ESS2

Summary

ESS2 (ess-2 spliceosome associated protein, HGNC:16817) is a protein-coding gene on chromosome 22q11.21, encoding Splicing factor ESS-2 homolog (Q96DF8). May be involved in pre-mRNA splicing. It is a common-essential gene (DepMap: required in 97.0% of cancer cell lines).

This gene is located within the minimal DGS critical region (MDGCR) thought to contain the gene(s) responsible for a group of developmental disorders. These disorders include DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and some familial or sporadic conotruncal cardiac defects which have been associated with microdeletion of 22q11.2. The encoded protein may be a component of C complex spliceosomes, and the orthologous protein in the mouse localizes to the nucleus. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 8220 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 206 total — 2 pathogenic
• GTEx eGene: eQTL in 43 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 39
• Cancer dependency (DepMap): dependent in 97.0% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.84 (unconstrained)
• MANE Select transcript: NM_022719
• Notable: 206 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16817
Approved symbol	ESS2
Name	ess-2 spliceosome associated protein
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	DGSI, Es2el, ES2, DGS-H, ESS-2, bis1
Ensembl gene	ENSG00000100056
Ensembl biotype	protein_coding
OMIM	601755
Entrez	8220

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 7 protein_coding, 5 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000252137

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 3: 1, TSL 5: 2

ENST00000252137, ENST00000434568, ENST00000469466, ENST00000472073, ENST00000909110, ENST00000909111, ENST00000909112, ENST00000951415, ENST00000951416, ENST00001034133, ENST00001034134, ENST00001034135, ENST00001034136, ENST00001132073

RefSeq mRNA: 1 — MANE Select: NM_022719 NM_022719

CCDS: CCDS13756

Canonical transcript exons

ENST00000252137 — 10 exons

Exon	Start	End
ENSE00000879093	19130279	19134475
ENSE00003470560	19135060	19135175
ENSE00003509646	19139855	19140024
ENSE00003524304	19138215	19138317
ENSE00003536450	19137323	19137432
ENSE00003568380	19142726	19142894
ENSE00003612419	19139612	19139729
ENSE00003633046	19142538	19142633
ENSE00003635250	19139159	19139292
ENSE00003848110	19144506	19144651

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 88.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.1665 / max 124.5055, expressed in 1814 samples.

Highest expression (Bgee): sperm, testis, granulocyte, male germ cell, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ESS2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 43 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 46 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	8.0e-74	-0.78	22:19144872:G:A
Testis	sqtl	9.9e-52	-1.06	22:19137870:A:C
Cells Cultured fibroblasts	eqtl	1.6e-49	-0.67	22:19144872:G:A
Esophagus Mucosa	eqtl	5.7e-43	-0.97	22:19144872:G:A
Lung	eqtl	2.2e-35	-0.58	22:19144872:G:A
Skin Sun Exposed Lower leg	eqtl	4.2e-35	-0.42	22:19144872:G:A
Adipose Visceral Omentum	eqtl	5.0e-33	-0.68	22:19144872:G:A
Adipose Subcutaneous	eqtl	1.2e-30	-0.58	22:19144872:G:A
Colon Transverse	eqtl	1.8e-29	-0.60	22:19144872:G:A
Thyroid	eqtl	2.0e-27	-0.60	22:19144872:G:A
Artery Tibial	eqtl	6.7e-26	-0.44	22:19144872:G:A
Artery Aorta	eqtl	2.2e-23	-0.50	22:19144867:A:T
Breast Mammary Tissue	eqtl	4.7e-20	-0.54	22:19144872:G:A
Esophagus Muscularis	eqtl	6.0e-17	-0.40	22:19144872:G:A
Testis	eqtl	2.0e-15	+0.21	22:19136439:T:C
Skin Not Sun Exposed Suprapubic	eqtl	2.0e-15	-0.33	22:19144872:G:A
Colon Sigmoid	eqtl	3.1e-13	-0.37	22:19144872:G:A
Nerve Tibial	eqtl	1.3e-12	-0.37	22:19144872:G:A
Heart Left Ventricle	eqtl	1.3e-12	-0.62	22:19144867:A:T
Stomach	eqtl	3.4e-12	-0.53	22:19144872:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
193131	15.9098	1814
193132	0.2566	125

