ELP1

Summary

ELP1 (elongator acetyltransferase complex subunit 1, HGNC:5959) is a protein-coding gene on chromosome 9q31.3, encoding Elongator complex protein 1 (O95163). Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine). It is a common-essential gene (DepMap: required in 94.1% of cancer cell lines).

The protein encoded by this gene is a scaffold protein and a regulator for three different kinases involved in proinflammatory signaling. The encoded protein can bind NF-kappa-B-inducing kinase and I-kappa-B kinases through separate domains and assemble them into an active kinase complex. Mutations in this gene have been associated with familial dysautonomia. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 8518 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary dysautonomia (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 2,717 total — 88 pathogenic, 283 likely-pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 94.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_003640

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5959
Approved symbol	ELP1
Name	elongator acetyltransferase complex subunit 1
Location	9q31.3
Locus type	gene with protein product
Status	Approved
Aliases	IKAP, TOT1, IKI3
Ensembl gene	ENSG00000070061
Ensembl biotype	protein_coding
OMIM	603722
Entrez	8518

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 21 retained_intron, 14 nonsense_mediated_decay, 13 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000374647, ENST00000467959, ENST00000495759, ENST00000537196, ENST00000674535, ENST00000674704, ENST00000674740, ENST00000674836, ENST00000674890, ENST00000674938, ENST00000674948, ENST00000675052, ENST00000675062, ENST00000675078, ENST00000675215, ENST00000675233, ENST00000675252, ENST00000675321, ENST00000675325, ENST00000675335, ENST00000675370, ENST00000675400, ENST00000675406, ENST00000675458, ENST00000675507, ENST00000675535, ENST00000675566, ENST00000675580, ENST00000675602, ENST00000675647, ENST00000675711, ENST00000675727, ENST00000675748, ENST00000675765, ENST00000675825, ENST00000675877, ENST00000675893, ENST00000675938, ENST00000675943, ENST00000675979, ENST00000676044, ENST00000676086, ENST00000676121, ENST00000676162, ENST00000676237, ENST00000676416, ENST00000676424, ENST00000676429, ENST00000861104, ENST00000933696, ENST00000933697

RefSeq mRNA: 3 — MANE Select: NM_003640 NM_001318360, NM_001330749, NM_003640

CCDS: CCDS6773, CCDS83394, CCDS94451

Canonical transcript exons

ENST00000374647 — 37 exons

Exon	Start	End
ENSE00000718492	108908305	108908404
ENSE00000718497	108911010	108911180
ENSE00000805965	108918811	108918901
ENSE00000805966	108919253	108919349
ENSE00000805967	108922842	108922927
ENSE00000805968	108926523	108926603
ENSE00000805969	108927372	108927453
ENSE00000805970	108929769	108929921
ENSE00000926779	108877995	108878149
ENSE00000926780	108878623	108878750
ENSE00000926781	108879446	108879557
ENSE00000926786	108891203	108891404
ENSE00000926787	108892986	108893083
ENSE00000926788	108893943	108894066
ENSE00000926789	108896496	108896644
ENSE00000926790	108896953	108897038
ENSE00000926791	108897148	108897285
ENSE00000926792	108898502	108898581
ENSE00000926793	108898671	108898749
ENSE00000926794	108899822	108899895
ENSE00000926795	108900260	108900375
ENSE00000926796	108901425	108901530
ENSE00000926797	108901628	108901681
ENSE00000926798	108902839	108902942
ENSE00000926799	108903563	108903669
ENSE00000983463	108906303	108906485
ENSE00001374133	108933864	108934124
ENSE00001464110	108930997	108931201
ENSE00003465955	108880052	108880165
ENSE00003505938	108889332	108889393
ENSE00003506176	108916204	108916297
ENSE00003527854	108917547	108917670
ENSE00003534111	108912264	108912494
ENSE00003611518	108867517	108869182
ENSE00003649676	108874895	108874970
ENSE00003653938	108881705	108881765
ENSE00003661467	108882125	108882187

