Intellectual disability, autosomal recessive 58

Summary

Intellectual disability, autosomal recessive 58 (MONDO:0014996) is a disease caused by ELP2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ELP2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 58
Mondo ID	MONDO:0014996
OMIM	617270
DOID	DOID:0081220
UMLS	C4310641
MedGen	934608
GARD	0013361
Is cancer (heuristic)	no

Also known as: autosomal recessive intellectual disability 58 · autosomal recessive non-syndromic intellectual disability caused by mutation in ELP2 · ELP2 autosomal recessive non-syndromic intellectual disability · ELP2-related disorder · intellectual developmental disorder, autosomal recessive 58 · intellectual disability, autosomal recessive 58 · intellectual disability, autosomal recessive type 58 · mental retardation, autosomal recessive 58 · mental retardation, autosomal recessive type 58 · MRT58

Data availability: 31 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 58

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

31 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 5 likely pathogenic, 5 pathogenic, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
225008	NM_018255.4(ELP2):c.617A>G (p.His206Arg)	ELP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3336513	NM_018255.4(ELP2):c.418C>T (p.Arg140Ter)	ELP2	Pathogenic	criteria provided, single submitter
3339533	NM_018255.4(ELP2):c.907C>T (p.Gln303Ter)	ELP2	Pathogenic	criteria provided, single submitter
374911	NM_018255.4(ELP2):c.1663A>C (p.Thr555Pro)	ELP2	Pathogenic	no assertion criteria provided
374912	NM_018255.4(ELP2):c.1385G>T (p.Arg462Leu)	ELP2	Pathogenic	no assertion criteria provided
870396	NM_018255.4(ELP2):c.1385G>A (p.Arg462Gln)	ELP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870397	NM_018255.4(ELP2):c.1657C>T (p.Gln553Ter)	ELP2	Pathogenic	criteria provided, single submitter
1992333	NM_018255.4(ELP2):c.2084_2087del (p.Val695fs)	ELP2	Likely pathogenic	criteria provided, single submitter
2573075	NM_018255.4(ELP2):c.2237del (p.Cys746fs)	ELP2	Likely pathogenic	criteria provided, single submitter
3067957	NM_018255.4(ELP2):c.1443_1458dup (p.Cys487fs)	ELP2	Likely pathogenic	criteria provided, single submitter
4292434	NM_018255.4(ELP2):c.2065C>T (p.Arg689Ter)	ELP2	Likely pathogenic	criteria provided, single submitter
4845862	NM_018255.4(ELP2):c.2209C>T (p.Arg737Ter)	ELP2	Likely pathogenic	criteria provided, single submitter
1012186	NM_018255.4(ELP2):c.293dup (p.Leu98fs)	ELP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033375	NM_018255.4(ELP2):c.178C>T (p.Arg60Ter)	ELP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225038	NM_018255.4(ELP2):c.1384C>T (p.Arg462Trp)	ELP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
788374	NM_018255.4(ELP2):c.2396C>T (p.Ala799Val)	ELP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1012183	NM_018255.4(ELP2):c.1331T>C (p.Leu444Ser)	ELP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1030307	NM_018255.4(ELP2):c.1239A>C (p.Arg413Ser)	ELP2	Uncertain significance	criteria provided, single submitter
1030308	NM_018255.4(ELP2):c.1381C>A (p.Leu461Ile)	ELP2	Uncertain significance	criteria provided, single submitter
1031244	NM_018255.4(ELP2):c.2236T>C (p.Cys746Arg)	ELP2	Uncertain significance	criteria provided, single submitter
1033373	NM_018255.4(ELP2):c.918A>T (p.Arg306Ser)	ELP2	Uncertain significance	criteria provided, single submitter
1033377	NM_018255.4(ELP2):c.2045A>T (p.Lys682Met)	ELP2	Uncertain significance	criteria provided, single submitter
1339828	NM_018255.4(ELP2):c.454C>A (p.Leu152Ile)	ELP2	Uncertain significance	criteria provided, single submitter
2505101	NM_018255.4(ELP2):c.1544C>T (p.Ala515Val)	ELP2	Uncertain significance	criteria provided, single submitter
3065744	NM_018255.4(ELP2):c.2438A>T (p.Asp813Val)	ELP2	Uncertain significance	criteria provided, single submitter
3376495	NM_018255.4(ELP2):c.1847C>T (p.Thr616Ile)	ELP2	Uncertain significance	criteria provided, single submitter
3892141	NM_018255.4(ELP2):c.128A>C (p.Tyr43Ser)	ELP2	Uncertain significance	criteria provided, single submitter
3892149	NM_018255.4(ELP2):c.553T>G (p.Cys185Gly)	ELP2	Uncertain significance	criteria provided, single submitter
4292017	NM_018255.4(ELP2):c.1220G>A (p.Gly407Asp)	ELP2	Uncertain significance	criteria provided, single submitter
4292653	NM_018255.4(ELP2):c.1125+3A>C	ELP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ELP2	Strong	Autosomal recessive	intellectual disability, autosomal recessive 58	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PGAP1	Orphanet:401820	Autosomal recessive spastic paraplegia type 67
PGAP1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ELP2	HGNC:18248	ENSG00000134759	Q6IA86	Elongator complex protein 2	gencc,clinvar
PGAP1	HGNC:25712	ENSG00000197121	Q75T13	GPI inositol-deacylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ELP2	Elongator complex protein 2	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).
PGAP1	GPI inositol-deacylase	GPI inositol-deacylase that catalyzes the remove of the acyl chain linked to the 2-OH position of inositol ring from the GPI-anchored protein (GPI-AP) in the endoplasmic reticulum.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ELP2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
PGAP1	Other/Unknown	no		PGAP1-ab_dom-like, AB_hydrolase_fold, PGAP1/BST1

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
left ovary	1
right ovary	1
endothelial cell	1
ganglionic eminence	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ELP2	253	ubiquitous	marker	left ovary, calcaneal tendon, right ovary
PGAP1	271	ubiquitous	marker	endothelial cell, ganglionic eminence, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ELP2	2,023
PGAP1	882

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ELP2	Q6IA86	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP1	Q75T13	89.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Attachment of GPI anchor to uPAR	1	634.4×	0.003	PGAP1
HATs acetylate histones	1	39.6×	0.025	ELP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
forebrain regionalization	1	1685.2×	0.004	PGAP1
positive regulation of ER to Golgi vesicle-mediated transport	1	1685.2×	0.004	PGAP1
attachment of GPI anchor to protein	1	1053.2×	0.004	PGAP1
regulation of receptor signaling pathway via JAK-STAT	1	702.2×	0.004	ELP2
tRNA wobble uridine modification	1	601.9×	0.004	ELP2
anterior/posterior axis specification	1	366.4×	0.006	PGAP1
embryonic pattern specification	1	271.8×	0.007	PGAP1
GPI anchor biosynthetic process	1	247.8×	0.007	PGAP1
transcription elongation by RNA polymerase II	1	221.7×	0.007	ELP2
regulation of translation	1	109.4×	0.012	ELP2
sensory perception of sound	1	50.5×	0.023	PGAP1
protein transport	1	21.9×	0.049	PGAP1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ELP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ELP2	0	0
PGAP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ELP2, PGAP1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ELP2	0	—
PGAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.