	10.4×	2e-03
Recognition and association of DNA glycosylase with site containing an affected purine	7	9.9×	4e-04
Cleavage of the damaged purine	7	9.9×	4e-04
Condensation of Prophase Chromosomes	9	9.8×	2e-04
SIRT1 negatively regulates rRNA expression	8	9.5×	3e-04
Chromatin modifications during the maternal to zygotic transition (MZT)	8	9.1×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of DNA recombination	5	28.4×	3e-04
chromosome condensation	5	21.3×	1e-03
nucleosome assembly	14	9.9×	1e-07
heterochromatin formation	7	9.0×	3e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	122
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

115 predictions. Top by Δscore:

Variant	Effect	Δscore
6:26055917:G:C	donor_gain	0.7100
6:26055977:G:C	donor_gain	0.7000
6:26056176:TGAG:T	donor_gain	0.6800
6:26056065:TTTTA:T	donor_gain	0.6400
6:26056167:CCAGG:C	donor_gain	0.6400
6:26055924:T:A	donor_gain	0.6200
6:26055916:AG:A	donor_gain	0.6000
6:26055835:AGCGG:A	donor_gain	0.5800
6:26055795:T:TA	donor_gain	0.5700
6:26055929:G:C	donor_gain	0.5700
6:26055951:T:TA	donor_gain	0.5700
6:26056161:TGC:T	donor_loss	0.5700
6:26056162:GC:G	donor_loss	0.5700
6:26056163:CTCA:C	donor_loss	0.5700
6:26056164:TCACC:T	donor_loss	0.5700
6:26056165:CACC:C	donor_loss	0.5700
6:26056166:ACCAG:A	donor_loss	0.5700
6:26056167:C:CG	donor_loss	0.5700
6:26055903:T:TA	donor_gain	0.5600
6:26056160:TTGC:T	donor_loss	0.5600
6:26055915:TAGCC:T	donor_gain	0.5400
6:26055916:AGCCA:A	donor_gain	0.5400
6:26055960:T:A	donor_gain	0.5400
6:26055963:T:TA	donor_gain	0.5300
6:26055860:G:C	donor_gain	0.5100
6:26055925:CTTGG:C	donor_gain	0.5100
6:26055926:TTGGT:T	donor_gain	0.5100
6:26055927:TGGTT:T	donor_gain	0.5100
6:26056086:C:A	donor_gain	0.5100
6:26056193:CGG:C	donor_gain	0.5100

AlphaMissense

1356 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:26056114:A:C	F105L	1.000
6:26056114:A:T	F105L	1.000
6:26056115:A:G	F105S	1.000
6:26056116:A:G	F105L	1.000
6:26056137:C:G	G98R	1.000
6:26056262:C:T	G56E	1.000
6:26056115:A:C	F105C	0.999
6:26056121:C:T	G103D	0.999
6:26056122:C:G	G103R	0.999
6:26056130:C:T	G100D	0.999
6:26056136:C:A	G98V	0.999
6:26056136:C:T	G98D	0.999
6:26056137:C:A	G98C	0.999
6:26056151:A:T	L93Q	0.999
6:26056178:A:T	L84H	0.999
6:26056190:A:C	I80S	0.999
6:26056193:C:G	R79P	0.999
6:26056194:G:T	R79S	0.999
6:26056240:T:A	K63N	0.999
6:26056240:T:G	K63N	0.999
6:26056263:C:G	G56R	0.999
6:26056263:C:T	G56R	0.999
6:26056298:A:T	I44N	0.999
6:26056111:T:A	K106N	0.998
6:26056111:T:G	K106N	0.998
6:26056119:A:G	S104P	0.998
6:26056121:C:A	G103V	0.998
6:26056122:C:A	G103C	0.998
6:26056125:A:G	S102P	0.998
6:26056127:G:T	A101D	0.998

dbSNP variants (sampled 300 via entrez): RS1000040165 (6:26055281 T>C), RS1000409096 (6:26055466 A>C), RS1000903196 (6:26056428 T>C), RS1000914731 (6:26058169 T>C), RS1001712340 (6:26055707 AAAG>A), RS1001826657 (6:26055647 T>C,G), RS1002634339 (6:26057816 T>G), RS1007194791 (6:26055503 G>C), RS1007330470 (6:26055583 G>A), RS1007709317 (6:26057029 G>A), RS1008854347 (6:26055439 A>C), RS1008976832 (6:26055321 A>G), RS1009478218 (6:26058408 G>A,C), RS1009589861 (6:26057887 C>T), RS1009642452 (6:26058200 T>C)