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.6227 / max 252.8718, expressed in 1804 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101866	19.0047	1801
101864	1.7179	781
101865	0.3874	172
101863	0.2039	98
101860	0.2004	22
101862	0.0952	16
101861	0.0133	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.89	gold quality
right adrenal gland cortex	UBERON:0035827	98.85	gold quality
right adrenal gland	UBERON:0001233	98.75	gold quality
adrenal cortex	UBERON:0001235	98.41	gold quality
left adrenal gland cortex	UBERON:0035825	98.36	gold quality
left adrenal gland	UBERON:0001234	98.34	gold quality
adrenal gland	UBERON:0002369	98.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.14	gold quality
cerebellar hemisphere	UBERON:0002245	96.07	gold quality
cerebellar cortex	UBERON:0002129	95.91	gold quality
pituitary gland	UBERON:0000007	95.33	gold quality
cerebellum	UBERON:0002037	95.05	gold quality
adenohypophysis	UBERON:0002196	94.96	gold quality
left ovary	UBERON:0002119	94.58	gold quality
right ovary	UBERON:0002118	94.43	gold quality
pigmented layer of retina	UBERON:0001782	94.28	gold quality
bronchial epithelial cell	CL:0002328	93.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.86	gold quality
middle temporal gyrus	UBERON:0002771	93.61	gold quality
ovary	UBERON:0000992	93.53	gold quality
right frontal lobe	UBERON:0002810	93.42	gold quality
primary visual cortex	UBERON:0002436	93.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.86	gold quality
germinal epithelium of ovary	UBERON:0001304	92.81	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.56	gold quality
tibia	UBERON:0000979	92.48	gold quality
cortical plate	UBERON:0005343	92.43	gold quality
epithelium of bronchus	UBERON:0002031	92.20	gold quality
occipital lobe	UBERON:0002021	92.11	gold quality
nucleus accumbens	UBERON:0001882	92.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.93

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ESR1, THRA, VDR

miRNA regulators (miRDB)

98 targeting ELP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4531	99.99	69.70	3181
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 36)

