ELP2

protein-coding

elongator acetyltransferase complex subunit 2, the group of WD repeat domain containing|Elongator acetyltransferase complex

Gene summary

The protein encoded by this gene is a core subunit of the elongator complex, a histone acetyltransferase complex that associates with RNA polymerase II. In addition to histone acetylation, the encoded protein effects transcriptional elongation and may help remodel chromatin. [provided by RefSeq, May 2016]

Previous symbols:

STATIP1

MANE transcript

NM_018255.4

Inheritance

ClinVar variants

P:24U:163B:42

Top phenotype

Intellectual developmental disorder, autosomal recessive 58

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr18:36,129,444-36,180,557

External References & Databases

Ensembl (ENSG00000134759)

Transcript & Mutation Effects

hg38 • Region Span ~51.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 58STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014996

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorder with motor featuresDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100516

Submitter: ClinGen

*ELP2* was first reported in relation to autosomal recessive complex neurodevelopmental disorder with motor features in 2011 (Najmabadi et al., PMID: 21937992). Affected individuals demonstrate a range of phenotypic severity included but not limited to intellectual disability, developmental delay, and autism spectrum disorder, as well as motor features including spastic diplegia, choreoathetosis, and ataxia. Eight variants (missense, nonsense, frameshift, and splice site) that have been reported in 7 probands within 6 publications (PMIDs: 25847581, 28726809, 33393008, 33510603, 34653680, 33976153) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function (PMID:33976153). This gene-disease relationship is also supported by *in vitro* functional assays for commonly reported missense variants as well as two mouse models (PMID: 33976153). Affinity, enzymatic activity, and *in vitro* analyses of purified human and murine *ELP2* proteins show that commonly identified single amino acid substitutions impair the activity and function of the *ELP2* complex in tRNA modification during translation. Two mouse models, a homozygous p.His206Arg and compound heterozygous p.His206Arg/p.Arg462Gln, modified using CRISPR-Cas9 editing exhibited physical manifestations of developmental delay and severe motor defects including stereotypic behavior in the form of repetitive self grooming and abnormal hind-limb clasping, features commonly identified in ID/ASD mouse models. Neuroimaging of the homozygous p.His206Arg mice revealed loss of axonal tract integrity among major cortical white matter in the brain (PMID:33976153). Lastly, morphologic abnormalities were identified in the cortical neurons of the mutant mice and impairment of neurogenesis was seen by analysis of the brain tissue at the peak of neurogenesis (PMID:33976153). In summary, there is definitive evidence supporting the relationship between *ELP2* and autosomal recessive complex neurodevelopmental disorder with motor features. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability/Autism GCEP on the meeting date June 23, 2025 (SOP Version 10).

intellectual developmental disorder, autosomal recessive 58MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014996

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 58STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014996

Submitter: G2P

intellectual developmental disorder, autosomal recessive 58STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014996

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 58AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21937992; 25847581

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ELP2 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 129

not providedTotal: 79

Intellectual developmental disorder, autosomal recessive 58Total: 34

ELP2-related disorderTotal: 20

not specifiedTotal: 12

Profound intellectual disabilityTotal: 5

Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndromeTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018255.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	23 clinvar	2 clinvar	29
missense	2 clinvar	4 clinvar	148 clinvar	15 clinvar	2 clinvar	171
nonsense	2 clinvar	7 clinvar	3 clinvar			12
start loss						0
frameshift	1 clinvar	8 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	5	19	163	38	4	229

Highest pathogenic variant AF is 0.00006567656

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 164 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018255.4	RefSeq	NP_060725.1	22	MANE Select
ENST00000358232.11	Ensembl	ENSP00000350967.6	22	MANE Select
NM_001242875.3	RefSeq	NP_001229804.1	23	Standard
NM_001242876.3	RefSeq	NP_001229805.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Chromatin modifying enzymes
HATs acetylate histones
Chromatin organization

Biological Process

tRNA wobble uridine modification
regulation of transcription by RNA polymerase II
transcription elongation from RNA polymerase II promoter
regulation of JAK-STAT cascade

Molecular Function

RNA polymerase II complex binding
protein kinase binding

Cellular Component

cytoplasm
cytosol
transcription elongation factor complex
Elongator holoenzyme complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000442325
Coding exons: 23
Length: 48503
Individuals with no LoFs: 125624
Homozygous LoFs: 0
Heterozygous LoFs: 124
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.575	419	453	0.924	0.0000219	5824
Missense (PolyPhen)		102	132.13	0.77194		1709
Synonymous	0.0151	162	162	0.998	0.00000839	1668
Loss of Function	2.30	40	59.1	0.677	0.00000308	642

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00073	0.00072	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00017	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.00052	0.00052	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates the ligand-dependent activation of STAT3. {ECO:0000250}.;
Disease: DISEASE: Mental retardation, autosomal recessive 58 (MRT58) [MIM:617270]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT58 transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:25847581}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.867
RVIS EVS: 1.21
RVIS percentile EVS: 93.02

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.778

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High