Top tissues by expression

showing 100 of 286 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	88.96	gold quality
right testis	UBERON:0004534	88.56	gold quality
left testis	UBERON:0004533	88.47	gold quality
granulocyte	CL:0000094	87.20	gold quality
testis	UBERON:0000473	86.76	gold quality
male germ cell	CL:0000015	86.65	gold quality
blood	UBERON:0000178	85.28	gold quality
skin of leg	UBERON:0001511	84.47	gold quality
skin of abdomen	UBERON:0001416	83.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.84	gold quality
lower esophagus	UBERON:0013473	83.83	gold quality
popliteal artery	UBERON:0002250	83.66	gold quality
tibial artery	UBERON:0007610	83.66	gold quality
sural nerve	UBERON:0015488	83.57	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.53	gold quality
cortical plate	UBERON:0005343	83.52	gold quality
adult organism	UBERON:0007023	83.45	gold quality
oocyte	CL:0000023	83.43	gold quality
aorta	UBERON:0000947	83.15	gold quality
prefrontal cortex	UBERON:0000451	82.92	gold quality
mucosa of stomach	UBERON:0001199	82.87	gold quality
zone of skin	UBERON:0000014	82.76	gold quality
left uterine tube	UBERON:0001303	82.74	gold quality
thoracic aorta	UBERON:0001515	82.74	gold quality
descending thoracic aorta	UBERON:0002345	82.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.68	gold quality
apex of heart	UBERON:0002098	82.67	gold quality
body of uterus	UBERON:0009853	82.66	gold quality
ascending aorta	UBERON:0001496	82.59	gold quality
right frontal lobe	UBERON:0002810	82.43	gold quality
gastrocnemius	UBERON:0001388	82.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	82.17	gold quality
ganglionic eminence	UBERON:0004023	82.14	gold quality
right coronary artery	UBERON:0001625	82.00	gold quality
left coronary artery	UBERON:0001626	81.97	gold quality
right ovary	UBERON:0002118	81.86	gold quality
body of stomach	UBERON:0001161	81.78	gold quality
esophagus	UBERON:0001043	81.73	gold quality
leukocyte	CL:0000738	81.58	gold quality
muscle of leg	UBERON:0001383	81.45	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.42	gold quality
stromal cell of endometrium	CL:0002255	81.40	gold quality
monocyte	CL:0000576	81.36	gold quality
mononuclear cell	CL:0000842	81.33	gold quality
left ovary	UBERON:0002119	81.20	gold quality
coronary artery	UBERON:0001621	81.13	gold quality
ectocervix	UBERON:0012249	80.91	gold quality
endocervix	UBERON:0000458	80.81	gold quality
tibial nerve	UBERON:0001323	80.80	gold quality
right adrenal gland cortex	UBERON:0035827	80.76	gold quality
right adrenal gland	UBERON:0001233	80.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.61	gold quality
left adrenal gland	UBERON:0001234	80.49	gold quality
left adrenal gland cortex	UBERON:0035825	80.49	gold quality
spleen	UBERON:0002106	80.39	gold quality
esophagus mucosa	UBERON:0002469	80.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.33	gold quality
secondary oocyte	CL:0000655	80.32	gold quality
amygdala	UBERON:0001876	80.30	gold quality
cingulate cortex	UBERON:0003027	80.21	gold quality
right lobe of thyroid gland	UBERON:0001119	80.17	gold quality
right atrium auricular region	UBERON:0006631	80.08	gold quality
neocortex	UBERON:0001950	80.07	gold quality
transverse colon	UBERON:0001157	80.02	gold quality
frontal cortex	UBERON:0001870	80.01	gold quality
right hemisphere of cerebellum	UBERON:0014890	80.00	gold quality
frontal lobe	UBERON:0016525	79.99	gold quality
left lobe of thyroid gland	UBERON:0001120	79.97	gold quality
anterior cingulate cortex	UBERON:0009835	79.92	gold quality
caudate nucleus	UBERON:0001873	79.88	gold quality
cerebellar hemisphere	UBERON:0002245	79.85	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.80	gold quality
cerebellar cortex	UBERON:0002129	79.77	gold quality
adenohypophysis	UBERON:0002196	79.77	gold quality
omental fat pad	UBERON:0010414	79.75	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.71	gold quality
peritoneum	UBERON:0002358	79.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	79.69	gold quality
nucleus accumbens	UBERON:0001882	79.67	gold quality
sigmoid colon	UBERON:0001159	79.66	gold quality
mucosa of transverse colon	UBERON:0004991	79.62	gold quality
upper lobe of left lung	UBERON:0008952	79.59	gold quality
ovary	UBERON:0000992	79.53	gold quality
putamen	UBERON:0001874	79.50	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	79.46	gold quality
amniotic fluid	UBERON:0000173	79.45	gold quality
spinal cord	UBERON:0002240	79.44	gold quality
adipose tissue	UBERON:0001013	79.37	gold quality
lower esophagus mucosa	UBERON:0035834	79.33	gold quality
adrenal cortex	UBERON:0001235	79.23	gold quality
thyroid gland	UBERON:0002046	79.22	gold quality
upper lobe of lung	UBERON:0008948	79.17	gold quality
anatomical system	UBERON:0000467	79.14	gold quality
material anatomical entity	UBERON:0000465	79.11	gold quality
vagina	UBERON:0000996	79.11	gold quality
multicellular organism	UBERON:0000468	79.10	gold quality
minor salivary gland	UBERON:0001830	79.04	gold quality
right uterine tube	UBERON:0001302	79.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.57