• novel role for the I kappa B kinase complex-associated protein (IKAP) in the regulation of activation of the mammalian stress response via the c-Jun N-terminal kinase (JNK)-signaling pathway (PMID:12058026)
• Genetics of familial dysautonomia; tissue-specific expression of a splicing mutation (REVIEW) (PMID:12102458)
• Tissue-specific reduction in splicing efficiency of this protein is due to the major mutation associated with familial dysautonomia. (PMID:12577200)
• The study results suggest that the polymorphisms in the coding region of the IKAP gene are unlikely to contribute to atopic disease risk in the Czech population. (PMID:12774215)
• whereas IKBKAP (Elongator) is recruited to both target and nontarget genes, only target genes display histone H3 hypoacetylation and progressively lower RNAPII density through the coding region in familial dysautonomia cells (PMID:16713582)
• Neurodevelopmental disease familial dysautonomia (FD)caused by a single-base change in the 5’ splice site (5’ss) of intron 20 in the IKBKAP gene (c.2204+6T>C). (PMID:16964593)
• investigated the nature of the FD splicing defect and the mechanism by which kinetin improves exon inclusion (PMID:17206408)
• IKAP/hELP1 may play a role in oligodendrocyte differentiation and/or myelin formation. (PMID:17591626)
• description of a humanized IKBKAP transgenic mouse that models a tissue-specific human splicing defect (PMID:17644305)
• IKBKAP may have a role in familial dysautonomia (PMID:18091349)
• Evidence for the role of the cytosolic interactions of IKAP in cell adhesion and migration, and support the notion that cell-motility deficiencies could contribute to familial dysautonomia. (PMID:18303054)
• IKAP is crucial for both vascular and neural development during embryogenesis and that protein function is conserved between mouse and human. (PMID:19015235)
• IKBKAP is a candidate gene for Hirschsprung’s disease and was mapped to chromosome 9q31 locus. (PMID:20361209)
• IKAP regulates contactin levels for appropriate cell-cell adhesion that could modulate neuronal growth of neurons during development (PMID:20671422)
• IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients. (PMID:21098405)
• Phosphatidylserine increases IKBKAP levels in familial dysautonomia cells (PMID:21209961)
• IKK complex-associated protein deficiency upregulates the microtubule destabilizing protein SCG10 and, in parallel, disorganizes the cytoskeleton (PMID:21273291)
• IKAP/hELP1 deficiency has an effect on gene expression in differentiating neuroblastoma cells, and possibly on familial dysautonomia (PMID:21559466)
• IKAP plays pleiotropic roles in both the peripheral and central nervous systems (PMID:22384137)
• Combined treatment with epigallocatechin gallate and genistein synergistically upregulates wild-type IKBKAP-encoded RNA and protein levels in familial dysautonomia-derived cells. (PMID:22495984)
• Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model for Familial dysautonomia. (PMID:23515154)
• Digoxin-mediated repression of SRSF3 expression plays a role in the digoxin-mediated inclusion of exon 20 in the IKBKAP transcript generated from the familial dysautonomia mutant allele. (PMID:23711097)
• IKBKAP mRNA levels decreased during a familial dysautonomia crisis and returned to baseline after recovery. The cause-and-effect relationship is unclear. (PMID:24268683)
• Hrr25 protein kinase directly modifies Elp1 on two sites and we provide evidence that phosphorylation plays a positive role in the tRNA modification (PMID:25569479)
• The formation of the Elp1 dimer contributes to its stability in vitro and in vivo and is required for the assembly of human Elongator complexes. (PMID:26261306)
• IKAP might be a vesicular like protein that might be involved in neuronal transport in hESC derived PNS neurons (PMID:26437462)
• overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP, supporting a potential interaction between NOVA1 and IKAP. (PMID:27483351)
• The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs. (PMID:29289840)
• This splice-switching class of molecules is the first to specifically correct the ELP1 exon 20 splicing defect. Our data provide proof of principle of ExSpeU1s-adeno-associated virus particles as a novel therapeutic strategy for FD. (PMID:29701768)
• Data indicate that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a negative regulator of IKK-complex-associated protein (IKBKAP) exon 20 splicing. (PMID:29762696)
• A secondary assay that measures ELP1 splicing in FD patient-derived fibroblasts. (PMID:30085848)
• postnatal correction of the underlying ELP1 splicing defect can rescue devastating disease phenotypes in a humanized ELP1 mouse model (PMID:30905397)
• The authors identified two potentially functional single nucleotide polymorphisms (IKBKAP rs4978754 C > T and TNFRSF1B rs677844 T > C) to be associated with survival of patients with non-small cell lung cancer. (PMID:30989732)
• Tumours from patients with ELP1-associated medulloblastoma subgroup Sonic Hedgehog were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming (PMID:32296180)
• Age-dependent regulation of ELP1 exon 20 splicing in Familial Dysautonomia by RNA Polymerase II kinetics and chromatin structure. (PMID:38829854)
• ELP1, the Gene Mutated in Familial Dysautonomia, Is Required for Normal Enteric Nervous System Development and Maintenance and for Gut Epithelium Homeostasis. (PMID:39138000)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	elp1	ENSDARG00000094204
mus_musculus	Elp1	ENSMUSG00000028431
rattus_norvegicus	Elp1	ENSRNOG00000016725
drosophila_melanogaster	Elp1	FBGN0037926
caenorhabditis_elegans	elpc-1	WBGENE00022463

Protein

Protein identifiers

Elongator complex protein 1 — O95163 (reviewed: O95163)

Alternative names: IkappaB kinase complex-associated protein, p150

All UniProt accessions (22): O95163, A0A6Q8PEX6, A0A6Q8PF66, A0A6Q8PF69, A0A6Q8PFB7, A0A6Q8PFC8, A0A6Q8PFH9, A0A6Q8PFN8, A0A6Q8PFX1, A0A6Q8PG86, A0A6Q8PGA6, A0A6Q8PGC4, A0A6Q8PGR0, A0A6Q8PGW3, A0A6Q8PH36, A0A6Q8PH48, A0A6Q8PHA0, A0A6Q8PHC9, A0A6Q8PHF4, A0A6Q8PHI5, F5H2T0, H0YDF3

UniProt curated annotations — full annotation on UniProt →

Function. Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine). The elongator complex catalyzes the formation of carboxymethyluridine in the wobble base at position 34 in tRNAs. Regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation. ELP1 binds to tRNA, mediating interaction of the elongator complex with tRNA. May act as a scaffold protein that assembles active IKK-MAP3K14 complexes (IKKA, IKKB and MAP3K14/NIK).

