H1-4

Summary

H1-4 (H1.4 linker histone, cluster member, HGNC:4718) is a protein-coding gene on chromosome 6p22.2, encoding Histone H1.4 (P10412). 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: 10.6% 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 3008 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 18
• Clinical variants (ClinVar): 248 total — 23 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.6% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005321

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4718
Approved symbol	H1-4
Name	H1.4 linker histone, cluster member
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	H1.4, H1e, H1s-4
Ensembl gene	ENSG00000168298
Ensembl biotype	protein_coding
OMIM	142220
Entrez	3008

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000304218

RefSeq mRNA: 1 — MANE Select: NM_005321 NM_005321

CCDS: CCDS4586

Canonical transcript exons

ENST00000304218 — 1 exons

Exon	Start	End
ENSE00001173828	26156329	26157115

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1484.7187 / max 33758.0162, expressed in 1827 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66478	1484.7187	1827

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.86	gold quality
tendon of biceps brachii	UBERON:0008188	97.19	gold quality
sural nerve	UBERON:0015488	97.05	gold quality
adrenal tissue	UBERON:0018303	96.85	gold quality
tendon	UBERON:0000043	96.60	gold quality
colonic epithelium	UBERON:0000397	95.87	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.28	gold quality
bone marrow cell	CL:0002092	86.18	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.82	silver quality
corpus callosum	UBERON:0002336	75.14	gold quality
secondary oocyte	CL:0000655	73.35	silver quality
hindlimb stylopod muscle	UBERON:0004252	72.54	gold quality
tonsil	UBERON:0002372	72.38	gold quality
bone marrow	UBERON:0002371	69.84	gold quality
islet of Langerhans	UBERON:0000006	66.21	gold quality
blood	UBERON:0000178	65.53	gold quality
medial globus pallidus	UBERON:0002477	65.38	silver quality
ventricular zone	UBERON:0003053	64.96	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	63.74	gold quality
pancreatic ductal cell	CL:0002079	63.37	silver quality
ectocervix	UBERON:0012249	62.28	gold quality
skin of abdomen	UBERON:0001416	62.13	gold quality
uterine cervix	UBERON:0000002	61.92	gold quality
lower esophagus mucosa	UBERON:0035834	61.37	gold quality
mucosa of transverse colon	UBERON:0004991	60.54	gold quality
urinary bladder	UBERON:0001255	60.42	gold quality
adenohypophysis	UBERON:0002196	59.94	gold quality
endocervix	UBERON:0000458	59.55	gold quality
zone of skin	UBERON:0000014	59.20	gold quality
pituitary gland	UBERON:0000007	58.88	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	17354.22
E-MTAB-9543	yes	7050.39
E-CURD-84	yes	2479.77
E-MTAB-7407	yes	1118.82
E-MTAB-9467	yes	32.76
E-CURD-122	yes	23.42
E-MTAB-9067	yes	11.93
E-MTAB-6911	no	418.89
E-MTAB-9689	no	141.43
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ATOH1
GLI1
HES5

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 10.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Allele-specific underacetylation of histone H4 downstream from promoter is associated with X-inactivation in human cells. (PMID:12498347)
• the lysine residue adjacent to the phosphorylation site found on the serine residue on the H1.4 peptide KARKSAGAAKR was also shown to be methylated, raising the question of whether the hypothesized “methyl/phos” switch could be extended to linker histones (PMID:15595731)
• Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins (PMID:19144645)
• PKA-mediated H1.4S35 phosphorylation dissociates H1.4 from mitotic chromatin but also suggest that this phosphorylation is necessary for specific mitotic functions. (PMID:21852232)
• the N-terminal domain of H1 is an important determinant of affinity and specificity of H1-chromatin interactions. (PMID:22425985)
• H1.4K34 acetylation is mediated by GCN5 and is preferentially enriched at promoters of active genes, where it stimulates transcription by increasing H1 mobility and recruiting a general transcription factor. (PMID:22465951)
• Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. (PMID:24435047)
• 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)
• This study identified and confirmed HIST1H1E protein changes within the postsynaptic density in schizophrenia. (PMID:25048004)
• 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. (PMID:26209608)
• Crystallographic studies of an histone H1.4K26me3:lysine demethylase 4A (KDM4A) complex iidicate a conserved binding geometry to that of H3K9me3. (PMID:30156264)
• The identification of 30 patients with HIST1H1E variants has allowed the clarification of the HIST1H1E syndrome phenotype. (PMID:31400068)
• Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature. (PMID:31910894)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	h1l1	ENSDARG00000074012
danio_rerio	si:dkey-23a13.9	ENSDARG00000105431
mus_musculus	H1f4	ENSMUSG00000051627
rattus_norvegicus	H1f4	ENSRNOG00000047459
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), H1-8 (ENSG00000178804), H1-5 (ENSG00000184357), H1-10 (ENSG00000184897), H1-7 (ENSG00000187166), H1-6 (ENSG00000187475), H1-2 (ENSG00000187837), H1-0 (ENSG00000189060)