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Spinal cord	tissue	22.8
Superior colliculi	tissue	22.5
Pons	tissue	22.1
Medulla oblongata	tissue	22.1
Midbrain	tissue	22.0
Substantia nigra	tissue	21.7
Thalamus	tissue	21.5
Cerebellum	tissue	21.5	high
Corpus callosum	tissue	21.3
Hippocampal formation	tissue	20.0
Putamen	tissue	19.6
Cerebral cortex	tissue	19.4	high
Somatosensory cortex	tissue	19.4
Hypothalamus	tissue	18.6
Occipital cortex	tissue	18.5
Prefrontal cortex	tissue	18.4
Ventral forebrain	tissue	18.2
Periaqueductal gray	tissue	17.7
Motor cortex	tissue	17.5
Olfactory bulb	tissue	17.5
Temporal cortex	tissue	17.4
Septum	tissue	17.3
Basal ganglia	tissue	17.2	medium
Entorhinal cortex	tissue	17.0
Retrosplenial and cingulate cortex	tissue	17.0
Frontal cortex	tissue	16.2
Retrosplenial cortex	tissue	16.0
Insular cortex	tissue	15.2
Caudate putamen	tissue	14.4
Amygdala	tissue	14.3
Nucleus accumbens	tissue	3.5
Locus coeruleus	tissue	3.3
Hippocampus	tissue	3.1	medium
Postcentral gyrus	tissue	2.6
Testis	tissue	1.9	high
Tongue	tissue	1.5
Skin 1	tissue	1.3	medium
Choroid plexus	tissue	1.3
Retina	tissue	1.2
Seminal vesicle	tissue	1.2	high
Pituitary gland	tissue	1.1
Ovary	tissue	1.0	medium
Vagina	tissue	0.9	low
Endometrium 1	tissue	0.9	medium
Lymph node	tissue	0.8	high
Esophagus	tissue	0.8	low
Skeletal muscle	tissue	0.8	medium
Smooth muscle	tissue	0.8	medium
Spleen	tissue	0.8	high
Thymus	tissue	0.8
Fallopian tube	tissue	0.8	medium
Heart muscle	tissue	0.7	medium
Prostate	tissue	0.7	high
Tonsil	tissue	0.7	high
Parathyroid gland	tissue	0.6	low
Appendix	tissue	0.6	high
Cervix	tissue	0.5	high
Stomach 1	tissue	0.5	high
Colon	tissue	0.5	high
Urinary bladder	tissue	0.5	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (22.8), Dorsal spinal cord (22.5), White matter (21.3), Dorsal hippocampus (20.0), Ventral hippocampus (18.1).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ESS2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 117 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-452-5P	99.65	69.63	1762

Functional genomics

gnomAD constraint: pLI 8.44e-07, LOEUF 0.844, missense Z 0.489 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000252137 — one region, missense o/e 0.94. DepMap (CRISPR cell-line fitness): dependent in 97.0% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): TUHR10TKB (-2.285), NCI-H226 (-2.224), AsPC-1 (-2.042), LS1034 (-1.998), SNB75 (-1.831), Lu-65 (-1.798), HLF (-1.683), HUP-T3 (-1.565), KMS-20 (-1.524), AM-38 (-1.515), SW837 (-1.5), COLO-678 (-1.49), G-292, clone A141B1 (-1.488), Caov-4 (-1.461), SK-MM-2 (-1.444).