Subunit / interactions. Homodimer; dimerization promotes ELP1 stability and elongator complex formation. Component of the elongator complex which consists of ELP1, ELP2, ELP3, ELP4, ELP5 and ELP6. Interacts preferentially with MAP3K14/NIK followed by IKK-alpha and IKK-beta.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Neuropathy, hereditary sensory and autonomic, 3 (HSAN3) [MIM:223900] A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN3 patients manifest a variety of symptoms such as alacrima, decreased taste, decreased sensitivity to pain and temperature, vasomotor instability, hypoactive or absent deep tendon reflexes, vomiting crises, and gastrointestinal dysfunction. The disease is caused by variants affecting the gene represented in this entry. Medulloblastoma (MDB) [MIM:155255] Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Pathway. tRNA modification; 5-methoxycarbonylmethyl-2-thiouridine-tRNA biosynthesis.

Similarity. Belongs to the ELP1/IKA1 family.

RefSeq proteins (3): NP_001305289, NP_001317678, NP_003631* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006849	Elp1	Family
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR056164	Beta-prop_ELP1_1st	Domain
IPR056165	Beta-prop_ELP1_2nd	Domain
IPR056166	TPR_ELP1	Domain
IPR056167	A-sol_ELP1	Domain
IPR056169	HB_ELP1	Domain

Pfam: PF04762, PF23797, PF23878, PF23925, PF23936

UniProt features (140 total): strand 64, helix 33, sequence variant 14, turn 13, modified residue 5, sequence conflict 4, region of interest 3, compositionally biased region 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8PTX	ELECTRON MICROSCOPY	2.87
5CQR	X-RAY DIFFRACTION	3.02
8PTZ	ELECTRON MICROSCOPY	3.35
8PTY	ELECTRON MICROSCOPY	3.58
8PU0	ELECTRON MICROSCOPY	4.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95163-F1	84.31	0.49

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 (5): 1174, 471, 804, 867, 1171

Mutagenesis-validated functional residues (1):

Position	Phenotype
1011	disruption of dimer formation, reduced protein stability and reduced interaction with elp2 and elp3. does not affect bin

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones

MSigDB gene sets: 267 (showing top): BIOCARTA_TNFR2_PATHWAY, GOBP_TRNA_METABOLIC_PROCESS, GCM_ZNF198, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RNA_MODIFICATION, GARY_CD5_TARGETS_DN, GCM_SUFU, BOYAULT_LIVER_CANCER_SUBCLASS_G1_UP, CAIRO_HEPATOBLASTOMA_UP, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GOBP_TRNA_PROCESSING, BIOCARTA_CD40_PATHWAY, ATGTTTC_MIR494

GO Biological Process (4): tRNA wobble uridine modification (GO:0002098), tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation (GO:0002926), regulation of translation (GO:0006417), tRNA processing (GO:0008033)

GO Molecular Function (2): tRNA binding (GO:0000049), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), elongator holoenzyme complex (GO:0033588)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Chromatin modifying enzymes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
tRNA wobble base modification	1
tRNA wobble uridine modification	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
RNA processing	1
tRNA metabolic process	1
RNA binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1

Protein interactions and networks

STRING

2355 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ELP1	ELP4	Q96EB1	987
ELP1	ELP3	Q9H9T3	986
ELP1	ELP2	Q6IA86	886
ELP1	ELP6	Q0PNE2	879
ELP1	KTI12	Q96EK9	833
ELP1	IKBKG	Q9Y6K9	775
ELP1	CHUK	O15111	738
ELP1	ELP5	Q8TE02	737
ELP1	WNK1	P54963	684
ELP1	TUBA1B	P04687	677
ELP1	SPTLC2	O15270	675
ELP1	RELA	Q04206	667
ELP1	FUT2	Q10981	624
ELP1	URM1	Q9BTM9	592
ELP1	SPTLC1	O15269	579

IntAct

122 interactions, top by confidence:

A	B	Type	Score
ELP1	ELP3	psi-mi:“MI:0915”(physical association)	0.840
ELP3	ELP1	psi-mi:“MI:0915”(physical association)	0.840
ELP3	ELP1	psi-mi:“MI:0914”(association)	0.840
TET3	OGT	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ELP2	ELP1	psi-mi:“MI:0914”(association)	0.620
ELP1	ELP2	psi-mi:“MI:0914”(association)	0.620
ELP1	ELP2	psi-mi:“MI:0915”(physical association)	0.620
ELP4	ELP1	psi-mi:“MI:0914”(association)	0.600
TTR	ELP1	psi-mi:“MI:0915”(physical association)	0.550
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
KPTN	EIF4G3	psi-mi:“MI:0914”(association)	0.530
PLEKHN1	ELP1	psi-mi:“MI:0914”(association)	0.530
ZNRD2	MYO9A	psi-mi:“MI:0914”(association)	0.530
CAMK2D	ELP1	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
POLR2A	ELP1	psi-mi:“MI:0915”(physical association)	0.520
ELP1	HTT	psi-mi:“MI:0915”(physical association)	0.510
HTT	ELP1	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (256): IKBKAP (Affinity Capture-MS), IKBKAP (Affinity Capture-MS), IKBKAP (Affinity Capture-MS), IKBKAP (Affinity Capture-MS), IKBKAP (Affinity Capture-MS), DPH3 (Co-fractionation), ELP3 (Co-fractionation), FOCAD (Co-fractionation), IKBKAP (Co-fractionation), IKBKAP (Co-fractionation), PSMA2 (Co-fractionation), PSMD11 (Co-fractionation), PSMD12 (Co-fractionation), PSMD4 (Co-fractionation), IKBKAP (Affinity Capture-MS)

ESM2 similar proteins: A1A5V9, A1L251, E7F654, F1Q7Z7, F4IQJ2, O01939, O74385, O94495, O95163, O95822, P12617, Q17DK2, Q18195, Q1LXS2, Q24050, Q294E0, Q38SD2, Q3SYG4, Q3TIR3, Q4R720, Q501D5, Q5I0I8, Q5N8Q4, Q5R8F5, Q5RET3, Q5ZJC7, Q60ZM2, Q66I84, Q6DRJ9, Q6NRQ2, Q6NU91, Q6PD74, Q7TT37, Q80ZG1, Q811G0, Q8BHY2, Q8L9Y2, Q8R2R3, Q8VHU4, Q8WTJ4

Diamond homologs: O95163, Q2TAQ1, Q7TT37, Q8VHU4, Q8WND5, Q9VGK7, Q06706

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ELP1	“form complex”	“Elongator complex”	binding
ELP1	up-regulates	MAPK8
MTOR	“up-regulates activity”	ELP1	phosphorylation
mTORC2	“up-regulates activity”	ELP1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

2717 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	88
Likely pathogenic	283
Uncertain significance	998
Likely benign	1018
Benign	127