Protein

Protein identifiers

Histone H1.4 — P10412 (reviewed: P10412)

Alternative names: Histone H1b, Histone H1s-4

All UniProt accessions (2): A3R0T8, P10412

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. Histones H1 are necessary for the condensation of nucleosome chains into higher-order structured fibers and promote formation of the H3K27me3 mark by the PRC2/EED-EZH2 complex. Ability to associate with nucleosomes and compact chromatin depends on linker DNA length and trajectory. 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.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Deamidation of Asn-76 and Asn-77 by CTPS1 in response to DNA damage promotes subsequent acetylation of histone H1 at Lys-75 (H1K75ac). Acetylated at Lys-26. Deacetylated at Lys-26 by SIRT1. Acetylated at Lys-34 (H1.3K34ac) by KAT2A; H1.3K34ac is enriched at promoters of active genes and stimulates transcription by increasing H1 mobility and recruiting TAF1. 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. Mono- and dimethylated at Lys-26 by EHMT2/G9a (H1.4K26me1 and H1.4K26me2, respectively). H1.4K26me1, H1.4K26me2 and H1.4K26me3 are demethylated by KDM4A. H1.4K26me is recognized by histone reader HP1 (CBX1, CBX3 and/or CBX5). H1 histones are progressively phosphorylated during the cell cycle, becoming maximally phosphorylated during late G2 phase and M phase, and being dephosphorylated sharply thereafter. Phosphorylated at Ser-27 by AURKB during mitosis. Simultaneous methylation at Lys-26 (H1.4K26me) and phosphorylation at Ser-27 (H1.4S27Ph) prevents binding by histone reader HP1 (CBX1, CBX3 and/or CBX5). Phosphorylation at Ser-36 by PKA during mitosis promotes dissociation from mitotic chromosome. Phosphorylation at Ser-187 by CDK9 is associated with transcription activation. Phosphorylation at Thr-146 highly increases during mitosis compared to interphase. 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-150 in response to DNA damage.

Disease relevance. Rahman syndrome (RMNS) [MIM:617537] An autosomal dominant syndrome characterized by intellectual disability and overgrowth manifesting as increased birth length, height, weight, and/or head circumference. The disease is caused by variants affecting the gene represented in this entry.

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.

Miscellaneous. This variant accounts for 60% of histone H1.

Similarity. Belongs to the histone H1/H5 family.

RefSeq proteins (1): NP_005312* (*=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 (65 total): modified residue 39, compositionally biased region 6, strand 5, mutagenesis site 4, helix 4, region of interest 2, sequence variant 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
3TZD	X-RAY DIFFRACTION	1.81
6H8P	X-RAY DIFFRACTION	1.98
5JJZ	X-RAY DIFFRACTION	2
7K5Y	ELECTRON MICROSCOPY	2.76
8H1T	ELECTRON MICROSCOPY	3
7K63	ELECTRON MICROSCOPY	3.03
8VG2	ELECTRON MICROSCOPY	3.04
9DDE	ELECTRON MICROSCOPY	3.2
7PF5	ELECTRON MICROSCOPY	3.8
7PF3	ELECTRON MICROSCOPY	4
7PF6	ELECTRON MICROSCOPY	4
7PFX	ELECTRON MICROSCOPY	4.3
7PFD	ELECTRON MICROSCOPY	4.4
7PFE	ELECTRON MICROSCOPY	4.4
7PFV	ELECTRON MICROSCOPY	4.4
7PFU	ELECTRON MICROSCOPY	5
7PEX	ELECTRON MICROSCOPY	5.1
7PF2	ELECTRON MICROSCOPY	5.1
7PFW	ELECTRON MICROSCOPY	5.2
7PFC	ELECTRON MICROSCOPY	6.4
7PEU	ELECTRON MICROSCOPY	7.2
7PEZ	ELECTRON MICROSCOPY	7.9
7PET	ELECTRON MICROSCOPY	9.5
7PFA	ELECTRON MICROSCOPY	9.7
7PFT	ELECTRON MICROSCOPY	9.8
7PF0	ELECTRON MICROSCOPY	11

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10412-F1	65.10	0.31

Antibody-complex structures (SAbDab): 2 — 7K5Y, 7K63

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 (39): 2, 2, 17, 18, 26, 26, 26, 26, 26, 27, 34, 34, 34, 34, 36, 46, 52, 52, 54, 63 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
27	abolished phosphorylation by aurkb.
75	mimics acetylation; increased chromatin accessibility.
75	abolished acetylation by ep300 in response to dna damage.
76–77	promotes acetylation at k-75 and dna repair in response to dna damage.

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: 234 (showing top): GOBP_CHROMOSOME_ORGANIZATION, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_CHROMOSOME_CONDENSATION, BILD_HRAS_ONCOGENIC_SIGNATURE, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GFI1_01, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, REACTOME_APOPTOSIS, HAN_SATB1_TARGETS_DN, GOBP_CHROMATIN_REMODELING, TTTNNANAGCYR_UNKNOWN, DURCHDEWALD_SKIN_CARCINOGENESIS_UP

GO Biological Process (6): 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), 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 deacetylase binding (GO:0042826), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): nucleosome (GO:0000786), euchromatin (GO:0000791), heterochromatin (GO:0000792), nucleus (GO:0005634), 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
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
cellular component organization	1
regulation of DNA-templated transcription	1
structural molecule activity	1
chromatin binding	1
chromatin DNA binding	1
nucleosome binding	1
enzyme binding	1
binding	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
chromosome	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1334 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H1-4	H1-7	Q75WM6	894
H1-4	H1-8	Q8IZA3	745
H1-4	MSX1	P28360	714
H1-4	H2AC19	P20670	707
H1-4	H2AC20	Q16777	707
H1-4	H2BC21	Q16778	705
H1-4	L3MBTL1	Q9Y468	675
H1-4	H3C1	P02295	647
H1-4	CBX5	P45973	596
H1-4	H1-3	P16402	594
H1-4	H1-2	P16403	586
H1-4	H2BC12	O60814	574
H1-4	CBX3	Q13185	572
H1-4	EHMT2	Q96KQ7	543
H1-4	KDM4A	O75164	540

IntAct

284 interactions, top by confidence:

A	B	Type	Score
N	HNRNPR	psi-mi:“MI:0914”(association)	0.730
H1-4	N	psi-mi:“MI:0915”(physical association)	0.710
FTSJ3	H1-4	psi-mi:“MI:0915”(physical association)	0.670
RPL10A	RRP8	psi-mi:“MI:0914”(association)	0.640
SNRPA1	HTATSF1	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
L3MBTL1	H1-4	psi-mi:“MI:0914”(association)	0.590
L3MBTL1	H1-4	psi-mi:“MI:0915”(physical association)	0.590
L3MBTL1	H1-4	psi-mi:“MI:0407”(direct interaction)	0.590
H1-4	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
UTP3	H1-4	psi-mi:“MI:0915”(physical association)	0.560
SYNGAP1	H1-4	psi-mi:“MI:0915”(physical association)	0.560
RPL14	H1-4	psi-mi:“MI:0915”(physical association)	0.560
BAZ1B	H1-4	psi-mi:“MI:0915”(physical association)	0.560
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
H1-4	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
ZCRB1	DKC1	psi-mi:“MI:0914”(association)	0.530
DHX57	APOD	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
H1-4	RRP8	psi-mi:“MI:0914”(association)	0.530
UBE3A	HERC2	psi-mi:“MI:0914”(association)	0.500
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460

BioGRID (958): HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), YBX2 (Affinity Capture-MS), HIST1H1E (Affinity Capture-MS), LEO1 (Affinity Capture-MS)

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

2 interactions.

A	Effect	B	Mechanism
AURKB	“up-regulates quantity by stabilization”	H1-4	phosphorylation
CDK9	“down-regulates activity”	H1-4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 204 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	25.1×	6e-05
SARS-CoV-1 modulates host translation machinery	6	13.8×	2e-04
Eukaryotic Translation Elongation	6	12.5×	3e-04
Eukaryotic Translation Initiation	5	11.5×	2e-03
Cap-dependent Translation Initiation	5	11.5×	2e-03
Peptide chain elongation	11	10.4×	2e-06
Viral mRNA Translation	11	10.4×	2e-06
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	11	10.3×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of DNA recombination	5	31.0×	1e-04
chromosome condensation	5	23.3×	5e-04
ribosomal large subunit biogenesis	6	14.7×	5e-04
cytoplasmic translation	12	12.3×	3e-07
nucleosome assembly	13	10.1×	3e-07
rRNA processing	8	6.3×	4e-03
chromatin organization	11	6.0×	5e-04
translation	10	5.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	9
Uncertain significance	109
Likely benign	86
Benign	2

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1191465	NM_005321.3(H1-4):c.443dup (p.Lys149fs)	Pathogenic
1679381	NM_005321.3(H1-4):c.416_419dup (p.Ala141fs)	Pathogenic
1685874	NM_005321.3(H1-4):c.396dup (p.Gly133fs)	Pathogenic
2577944	NM_005321.3(H1-4):c.444dup (p.Lys149fs)	Pathogenic
2631828	NM_005321.3(H1-4):c.445_446del (p.Lys149fs)	Pathogenic
2663829	NM_005321.3(H1-4):c.455AGA[1] (p.Lys153del)	Pathogenic
3024464	NM_005321.3(H1-4):c.410dup (p.Pro138fs)	Pathogenic
3064024	NM_005321.3(H1-4):c.410_415delinsTCCT (p.Lys137fs)	Pathogenic
3340665	NM_005321.3(H1-4):c.446_447insT (p.Lys149fs)	Pathogenic
428606	NM_005321.3(H1-4):c.441dup (p.Lys148fs)	Pathogenic
428607	NM_005321.3(H1-4):c.436_458del (p.Thr146fs)	Pathogenic
4674616	NM_005321.3(H1-4):c.385_386del (p.Lys129fs)	Pathogenic
503824	NM_005321.3(H1-4):c.433dup (p.Ala145fs)	Pathogenic
523954	NM_005321.3(H1-4):c.454_455insT (p.Lys152fs)	Pathogenic
635258	NM_005321.3(H1-4):c.425_431delinsAGGGGGTT (p.Thr142fs)	Pathogenic
635259	NM_005321.3(H1-4):c.425delinsAG (p.Thr142fs)	Pathogenic
635260	NM_005321.3(H1-4):c.447dup (p.Ser150fs)	Pathogenic
817291	NM_005321.3(H1-4):c.392dup (p.Ala132fs)	Pathogenic
817475	NM_005321.3(H1-4):c.430delinsCC (p.Ala144fs)	Pathogenic
817681	NM_005321.3(H1-4):c.444_466del (p.Lys149fs)	Pathogenic
870827	NM_005321.3(H1-4):c.435dup (p.Thr146fs)	Pathogenic
975953	NM_005321.3(H1-4):c.365dup (p.Ala123fs)	Pathogenic
992673	NM_005321.3(H1-4):c.431dup (p.Ala145fs)	Pathogenic
1527962	NM_005321.3(H1-4):c.509_549del (p.Ala170fs)	Likely pathogenic
3336891	NM_005321.3(H1-4):c.436dup (p.Thr146fs)	Likely pathogenic
3338096	NM_005321.3(H1-4):c.502_518del (p.Lys168fs)	Likely pathogenic
3393326	NM_005321.3(H1-4):c.197T>C (p.Leu66Pro)	Likely pathogenic
4293006	NM_005321.3(H1-4):c.472del (p.Ala158fs)	Likely pathogenic
432775	NM_005321.3(H1-4):c.277del (p.Leu93fs)	Likely pathogenic
800337	NM_005321.3(H1-4):c.133A>C (p.Thr45Pro)	Likely pathogenic

SpliceAI

110 predictions. Top by Δscore:

Variant	Effect	Δscore
6:26156544:A:AC	acceptor_gain	0.6100
6:26156639:TCTC:T	donor_gain	0.5800
6:26156647:GCCTG:G	donor_gain	0.5700
6:26156919:A:T	donor_gain	0.5600
6:26156634:C:G	donor_gain	0.5300
6:26156465:C:T	donor_gain	0.5200
6:26156648:CCTGG:C	donor_loss	0.5100
6:26156649:CTG:C	donor_loss	0.5100
6:26156652:GT:G	donor_loss	0.5100
6:26156653:T:TC	donor_loss	0.5100
6:26156654:G:GG	donor_loss	0.5100
6:26156545:A:G	acceptor_gain	0.5000
6:26156655:AG:A	donor_loss	0.5000
6:26156917:C:T	donor_gain	0.5000
6:26156758:C:T	donor_gain	0.4900
6:26156656:G:C	donor_loss	0.4800
6:26156544:AAG:A	acceptor_gain	0.4700
6:26156863:C:T	donor_gain	0.4700
6:26157047:G:GG	donor_gain	0.4700
6:26157048:TAGA:T	donor_gain	0.4700
6:26157049:AGAA:A	donor_gain	0.4700
6:26157046:A:AG	donor_gain	0.4600
6:26156881:C:G	donor_gain	0.4500
6:26156971:T:G	donor_gain	0.4500
6:26156858:G:GT	donor_gain	0.4400
6:26156867:G:GT	donor_gain	0.4400
6:26156941:C:T	donor_gain	0.4400
6:26156652:G:GG	donor_gain	0.4300
6:26156543:CA:C	acceptor_gain	0.4100
6:26156546:GGAGC:G	acceptor_gain	0.4100

AlphaMissense

1396 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:26156682:G:C	G98R	1.000
6:26156703:T:C	F105L	1.000
6:26156704:T:C	F105S	1.000
6:26156705:C:A	F105L	1.000
6:26156705:C:G	F105L	1.000
6:26156521:T:A	I44N	0.999
6:26156556:G:C	G56R	0.999
6:26156557:G:A	G56D	0.999
6:26156575:T:A	L62H	0.999
6:26156579:G:C	K63N	0.999
6:26156579:G:T	K63N	0.999
6:26156626:G:C	R79P	0.999
6:26156629:T:G	I80S	0.999
6:26156641:T:A	L84H	0.999
6:26156668:T:A	L93Q	0.999
6:26156682:G:A	G98S	0.999
6:26156682:G:T	G98C	0.999
6:26156683:G:A	G98D	0.999
6:26156683:G:T	G98V	0.999
6:26156689:G:A	G100D	0.999
6:26156697:G:C	G103R	0.999
6:26156698:G:A	G103D	0.999
6:26156704:T:G	F105C	0.999
6:26156521:T:C	I44T	0.998
6:26156521:T:G	I44S	0.998
6:26156529:G:C	A47P	0.998
6:26156533:T:A	V48D	0.998
6:26156556:G:T	G56C	0.998
6:26156577:A:G	K63E	0.998
6:26156625:C:A	R79S	0.998

dbSNP variants (sampled 300 via entrez): RS1002598295 (6:26157589 G>A), RS1003595309 (6:26157128 A>G,T), RS1003674986 (6:26155004 G>A), RS1003944586 (6:26156711 C>A,G,T), RS1005410570 (6:26157192 C>A,T), RS1005746084 (6:26154779 C>G,T), RS1006400242 (6:26157300 T>C), RS1006747003 (6:26156230 G>A,T), RS1010833563 (6:26156883 G>A,C,T), RS1010902431 (6:26157208 GGA>G), RS1011352218 (6:26157131 G>A,C), RS1011830749 (6:26157212 A>G), RS1012710030 (6:26155321 G>C), RS1013233547 (6:26157454 G>GTAA), RS1014310408 (6:26155682 G>T)

Disease associations

OMIM: gene MIM:142220 | disease phenotypes: MIM:617537, MIM:610954, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
Rahman syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (5): Rahman syndrome (MONDO:0044323), syndromic intellectual disability (MONDO:0000508), Pitt-Hopkins syndrome (MONDO:0012589), neurodevelopmental disorder (MONDO:0700092), plasma cell myeloma (MONDO:0009693)

Orphanet (5): Autosomal dominant intellectual disability-craniofacial dysmorphism-macrocephaly-hypotonia syndrome due to H1-4 mutation (Orphanet:642763), Rare genetic syndromic intellectual disability (Orphanet:183763), Pitt-Hopkins syndrome (Orphanet:2896), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000256	Macrocephaly
HP:0000293	Full cheeks
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000646	Amblyopia
HP:0000739	Anxiety
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001319	Neonatal hypotonia
HP:0001582	Redundant skin
HP:0001762	Talipes equinovarus
HP:0002119	Ventriculomegaly
HP:0002751	Kyphoscoliosis
HP:0003577	Congenital onset
HP:0003623	Neonatal onset
HP:0003764	Nevus
HP:0005616	Accelerated skeletal maturation
HP:0009890	High anterior hairline
HP:0011968	Feeding difficulties
HP:0012385	Camptodactyly
HP:0012450	Chronic constipation
HP:0033725	Thin corpus callosum

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002647_133	Height	8.000000e-22
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
GCST004749_62	Lung cancer in ever smokers	2.000000e-07
GCST004750_80	Squamous cell lung carcinoma	6.000000e-12
GCST005316_559	Intelligence (MTAG)	4.000000e-10
GCST006269_1088	General cognitive ability	4.000000e-11
GCST008163_5	Height	4.000000e-06
GCST010002_50	Refractive error	4.000000e-34
GCST010141_1	Beef consumption	7.000000e-13
GCST010143_19	Meat-related diet	5.000000e-13
GCST010143_31	Meat-related diet	7.000000e-09
GCST010244_417	Triglyceride levels	7.000000e-10
GCST012228_139	Waist-hip index	7.000000e-09
GCST012230_338	Waist-to-hip ratio adjusted for BMI	8.000000e-09
GCST90020028_928	Hip circumference adjusted for BMI	3.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0008111	diet measurement
EFO:0004530	triglyceride measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D065886	Neurodevelopmental Disorders	F03.625
C537403	Pitt-Hopkins syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066376 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.29	Kd	5188	nM	CHEMBL5653589
5.29	ED50	5188	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 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	2148507: Binding affinity to human HIST1H1E incubated for 45 mins by Kinobead based pull down assay	kd	5.1880	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	affects cotreatment, increases expression, decreases expression	3
Benzo(a)pyrene	decreases expression	3
methylmercuric chloride	increases expression	2
bisphenol A	decreases expression	2
Caffeine	increases phosphorylation, increases expression	2
Doxorubicin	increases expression, affects response to substance	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation, affects cotreatment	2
Copper Sulfate	decreases expression, increases expression	2
6,7-dimethoxy-2-(pyrrolidin-1-yl)-N-(5-(pyrrolidin-1-yl)pentyl)quinazolin-4-amine	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
propionaldehyde	decreases expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, decreases expression, affects localization	1
decabromobiphenyl ether	increases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
gossypol acetic acid	decreases expression	1
versicolorin A	decreases expression	1
hydroquinone	decreases expression	1
perfluorodecanoic acid	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	increases expression	1
brequinar	decreases expression	1
dinophysistoxin 1	decreases expression	1
picene	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651549	Binding	Binding affinity to human HIST1H1E 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

14 cell lines: 14 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C9K0	WAe001-A-91	Embryonic stem cell	Male
CVCL_C9K1	WAe001-A-92	Embryonic stem cell	Male
CVCL_C9KC	WAe001-A-E	Embryonic stem cell	Male
CVCL_C9KD	WAe001-A-F	Embryonic stem cell	Male
CVCL_C9KM	WAe001-A-O	Embryonic stem cell	Male
CVCL_C9KN	WAe001-A-P	Embryonic stem cell	Male
CVCL_C9KT	WAe001-A-U	Embryonic stem cell	Male
CVCL_C9KU	WAe001-A-V	Embryonic stem cell	Male
CVCL_C9KZ	WAe001-A-1A	Embryonic stem cell	Male
CVCL_C9L0	WAe001-A-1B	Embryonic stem cell	Male

Clinical trials (associated diseases)

300 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,
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study
NCT05722405	PHASE4	RECRUITING	Ixazomib Plus Low-dose Lenalidomide Versus Ixazomib Alone for Maintenance Treatment of High Risk Multiple Myeloma
NCT05855122	PHASE4	UNKNOWN	Safety and ASCT-related Symptom Burden Optimization of Tocilizumab in ASCT Following HD Melphalan Conditioning for Multiple Myeloma Patients
NCT05944783	PHASE4	NOT_YET_RECRUITING	Bioequivalence Studies of Dasatinib 100 Mg