Literature-anchored findings (GeneRIF, showing 2)

• Experiments using Ess2 deletion mutants showed that a C-terminus deletion mutant of Ess2 (1-399 a. a.) lost its ability to associate with snRNAs, whereas the N-terminus domain of Ess2 (1-200 a. a.) associated with retinoic acid receptor-related orphan receptor gamma/gamma-t, but not with snRNAs. (PMID:29454968)
• Transcriptional coregulator Ess2 controls survival of post-thymic CD4(+) T cells through the Myc and IL-7 signaling pathways. (PMID:35933014)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ess2	ENSDARG00000060922
mus_musculus	Ess2	ENSMUSG00000003527
rattus_norvegicus	Ess2	ENSRNOG00000000283
drosophila_melanogaster	Es2	FBGN0023506
caenorhabditis_elegans		WBGENE00018371

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:107854) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 8 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal CD4-positive, alpha-beta T cell physiology	1
increased NK T cell number	1
decreased memory T cell number	1
decreased CD4-positive, alpha-beta T cell number	1
decreased CD8-positive, alpha-beta T cell number	1
increased gamma-delta T cell number	1
embryonic lethality, complete penetrance	1
decreased CD8-positive, naive alpha-beta T cell number	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Schizosaccharomyces pombe 972h-	O59793	30.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GSC2	protein-coding	2928
SLC25A1	protein-coding	6576
CLTCL1	protein-coding	8218
LINC01311	ncRNA	100652736
TSSK2	protein-coding	23617
DGCR11	ncRNA	25786
DGCR2	protein-coding	9993
FAM246C	protein-coding	117134596
DGCR5	ncRNA	26220

Protein

Protein identifiers

Splicing factor ESS-2 homolog — Q96DF8 (reviewed: Q96DF8)

Alternative names: DiGeorge syndrome critical region 13, DiGeorge syndrome critical region 14, DiGeorge syndrome protein H, Protein ES2

All UniProt accessions (2): Q96DF8, F8WEF8

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in pre-mRNA splicing.

Subunit / interactions. Identified in the spliceosome C complex. Interacts with FRA10AC1.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in heart, brain and skeletal muscle. Detected at low levels in placenta.

Similarity. Belongs to the ESS2 family.

RefSeq proteins (1): NP_073210* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019148	Nuclear_protein_DGCR14_ESS-2	Family

Pfam: PF09751

UniProt features (27 total): modified residue 6, helix 5, compositionally biased region 4, region of interest 3, sequence variant 3, strand 2, turn 2, chain 1, cross-link 1

Structure

Experimental structures (PDB)

5 structures by resolution:

PDB	Title	Method	Resolution (Å)
9S2E	Human intron-lariat spliceosome-Aquarius (ILSaqr)	ELECTRON MICROSCOPY	2.4
8C6J	Human spliceosomal PM5 C* complex	ELECTRON MICROSCOPY	2.8
9XU3	Human minor spliceosome exon-ligation-ready C* complex (prior to step-II)	ELECTRON MICROSCOPY	3
9FMD	Integrative model of the human post-catalytic spliceosome (P-complex)	ELECTRON MICROSCOPY	3.3
8RO2	Integrative Structure of the human intron lariat Spliceosome (ILS’')	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96DF8-F1	68.41	0.13

Human Protein Atlas

Protein class: Predicted intracellular proteins, Human disease related genes, Other congenital disorders, Chromosomal abnormalities, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH enhanced · IF approved

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 (7)

Type	Positions
Phosphoserine	292, 391, 395
Phosphothreonine	386, 3
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	142
N-acetylmethionine	1

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 176 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MODULE_70, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_RNA_SPLICING, LIAO_METASTASIS, GOCC_CATALYTIC_STEP_2_SPLICEOSOME, GOCC_SPLICEOSOMAL_COMPLEX, GOCC_RIBONUCLEOPROTEIN_COMPLEX, KIM_WT1_TARGETS_DN, STARK_HYPPOCAMPUS_22Q11_DELETION_DN, MARTENS_TRETINOIN_RESPONSE_UP

GO Biological Process (4): mRNA splicing, via spliceosome (GO:0000398), nervous system development (GO:0007399), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), catalytic step 2 spliceosome (GO:0071013), spliceosomal complex (GO:0005681)

GO top-level categories

14 GO namespaces:

Category	Terms
RNA processing	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
system development	1
animal gross anatomical part developmental process	1
mRNA metabolic process	1
binding	1
intracellular membrane-bounded organelle	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
nuclear protein-containing complex	1
ribonucleoprotein complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 2 of 8 annotations. The rest are phylogenetic / computational / electronic (IEA).

2 experimentally-supported GO terms:

GO term	NS	Evidence
mRNA splicing, via spliceosome	BP	mutant phenotype
catalytic step 2 spliceosome	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 1,030 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESS2	GATD3	P0DPI2	883
ESS2	DGCR2	P98153	880
ESS2	SLC25A1	P53007	811
ESS2	UFD1	Q92890	753
ESS2	HIRA	P54198	729
ESS2	CLTCL1	P53675	715
ESS2	GSC2	O15499	626
ESS2	RPS7	P23821	610
ESS2	CLTC	Q00610	552
ESS2	MRPL40	Q9NQ50	520
ESS2	TANGO2	Q6ICL3	464
ESS2	CRNKL1	Q9BZJ0	455
ESS2	MED15	Q96RN5	444
ESS2	GPATCH1	Q9BRR8	440
ESS2	DHX38	Q92620	435

IntAct

Human interaction partners of ESS2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

26 partners by confidence:

Partner	Interaction type	MIscore	Records
FRA10AC1	physical association	0.730	3
ACADS	association	0.640	1
PRPF19	physical association	0.620	1
ARMC7	physical association	0.560	3
CCDC57	physical association	0.560	3
DGCR6	physical association	0.560	3
EXOC8	physical association	0.560	3
GFAP	physical association	0.560	3
JPH3	physical association	0.560	3
NXF1	physical association	0.560	3
OIP5	physical association	0.560	3
QARS1	physical association	0.560	3
SMARCD1	physical association	0.560	3
HSPA8	association	0.530	2
NEDD4	direct interaction	0.440	1
YAP1	direct interaction	0.440	1
CDK5RAP3	physical association	0.370	1
CRP	physical association	0.370	1
DHX16	physical association	0.370	1
PFDN1	physical association	0.370	1
RACK1	physical association	0.370	1
RBM4	physical association	0.370	1
TTC14	physical association	0.370	1
VIM	physical association	0.370	1
WNK2	physical association	0.370	1
CDC40	association	0.350	1

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
C complex spliceosome	80	RBM8A, ZCCHC8, EFTUD2, HNRNPK, PNN, SRSF1, CDC40, DHX35, HNRNPA2B1, HNRNPC, SF3B3, SYNCRIP, U2AF1, PLRG1, RBM22, SNRNP40, SNRPB2, EIF4A3, FRG1, GPATCH1, HNRNPA3, PPIL1, SF3B1, DHX38, HNRNPR, LSM2, LSM3, SNRPE, DDX23, HNRNPU, MTREX, SLU7, AQR, CWC15, CWC22, DDX41, PABPC1, SF3B2, SNRPD1, SNRPD2, DHX8, CWC27, HNRNPA1, HNRNPH1, MAGOH, SF3A1, PPIE, PPIL3, PRP4K, PRPF6, RALY, SNRPA1, SYF2, TFIP11, CACTIN, CRNKL1, DDX5, SF3A3, SNRNP200, SNRPD3, SNRPF, SRRM1, ALYREF, PPWD1, PRPF19, RBMX, SF3A2, SRRM2, WDR83, XAB2, CDC5L, HNRNPF, SART1, SNRPG, ESS2, ISY1, SNRPB, SNW1, HNRNPM, PRPF8

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Dengue Virus-Host Interactions	5	12.0×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mRNA splicing, via spliceosome	5	18.3×	2e-03

Disease & clinical

Genetic variants

Variant evidence for ESS2: 206 ClinVar records (2 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	162
Likely benign	13
Benign	5

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
625622	GRCh37/hg19 22q11.21(chr22:18923898-21431174)	Pathogenic	criteria provided, single submitter	1
4796089	GRCh38/hg38 22q11.21(chr22:18929330-21110475)x3	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ESS2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 897):

Position(s)	Effect	Δscore	Sites
22:19135058–19135059	donor_loss	1.0000	5
22:19135176–19135177	acceptor_loss	1.0000	4
22:19137321–19137322	donor_loss	1.0000	3
22:19137433–19137434	acceptor_loss	1.0000	5
22:19137441	acceptor_gain	1.0000
22:19139157–19139158	donor_loss	1.0000	5
22:19139293–19139294	acceptor_loss	1.0000	5
22:19139298	acceptor_gain	1.0000
22:19139302	acceptor_gain	1.0000
22:19139610–19139611	donor_loss	1.0000	4

AlphaMissense

1,045 missense substitutions predicted likely pathogenic (of 3,086 scored), across 259 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D159	8	0.993	0.997
D411	8	0.971	0.989
F344	8	0.969	0.999
D54	8	0.959	0.985
F163	8	0.954	0.997
F56	8	0.953	0.999
F108	8	0.953	0.994
N222	8	0.953	0.995
D283	8	0.924	0.976
D461	8	0.910	0.982
F476	8	0.909	0.980
S157	8	0.906	0.998
S417	8	0.898	0.996
D149	8	0.892	0.964
F251	8	0.866	0.993
N248	8	0.847	0.972
D58	8	0.732	0.883
F55	7	0.990	0.999
W318	7	0.990	0.999
F151	7	0.980	0.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000158
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	favorable	0.00075

Disease associations

OMIM: gene MIM:601755 | disease phenotypes:

HPO phenotypes

39 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000194	Open mouth
HP:0000201	Pierre-Robin sequence
HP:0000220	Velopharyngeal insufficiency
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000414	Bulbous nose
HP:0000430	Underdeveloped nasal alae
HP:0000581	Blepharophimosis
HP:0000598	Abnormality of the ear
HP:0000627	Posterior embryotoxon
HP:0000712	Emotional lability
HP:0000718	Aggressive behavior
HP:0000829	Hypoparathyroidism
HP:0001155	Abnormality of the hand
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001328	Specific learning disability
HP:0001537	Umbilical hernia
HP:0001611	Hypernasal speech
HP:0001629	Ventricular septal defect
HP:0001636	Tetralogy of Fallot
HP:0001883	Talipes
HP:0002627	Right aortic arch with mirror image branching
HP:0002719	Recurrent infections
HP:0002901	Hypocalcemia
HP:0004322	Short stature
HP:0004935	Pulmonary artery atresia
HP:0006549	Unilateral primary pulmonary dysgenesis
HP:0011590	Double aortic arch
HP:0011611	Interrupted aortic arch
HP:0011840	Abnormal T cell physiology
HP:0011999	Paranoia
HP:0012841	Retinal vascular tortuosity
HP:0045025	Narrow palpebral fissure

GWAS associations

4 associations:

Study	Trait	p-value
GCST009391_381	Metabolite levels	8e-7
GCST009391_469	Metabolite levels	1e-6
GCST009391_390	Metabolite levels	3e-6
GCST009391_1016	Metabolite levels	8e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0010442	triacylglycerol 58:8 measurement
EFO:0010434	triacylglycerol 56:7 measurement
EFO:0010435	triacylglycerol 56:8 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
coumarin	increases phosphorylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Atrazine	decreases expression	1
Caffeine	increases phosphorylation	1
Doxorubicin	increases expression	1
Lead	decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Quercetin	decreases phosphorylation	1
Selenium	increases expression	1
Smoke	decreases expression	1
Sulindac	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Valproic Acid	decreases expression	1
Vitamin E	increases expression	1
Cyclosporine	increases expression	1
tert-Butylhydroperoxide	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.