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069002	NC_000009.11:g.(?111665109)(111665959_?)del	Pathogenic
1069003	NC_000009.11:g.(?111692039)(111693436_?)del	Pathogenic
1069004	NC_000009.11:g.(?111642322)(111644477_?)del	Pathogenic
1069633	NM_003640.5(ELP1):c.2642T>A (p.Leu881Ter)	Pathogenic
1073791	NM_003640.5(ELP1):c.254_255dup (p.Ala86fs)	Pathogenic
1074081	NM_003640.5(ELP1):c.909_919del (p.Trp304fs)	Pathogenic
1075805	NM_003640.5(ELP1):c.982dup (p.Tyr328fs)	Pathogenic
1075871	NM_003640.5(ELP1):c.3060dup (p.Ala1021fs)	Pathogenic
1299759	NM_003640.5(ELP1):c.312T>C (p.Cys104=)	Pathogenic
1373264	NM_003640.5(ELP1):c.2088del (p.Ile697fs)	Pathogenic
1382186	NC_000009.11:g.(?111673280)(111679960_?)del	Pathogenic
1391848	NM_003640.5(ELP1):c.3475dup (p.His1159fs)	Pathogenic
1451358	NM_003640.5(ELP1):c.1333del (p.Ser445fs)	Pathogenic
1451362	NM_003640.5(ELP1):c.3765dup (p.Gln1256fs)	Pathogenic
1453794	NM_003640.5(ELP1):c.1696_1697del (p.Thr566fs)	Pathogenic
1455733	NC_000009.11:g.(?111681081)(111681639_?)del	Pathogenic
1455785	NM_003640.5(ELP1):c.3866_3870del (p.Pro1289fs)	Pathogenic
1457404	NM_003640.5(ELP1):c.1052G>A (p.Trp351Ter)	Pathogenic
1460208	NM_003640.5(ELP1):c.1433del (p.Arg478fs)	Pathogenic
1705187	NC_000009.11:g.(111644468_111651611)(111696613?)del	Pathogenic
1799835	NM_003640.5(ELP1):c.836del (p.Thr279fs)	Pathogenic
1799840	NM_003640.5(ELP1):c.2624_2625del (p.Glu875fs)	Pathogenic
1799898	NM_003640.5(ELP1):c.599G>A (p.Trp200Ter)	Pathogenic
1961032	NM_003640.5(ELP1):c.3829dup (p.Thr1277fs)	Pathogenic
2003219	NM_003640.5(ELP1):c.2891del (p.Asn963_Leu964insTer)	Pathogenic
2004156	NM_003640.5(ELP1):c.1961del (p.Thr654fs)	Pathogenic
2015722	NM_003640.5(ELP1):c.94del (p.Thr32fs)	Pathogenic
2018468	NM_003640.5(ELP1):c.881G>A (p.Trp294Ter)	Pathogenic
2021650	NM_003640.5(ELP1):c.3200dup (p.Met1067fs)	Pathogenic
2024774	NC_000009.12:g.108929922del	Pathogenic

SpliceAI

5840 predictions. Top by Δscore:

Variant	Effect	Δscore
9:108874890:CTAA:C	donor_loss	1.0000
9:108874891:TAA:T	donor_loss	1.0000
9:108874892:AAC:A	donor_loss	1.0000
9:108874893:A:AC	donor_gain	1.0000
9:108874893:A:AG	donor_loss	1.0000
9:108874894:C:CC	donor_gain	1.0000
9:108874894:C:CT	donor_loss	1.0000
9:108874969:AC:A	acceptor_gain	1.0000
9:108874970:CC:C	acceptor_gain	1.0000
9:108877990:CTT:C	donor_loss	1.0000
9:108877991:TTA:T	donor_loss	1.0000
9:108877992:TAC:T	donor_loss	1.0000
9:108877993:A:AC	donor_gain	1.0000
9:108877993:AC:A	donor_gain	1.0000
9:108877994:C:CG	donor_gain	1.0000
9:108877994:CC:C	donor_gain	1.0000
9:108877994:CCG:C	donor_gain	1.0000
9:108877994:CCGGG:C	donor_gain	1.0000
9:108878105:C:CT	acceptor_gain	1.0000
9:108878111:C:CT	acceptor_gain	1.0000
9:108878150:C:CC	acceptor_gain	1.0000
9:108878618:TATA:T	donor_loss	1.0000
9:108878620:TACC:T	donor_loss	1.0000
9:108878621:A:AC	donor_gain	1.0000
9:108878621:A:AT	donor_loss	1.0000
9:108878622:C:CC	donor_gain	1.0000
9:108878622:CCTTT:C	donor_gain	1.0000
9:108878652:T:TA	donor_gain	1.0000
9:108878652:TC:T	donor_gain	1.0000
9:108878658:AGTG:A	donor_gain	1.0000

AlphaMissense

8791 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:108878738:C:A	K1195N	0.997
9:108878738:C:G	K1195N	0.997
9:108916282:A:G	W294R	0.997
9:108916282:A:T	W294R	0.997
9:108918815:A:G	W246R	0.997
9:108918815:A:T	W246R	0.997
9:108919304:A:G	W200R	0.997
9:108919304:A:T	W200R	0.997
9:108912402:A:G	W351R	0.996
9:108912402:A:T	W351R	0.996
9:108927403:A:C	S118R	0.996
9:108927403:A:T	S118R	0.996
9:108927405:T:G	S118R	0.996
9:108878726:T:A	K1199N	0.995
9:108878726:T:G	K1199N	0.995
9:108896512:G:T	A907D	0.995
9:108900297:A:T	V698D	0.995
9:108912454:C:A	K333N	0.995
9:108912454:C:G	K333N	0.995
9:108878740:T:C	K1195E	0.994
9:108894065:T:C	D913G	0.994
9:108896513:C:G	A907P	0.994
9:108899885:C:A	G714V	0.994
9:108878699:T:A	K1208N	0.993
9:108878699:T:G	K1208N	0.993
9:108893978:C:G	R942P	0.993
9:108899881:G:C	N715K	0.993
9:108899881:G:T	N715K	0.993
9:108912486:A:G	W323R	0.993
9:108912486:A:T	W323R	0.993