Disease associations

OMIM: gene MIM:142710 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): breast ductal adenocarcinoma (MONDO:0005590)

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST004521_113	Autism spectrum disorder or schizophrenia	3.000000e-19
GCST004521_169	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_69	Autism spectrum disorder or schizophrenia	8.000000e-24
GCST004521_83	Autism spectrum disorder or schizophrenia	1.000000e-13
GCST006940_33	Neurociticism	7.000000e-09
GCST008747_140	Estimated glomerular filtration rate	4.000000e-07
GCST009936_10	Venous thromboembolism	9.000000e-06
GCST010002_50	Refractive error	4.000000e-34
GCST010142_16	Fish- and plant-related diet	2.000000e-10
GCST010142_19	Fish- and plant-related diet	4.000000e-10
GCST010142_34	Fish- and plant-related diet	7.000000e-09
GCST010142_35	Fish- and plant-related diet	8.000000e-09
GCST010142_42	Fish- and plant-related diet	1.000000e-08
GCST010142_7	Fish- and plant-related diet	3.000000e-12
GCST010702_75	Subcortical volume (MOSTest)	3.000000e-11
GCST010703_272	Brain morphology (MOSTest)	7.000000e-16
GCST90002396_274	Mean reticulocyte volume	2.000000e-13
GCST90016674_20	Liver iron content	2.000000e-39

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724671 (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
8.05	Kd	8.942	nM	CHEMBL5653589
8.05	ED50	8.942	nM	CHEMBL5653589
6.68	Kd	208.8	nM	CHEMBL3752910
6.68	ED50	208.8	nM	CHEMBL3752910
5.00	IC50	1e+04	nM	MOLIBRESIB

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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148506: Binding affinity to human HIST1H1C incubated for 45 mins by Kinobead based pull down assay	kd	0.0089	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148506: Binding affinity to human HIST1H1C incubated for 45 mins by Kinobead based pull down assay	kd	0.2088	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	2178965: Inhibition of HIST1H1C (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	5
Benzo(a)pyrene	increases expression	4
Estradiol	affects cotreatment, increases expression	4
Cyclosporine	increases expression, affects expression, decreases expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
Cisplatin	decreases expression, increases expression, affects cotreatment	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Tretinoin	affects cotreatment, decreases expression, increases expression	3
Aflatoxin B1	affects expression, affects cotreatment, decreases expression, increases expression	3
Cadmium Chloride	increases abundance, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
cobaltous chloride	decreases expression	2
perfluorooctanoic acid	increases expression, affects cotreatment	2
Zoledronic Acid	increases expression	2
Acetaminophen	increases expression	2
Doxorubicin	increases expression, affects response to substance	2
Rotenone	increases expression	2
Silicon Dioxide	increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
beta-Naphthoflavone	affects cotreatment, decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
sotorasib	affects cotreatment, increases expression	1
dicrotophos	decreases expression	1
chloroacetaldehyde	increases expression	1
deoxynivalenol	increases 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
CHEMBL5651548	Binding	Binding affinity to human HIST1H1C 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

16 cell lines: 14 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1FK	Abcam A-549 H1-2 KO	Cancer cell line	Male
CVCL_B1TE	Abcam HeLa H1-2 KO	Cancer cell line	Female
CVCL_C9JW	WAe001-A-87	Embryonic stem cell	Male
CVCL_C9JX	WAe001-A-88	Embryonic stem cell	Male
CVCL_C9K8	WAe001-A-A	Embryonic stem cell	Male
CVCL_C9K9	WAe001-A-B	Embryonic stem cell	Male
CVCL_C9KI	WAe001-A-K	Embryonic stem cell	Male
CVCL_C9KJ	WAe001-A-L	Embryonic stem cell	Male
CVCL_C9KR	WAe001-A-S	Embryonic stem cell	Male
CVCL_C9KS	WAe001-A-T	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery