H2AC4

Summary

H2AC4 (H2A clustered histone 4, HGNC:4734) is a protein-coding gene on chromosome 6p22.2, encoding Histone H2A type 1-B/E (P04908). Core component of nucleosome. It is a selective cancer dependency (DepMap: 37.9% of cell lines).

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2A family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6p22-p21.3.

Source: NCBI Gene 8335 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 38 total
• Cancer dependency (DepMap): dependent in 37.9% of screened cell lines
• MANE Select transcript: NM_003513

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4734
Approved symbol	H2AC4
Name	H2A clustered histone 4
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	H2A/m
Ensembl gene	ENSG00000278463
Ensembl biotype	protein_coding
OMIM	602795
Entrez	8335

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000615868

RefSeq mRNA: 1 — MANE Select: NM_003513 NM_003513

CCDS: CCDS4574

Canonical transcript exons

ENST00000615868 — 1 exons

Exon	Start	End
ENSE00003740156	26033092	26033618

Expression profiles

Bgee: expression breadth ubiquitous, 107 present calls, max score 93.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 208.0609 / max 3845.8254, expressed in 1770 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72299	208.0609	1770

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	93.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.02	gold quality
adrenal tissue	UBERON:0018303	85.31	gold quality
colonic epithelium	UBERON:0000397	75.11	gold quality
calcaneal tendon	UBERON:0003701	73.00	gold quality
buccal mucosa cell	CL:0002336	70.98	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.55	gold quality
tendon	UBERON:0000043	69.28	gold quality
tendon of biceps brachii	UBERON:0008188	64.00	gold quality
bone marrow	UBERON:0002371	60.33	gold quality
granulocyte	CL:0000094	58.55	gold quality
ventricular zone	UBERON:0003053	58.29	gold quality
skin of hip	UBERON:0001554	53.70	silver quality
sperm	CL:0000019	52.73	gold quality
tonsil	UBERON:0002372	50.99	gold quality
upper leg skin	UBERON:0004262	50.72	silver quality
blood vessel layer	UBERON:0004797	49.29	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
ganglionic eminence	UBERON:0004023	48.71	gold quality
mucosa of stomach	UBERON:0001199	48.31	gold quality
Brodmann (1909) area 46	UBERON:0006483	48.30	gold quality
middle temporal gyrus	UBERON:0002771	47.63	gold quality
adult organism	UBERON:0007023	47.35	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
renal glomerulus	UBERON:0000074	46.86	gold quality
mammalian vulva	UBERON:0000997	46.84	gold quality
metanephric glomerulus	UBERON:0004736	46.77	gold quality
nephron tubule	UBERON:0001231	46.71	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-109979	no	5.80
E-ANND-3	no	1.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 37.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• Inhibition of HIST1H2AB suppresses the proliferation of lung adenocarcinoma. (PMID:36511295)

Cross-species orthologs

23 orthologs

Organism	Symbol	Gene ID
mus_musculus	H2ac11	ENSMUSG00000069301
mus_musculus	H2ac13	ENSMUSG00000071516
rattus_norvegicus	hist1h2ail2	ENSRNOG00000074453
drosophila_melanogaster	His2A:CG31618	FBGN0051618
drosophila_melanogaster	His2A:CG33808	FBGN0053808
drosophila_melanogaster	His2A:CG33814	FBGN0053814
drosophila_melanogaster	His2A:CG33817	FBGN0053817
drosophila_melanogaster	His2A:CG33820	FBGN0053820
drosophila_melanogaster	His2A:CG33823	FBGN0053823
drosophila_melanogaster	His2A:CG33826	FBGN0053826
drosophila_melanogaster	His2A:CG33829	FBGN0053829
drosophila_melanogaster	His2A:CG33832	FBGN0053832
drosophila_melanogaster	His2A:CG33835	FBGN0053835
drosophila_melanogaster	His2A:CG33838	FBGN0053838
drosophila_melanogaster	His2A:CG33841	FBGN0053841
drosophila_melanogaster	His2A:CG33844	FBGN0053844
drosophila_melanogaster	His2A:CG33847	FBGN0053847
drosophila_melanogaster	His2A:CG33850	FBGN0053850
drosophila_melanogaster	His2A:CG33853	FBGN0053853
drosophila_melanogaster	His2A:CG33856	FBGN0053856
drosophila_melanogaster	His2A:CG33859	FBGN0053859
drosophila_melanogaster	His2A:CG33862	FBGN0053862
drosophila_melanogaster	His2A:CG33865	FBGN0053865

Paralogs (27): MACROH2A2 (ENSG00000099284), H2AZ2 (ENSG00000105968), MACROH2A1 (ENSG00000113648), H2AZ1 (ENSG00000164032), H2AC1 (ENSG00000164508), H2AC6 (ENSG00000180573), H2AC25 (ENSG00000181218), H2AC20 (ENSG00000184260), H2AC21 (ENSG00000184270), H2AX (ENSG00000188486), H2AC13 (ENSG00000196747), H2AC11 (ENSG00000196787), H2AC7 (ENSG00000196866), H2AL3 (ENSG00000229674), H2AJ (ENSG00000246705), H2AL1Q (ENSG00000249467), H2AB1 (ENSG00000274183), H2AC12 (ENSG00000274997), H2AC15 (ENSG00000275221), H2AC14 (ENSG00000276368), H2AC16 (ENSG00000276903), H2AC8 (ENSG00000277075), H2AB3 (ENSG00000277745), H2AB2 (ENSG00000277858), H2AC17 (ENSG00000278677), H2AC18 (ENSG00000288825), H2AC19 (ENSG00000288859)

Protein

Protein identifiers

Histone H2A type 1-B/E — P04908 (reviewed: P04908)

Alternative names: Histone H2A.2, Histone H2A/a, Histone H2A/m

All UniProt accessions (2): P04908, Q08AJ9

UniProt curated annotations — full annotation on UniProt →

Function. Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.

Subunit / interactions. The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Deiminated on Arg-4 in granulocytes upon calcium entry. Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of ‘Lys-27’ of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers. Following DNA double-strand breaks (DSBs), it is ubiquitinated through ‘Lys-63’ linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and ‘Lys-63’-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend ‘Lys-63’-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired. H2AK119Ub and ionizing radiation-induced ‘Lys-63’-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events. Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription. Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex. Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage. 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. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.

Similarity. Belongs to the histone H2A family.

RefSeq proteins (1): NP_003504* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002119	Histone_H2A	Family
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR032454	Histone_H2A_C	Domain
IPR032458	Histone_H2A_CS	Conserved_site

Pfam: PF00125, PF16211

UniProt features (58 total): modified residue 36, helix 6, strand 4, cross-link 3, turn 3, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

356 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7VZ4	ELECTRON MICROSCOPY	1.89
6ACL	X-RAY DIFFRACTION	1.92
8I17	X-RAY DIFFRACTION	1.98
5B0Z	X-RAY DIFFRACTION	1.99
5Y0D	X-RAY DIFFRACTION	1.99
6IPU	X-RAY DIFFRACTION	1.99
8UQA	X-RAY DIFFRACTION	2.05
5Y0C	X-RAY DIFFRACTION	2.09
8Q3E	X-RAY DIFFRACTION	2.17
5X7X	X-RAY DIFFRACTION	2.18
5AV6	X-RAY DIFFRACTION	2.2
5AV8	X-RAY DIFFRACTION	2.2
5AV9	X-RAY DIFFRACTION	2.2
5B31	X-RAY DIFFRACTION	2.2
6KE9	X-RAY DIFFRACTION	2.22
6IQ4	X-RAY DIFFRACTION	2.25
6JXD	X-RAY DIFFRACTION	2.25
8KB5	ELECTRON MICROSCOPY	2.26
8UQ9	X-RAY DIFFRACTION	2.3
8Q3X	X-RAY DIFFRACTION	2.3
8UQ8	X-RAY DIFFRACTION	2.34
5B32	X-RAY DIFFRACTION	2.35
8JLB	ELECTRON MICROSCOPY	2.36
8YBJ	ELECTRON MICROSCOPY	2.38
3AZG	X-RAY DIFFRACTION	2.4
5AV5	X-RAY DIFFRACTION	2.4
5AVB	X-RAY DIFFRACTION	2.4
5AVC	X-RAY DIFFRACTION	2.4
6JR1	X-RAY DIFFRACTION	2.4
8JLD	ELECTRON MICROSCOPY	2.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04908-F1	91.03	0.80

Antibody-complex structures (SAbDab): 8 — 6E0C, 6E0P, 7K5X, 7K5Y, 7K60, 7K61, 7K63, 8VFX

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): 10, 10, 10, 10, 10, 14, 14, 16, 37, 37, 37, 37, 75, 76, 96, 96, 96, 96, 96, 105 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
2	blocks the inhibition of transcription by rps6ka5/msk1.

Function

Pathways and Gene Ontology

Reactome pathways

55 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214815	HDACs deacetylate histones
R-HSA-3214847	HATs acetylate histones
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-427359	SIRT1 negatively regulates rRNA expression
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-5334118	DNA methylation
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-5625886	Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
R-HSA-5689603	UCH proteinases
R-HSA-5689880	Ub-specific processing proteases
R-HSA-5689901	Metalloprotease DUBs
R-HSA-606279	Deposition of new CENPA-containing nucleosomes at the centromere
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-73728	RNA Polymerase I Promoter Opening

MSigDB gene sets: 196 (showing top): REACTOME_MEIOTIC_RECOMBINATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, GOLDRATH_ANTIGEN_RESPONSE, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GERY_CEBP_TARGETS, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_CENTROMERIC_REGION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, NEMETH_INFLAMMATORY_RESPONSE_LPS_DN, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (4): chromatin organization (GO:0006325), negative regulation of cell population proliferation (GO:0008285), heterochromatin formation (GO:0031507), protein localization to CENP-A containing chromatin (GO:0061644)

GO Molecular Function (4): DNA binding (GO:0003677), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (5): nucleosome (GO:0000786), nucleus (GO:0005634), CENP-A containing nucleosome (GO:0043505), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Cellular Senescence	3
Chromatin modifying enzymes	3
Depyrimidination	2
Depurination	2
Negative epigenetic regulation of rRNA expression	2
Positive epigenetic regulation of rRNA expression	2
Meiosis	1
Telomere Maintenance	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Epigenetic regulation of gene expression	1
Mitotic Prophase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromatin	2
cellular component organization	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
protein localization to chromatin	1
protein localization to chromosome, centromeric region	1
nucleic acid binding	1
structural molecule activity	1
protein dimerization activity	1
binding	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nucleosome	1
CENP-A containing chromatin	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H2AC4	H2BC21	Q16778	940
H2AC4	H4C16	P02304	856
H2AC4	H3C1	P02295	846
H2AC4	H1-1	Q02539	743
H2AC4	H2BC8	P02278	690
H2AC4	H2BC5	P58876	689
H2AC4	H2BC3	P33778	634
H2AC4	H2BC12	O60814	606
H2AC4	H1-5	P16401	599
H2AC4	H2BC14	Q99879	591
H2AC4	H3C14	Q71DI3	563
H2AC4	H3-3A	P06351	561
H2AC4	UBA1	P22314	462
H2AC4	H2BC17	P23527	452
H2AC4	H1-2	P16403	438

IntAct

215 interactions, top by confidence:

A	B	Type	Score
H2AC4	H4C16	psi-mi:“MI:0915”(physical association)	0.900
H2AC4	H2BC11	psi-mi:“MI:0915”(physical association)	0.850
H2AC4	H2BC11	psi-mi:“MI:0407”(direct interaction)	0.850
CXXC1	SETD1A	psi-mi:“MI:0914”(association)	0.760
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730
H2AC4	PPM1G	psi-mi:“MI:0914”(association)	0.670
H3-4	H2AC4	psi-mi:“MI:0915”(physical association)	0.590
HP1BP3	H2AC4	psi-mi:“MI:0915”(physical association)	0.560
H2AC4	H2BC15	psi-mi:“MI:0915”(physical association)	0.560
H2AC4	H3C13	psi-mi:“MI:0915”(physical association)	0.550
H2AC4	H2BC12	psi-mi:“MI:0915”(physical association)	0.530
CBX6	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
H1-6	ZNF724	psi-mi:“MI:0914”(association)	0.530
HP1BP3	IPO8	psi-mi:“MI:0914”(association)	0.530
UBE3A	HERC2	psi-mi:“MI:0914”(association)	0.500
		psi-mi:“MI:0915”(physical association)	0.500

BioGRID (1018): HIST1H2AE (Affinity Capture-MS), HIST1H2AB (Biochemical Activity), HIST1H2AB (Reconstituted Complex), HIST1H2AB (Affinity Capture-Western), HIST1H2AB (Affinity Capture-Western), UBC (Affinity Capture-Western), HIST1H2AE (Affinity Capture-RNA), HIST1H2AE (Affinity Capture-RNA), HIST1H2AE (Affinity Capture-RNA), HIST1H2AB (Biochemical Activity), HIST1H2AB (Biochemical Activity), HIST1H2AB (Biochemical Activity), HIST1H2AB (Biochemical Activity), HIST1H2AB (Reconstituted Complex), HIST1H2AB (Affinity Capture-Western)

ESM2 similar proteins: A1A4R1, A9UMV8, C0HKE1, C0HKE2, C0HKE3, C0HKE4, C0HKE5, C0HKE6, C0HKE7, C0HKE8, C0HKE9, P02262, P02263, P02270, P04908, P06897, P0C0S8, P0C0S9, P0C169, P0C170, P0CC09, P13912, P19178, P20671, P21896, P27325, P35061, P35062, P70082, P84052, Q07135, Q16777, Q3ZBX9, Q4FZT6, Q4R3X5, Q64522, Q64523, Q64598, Q6FI13, Q6GSS7

Diamond homologs: A0A097I1R9, A0A097I2B5, A0A0D2UG83, A1A4R1, A1CJ10, A1D8G8, A3LXE7, A3LZZ0, A5DBG4, A5DJJ2, A5DWF1, A5DXC6, A9UMV8, C0HKE1, C0HKE2, C0HKE3, C0HKE4, C0HKE5, C0HKE6, C0HKE7, C0HKE8, C0HKE9, L7HZV6, O74268, P02262, P02263, P02264, P04908, P04909, P04910, P04911, P04912, P06897, P07793, P08844, P0C0S8, P0C0S9, P0C169, P0C170, P0C952

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
KDM4C	“down-regulates activity”	H2AC4	demethylation
H2AC4	“form complex”	“Nucleosome_H3.3 variant”	binding
SLBP	“up-regulates quantity by expression”	H2AC4	“translation regulation”
DZIP3	“up-regulates activity”	H2AC4	monoubiquitination
H2AC4	“form complex”	“CENP-A nucleosome”	binding
H2AC4	“form complex”	“Nucleosome_H3.1 variant”	binding
H2AC4	“form complex”	“Nucleosome_H3.1t variant”	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 Senescence-Associated Heterochromatin Foci (SAHF)	6	32.0×	3e-07
Replacement of protamines by nucleosomes in the male pronucleus	11	23.7×	7e-11
Packaging Of Telomere Ends	11	19.2×	3e-10
Recognition and association of DNA glycosylase with site containing an affected purine	11	17.8×	4e-10
Cleavage of the damaged purine	11	17.8×	4e-10
RNA Polymerase I Promoter Opening	12	17.5×	1e-10
ChAHP complex assembly	12	17.5×	1e-10
Inhibition of DNA recombination at telomere	13	17.3×	5e-11

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of DNA recombination	5	35.1×	1e-04
chromosome condensation	5	26.3×	3e-04
nucleosome assembly	18	15.8×	7e-14
chromatin organization	10	6.2×	1e-03
chromatin remodeling	12	5.5×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

67 predictions. Top by Δscore:

Variant	Effect	Δscore
6:26033524:AG:A	donor_gain	0.8300
6:26033525:G:C	donor_gain	0.7700
6:26033455:G:A	donor_gain	0.7400
6:26033399:TCAAG:T	donor_gain	0.7300
6:26033400:CAAGC:C	donor_gain	0.7300
6:26033401:AAGCA:A	donor_gain	0.7300
6:26033542:ACCG:A	donor_gain	0.6400
6:26033543:CCGC:C	donor_gain	0.6400
6:26033343:T:TA	donor_gain	0.6300
6:26033182:T:A	donor_gain	0.6100
6:26033287:AAGCT:A	donor_gain	0.5800
6:26033183:C:A	donor_gain	0.5600
6:26033401:A:AC	donor_gain	0.5200
6:26033452:G:C	donor_gain	0.5100
6:26033544:CGCC:C	donor_gain	0.5000
6:26033291:T:A	donor_gain	0.4500
6:26033397:A:AC	donor_gain	0.4500
6:26033398:C:CC	donor_gain	0.4500
6:26033545:G:GA	donor_gain	0.4500
6:26033288:AGCT:A	donor_gain	0.4200
6:26033538:CT:C	donor_gain	0.4200
6:26033539:TT:T	donor_gain	0.4200
6:26033540:TT:T	donor_gain	0.4200
6:26033545:G:T	donor_gain	0.4200
6:26033292:C:CA	donor_gain	0.3900
6:26033495:TGCA:T	donor_gain	0.3900
6:26033178:A:AC	donor_gain	0.3700
6:26033179:C:CC	donor_gain	0.3700
6:26033401:AAG:A	donor_gain	0.3700
6:26033451:AGTTG:A	donor_gain	0.3700

AlphaMissense

822 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000820399 (6:26033566 C>T), RS1001440888 (6:26034690 A>G,T), RS1001822488 (6:26034700 C>A,T), RS1002441844 (6:26033590 A>C,G,T), RS1004341301 (6:26034374 C>T), RS1004679479 (6:26034373 G>A), RS1006487604 (6:26035412 C>G,T), RS1006839948 (6:26033345 T>C,G), RS1006915413 (6:26033207 G>A,C), RS1007049669 (6:26032981 T>A), RS1007840826 (6:26034014 C>A,T), RS1009561261 (6:26033937 T>C), RS1010748387 (6:26032785 CTT>C), RS1011422886 (6:26034465 G>A,C), RS1014427194 (6:26034653 G>A)

Disease associations

OMIM: gene MIM:602795 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 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
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

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
sodium arsenite	affects cotreatment, increases abundance, decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Silicon Dioxide	affects secretion, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
propionaldehyde	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
versicolorin A	decreases expression	1
phenethyl isothiocyanate	decreases expression	1
polyhexamethyleneguanidine	affects expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
incobotulinumtoxinA	decreases expression	1
MT19c compound	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases expression	1
Berberine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Cannabidiol	decreases expression	1
Cisplatin	decreases expression	1
Drugs, Chinese Herbal	decreases expression	1
Isoflavones	affects expression	1
Lucanthone	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Paraoxon	decreases expression	1

Clinical trials (associated diseases)

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