dbSNP variants (sampled 300 via entrez): RS1000031681 (9:108935848 T>G), RS1000043423 (9:108901468 G>A,T), RS1000210538 (9:108895896 C>G,T), RS1000251772 (9:108907205 T>C), RS1000344298 (9:108878907 T>C), RS1000406863 (9:108930677 C>A,T), RS1000425973 (9:108924230 T>C), RS1000435518 (9:108926795 T>C), RS1000503824 (9:108897712 G>A), RS1000504754 (9:108872675 G>A), RS1000511708 (9:108895677 G>A), RS1000584212 (9:108931753 G>A), RS1000587680 (9:108879214 C>T), RS1000654268 (9:108930531 A>G), RS1000683729 (9:108932898 C>T)

Disease associations

OMIM: gene MIM:603722 | disease phenotypes: MIM:223900, MIM:155255, MIM:162400, MIM:118220

GenCC curated gene-disease

Disease	Classification	Inheritance
primary dysautonomia	Definitive	Autosomal recessive
Riley-Day syndrome	Definitive	Autosomal recessive
medulloblastoma	Strong	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (7): Riley-Day syndrome (MONDO:0009131), medulloblastoma (MONDO:0007959), hereditary sensory and autonomic neuropathy (MONDO:0015364), primary dysautonomia (MONDO:0021809), Charcot-Marie-Tooth disease (MONDO:0015626), Gaucher disease (MONDO:0018150), neurodevelopmental disorder (MONDO:0700092)

Orphanet (5): Familial dysautonomia (Orphanet:1764), Medulloblastoma (Orphanet:616), Hereditary sensory and autonomic neuropathy (Orphanet:140471), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Gaucher disease (Orphanet:355)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000096	Glomerular sclerosis
HP:0000224	Hypogeusia
HP:0000495	Recurrent corneal erosions
HP:0000522	Alacrima
HP:0000545	Myopia
HP:0000615	Abnormal pupil morphology
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000822	Hypertension
HP:0000966	Hypohidrosis
HP:0000975	Hyperhidrosis
HP:0001063	Acrocyanosis
HP:0001069	Episodic hyperhidrosis
HP:0001100	Heterochromia iridis
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001278	Orthostatic hypotension
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001442	Typified by somatic mosaicism
HP:0001510	Growth delay
HP:0001649	Tachycardia
HP:0001954	Recurrent fever

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST006073_17	Tenofovir clearance in HIV infection	9.000000e-06
GCST007899_19	Fasting blood glucose	5.000000e-06
GCST008839_401	Height	3.000000e-13
GCST010397_92	Gut microbiota (bacterial taxa, rank normal transformation method)	2.000000e-08
GCST90000025_417	Appendicular lean mass	6.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D004402	Dysautonomia, Familial	C10.177.575.300; C10.500.250.309; C10.574.500.493.250; C10.668.829.800.175.250; C16.131.666.310.309; C16.320.400.415.309
D005776	Gaucher Disease	C10.228.140.163.100.435.825.400; C16.320.565.189.435.825.400; C16.320.565.398.641.803.441; C16.320.565.595.554.825.400; C18.452.132.100.435.825.400; C18.452.584.563.641.803.441; C18.452.648.189.435.825.400; C18.452.648.398.641.803.441; C18.452.648.595.554.825.400
D009477	Hereditary Sensory and Autonomic Neuropathies	C10.500.250; C10.574.500.493; C10.668.829.800.175; C16.131.666.310; C16.320.400.415
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D065886	Neurodevelopmental Disorders	F03.625
D054969	Primary Dysautonomias	C10.177.575

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1818 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.05	Kd	89.95	nM	CHEMBL5653589
6.97	ED50	106.8	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2148580: Binding affinity to human IKBKAP incubated for 45 mins by Kinobead based pull down assay	kd	0.0900	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Rotenone	decreases expression	3
Tetrachlorodibenzodioxin	decreases expression, increases expression	3
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases mutagenesis	2
Aflatoxin B1	decreases methylation, increases methylation	2
FR900359	decreases phosphorylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
coumarin	increases phosphorylation	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
azoxystrobin	decreases expression	1
deguelin	decreases expression	1
K 7174	decreases expression	1
motexafin gadolinium	affects cotreatment, decreases expression	1
pyrachlostrobin	decreases expression	1
picoxystrobin	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Amiodarone	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	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
CHEMBL5651622	Binding	Binding affinity to human IKBKAP 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

58 cell lines: 36 transformed cell line, 18 finite cell line, 3 induced pluripotent stem cell, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_7302	GM00850	Finite cell line	Male
CVCL_7415	GM04663	Finite cell line	Female
CVCL_A4ZJ	BGUi006-A	Induced pluripotent stem cell	Male
CVCL_A4ZK	BGUi007-A	Induced pluripotent stem cell	Male
CVCL_AA18	GM02341	Finite cell line	Male
CVCL_AA19	GM02342	Finite cell line	Male
CVCL_AA20	GM02343	Finite cell line	Female
CVCL_AA22	GM04585	Transformed cell line	Female
CVCL_AA23	GM04586	Finite cell line	Female
CVCL_AA24	GM04587	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02875314	PHASE4	ACTIVE_NOT_RECRUITING	HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT00085735	PHASE3	COMPLETED	Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma
NCT00336024	PHASE3	COMPLETED	Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
NCT00392327	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET
NCT01351870	PHASE3	COMPLETED	Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (PNET4)
NCT07291102	PHASE3	NOT_YET_RECRUITING	Comparison of Neurocognitive Outcome in Two Standard Regimen for Treatment of Low-risk Medulloblastoma
NCT01212484	PHASE3	COMPLETED	Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia
NCT01987219	PHASE3	COMPLETED	The Effects Of Bronchodilator Therapy On Respiratory And Autonomic Function In Patients With Familial Dysautonomia
NCT00031590	PHASE2	TERMINATED	Low-Dose Radiation and Combination Chemotherapy Following Surgery in Children With Newly Diagnosed Medulloblastoma
NCT00180791	PHASE2	UNKNOWN	High Risk Primitive Neuroectodermal (PNET) Brain Tumors in Childhood
NCT00180947	PHASE2	UNKNOWN	Study of Vinorelbine and Cyclofosfamide Among Patients With Refractory Tumours or in Relapse
NCT00404495	PHASE2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.
NCT00407433	PHASE2	COMPLETED	Clinical Studies of Gemcitabine-Oxaliplatin
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00601003	PHASE2	COMPLETED	Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01217437	PHASE2	COMPLETED	Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors
NCT01326104	PHASE2	COMPLETED	Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01542736	PHASE2	COMPLETED	Concurrent Carboplatin and Reduced Dose Craniospinal Radiation for Medulloblastoma and Primitive Neuroectodermal Tumor (PNET)
NCT01708174	PHASE2	COMPLETED	A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
NCT01857453	PHASE2	UNKNOWN	Interest of a Dose Decrease for Radiotherapy Associated With Chemotherapy for Treatment of Standard Risk Adult Medulloblastomas
NCT01878617	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
NCT02017964	PHASE2	COMPLETED	Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed, Non-metastatic Desmoplastic Medulloblastoma
NCT02441062	PHASE2	COMPLETED	Impact of Ga-68 DOTATOC PET-CT Imaging in Management of Neuroendocrine Tumors
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02681705	PHASE2	UNKNOWN	Radiation Therapy and Combination Chemotherapy for Medulloblastoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT02724579	PHASE2	ACTIVE_NOT_RECRUITING	Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma
NCT03013387	PHASE2	WITHDRAWN	Dosimetry Guided PRRT With 90Y-DOTATOC
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03257631	PHASE2	COMPLETED	A Study of Pomalidomide Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors