Intellectual developmental disorder, autosomal recessive 74

Summary

Intellectual developmental disorder, autosomal recessive 74 (MONDO:0014951) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, autosomal recessive 74
Mondo ID	MONDO:0014951
OMIM	617169
DOID	DOID:0081218, DOID:0112104
UMLS	C4310684
MedGen	934651
GARD	0016208
Is cancer (heuristic)	no

Also known as: APC2 Sotos syndrome · intellectual developmental disorder, autosomal recessive 74 · Sotos syndrome caused by mutation in APC2 · Sotos syndrome type 3

Data availability: 34 ClinVar variants · 1 GenCC gene-disease record.

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 developmental disorder, autosomal recessive 74

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 disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, 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

34 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 4 likely pathogenic, 2 benign, 2 pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1339351	NM_005883.3(APC2):c.6620C>T (p.Pro2207Leu)	APC2	Pathogenic	no assertion criteria provided
267259	NM_005883.3(APC2):c.5199dup (p.Lys1734fs)	APC2	Pathogenic	no assertion criteria provided
3255193	NM_005883.3(APC2):c.409del (p.Glu137fs)	APC2	Likely pathogenic	criteria provided, single submitter
3377277	NM_005883.3(APC2):c.6184_6193del (p.Pro2062fs)	APC2	Likely pathogenic	criteria provided, single submitter
3393101	NM_005883.3(APC2):c.797dup (p.Gln267fs)	APC2	Likely pathogenic	criteria provided, single submitter
4796569	NM_005883.3(APC2):c.935dup (p.Cys313fs)	APC2	Likely pathogenic	criteria provided, single submitter
2191297	NM_005883.3(APC2):c.1628G>A (p.Arg543Gln)	APC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
741140	NM_005883.3(APC2):c.3656C>T (p.Ala1219Val)	APC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028956	NM_005883.3(APC2):c.4616G>C (p.Arg1539Pro)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1028957	NM_005883.3(APC2):c.583C>T (p.Arg195Cys)	APC2	Uncertain significance	criteria provided, single submitter
1033035	NM_005883.3(APC2):c.5772G>C (p.Gln1924His)	APC2	Uncertain significance	criteria provided, single submitter
1033036	NM_005883.3(APC2):c.6111C>T (p.Phe2037=)	APC2	Uncertain significance	criteria provided, single submitter
1033037	NM_005883.3(APC2):c.757C>T (p.Pro253Ser)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033038	NM_005883.3(APC2):c.796C>A (p.Pro266Thr)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1339352	NM_005883.3(APC2):c.1063G>A (p.Val355Ile)	APC2	Uncertain significance	criteria provided, single submitter
1683633	NM_005883.3(APC2):c.2595C>A (p.His865Gln)	APC2	Uncertain significance	criteria provided, single submitter
1690984	NM_005883.3(APC2):c.1778C>T (p.Ser593Leu)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2039016	NM_005883.3(APC2):c.3019G>A (p.Gly1007Ser)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2052144	NM_005883.3(APC2):c.5591C>T (p.Pro1864Leu)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2524043	NM_005883.3(APC2):c.278C>T (p.Pro93Leu)	APC2	Uncertain significance	criteria provided, single submitter
3068058	NM_005883.3(APC2):c.4603C>T (p.Arg1535Cys)	APC2	Uncertain significance	criteria provided, single submitter
3377273	NM_005883.3(APC2):c.2686C>G (p.Arg896Gly)	APC2	Uncertain significance	criteria provided, single submitter
3377274	NM_005883.3(APC2):c.2651C>A (p.Pro884Gln)	APC2	Uncertain significance	criteria provided, single submitter
3412885	NM_005883.3(APC2):c.5872G>C (p.Gly1958Arg)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583510	NM_005883.3(APC2):c.2372C>T (p.Ala791Val)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3583511	NM_005883.3(APC2):c.2518_2523dup (p.Ala841_Lys842insAlaAla)	APC2	Uncertain significance	criteria provided, single submitter
3583512	NM_005883.3(APC2):c.5123G>T (p.Arg1708Leu)	APC2	Uncertain significance	criteria provided, multiple submitters, no conflicts
4277715	NM_005883.3(APC2):c.445G>C (p.Glu149Gln)	APC2	Uncertain significance	criteria provided, single submitter
4277717	NM_005883.3(APC2):c.2695G>C (p.Glu899Gln)	APC2	Uncertain significance	criteria provided, single submitter
4531708	NM_005883.3(APC2):c.5944G>C (p.Gly1982Arg)	APC2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 1 · 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
APC2	Limited	Unknown	intellectual developmental disorder, autosomal recessive 74	6
SLC25A23	Limited	Unknown	intellectual developmental disorder, autosomal recessive 74	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APC2	Orphanet:821	Sotos syndrome

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
SLC25A23	HGNC:19375	ENSG00000125648	Q9BV35	Mitochondrial adenyl nucleotide antiporter SLC25A23	gencc,clinvar
APC2	HGNC:24036	ENSG00000115266	O95996	Adenomatous polyposis coli protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A23	Mitochondrial adenyl nucleotide antiporter SLC25A23	Electroneutral antiporter that mediates the transport of adenine nucleotides through the inner mitochondrial membrane.
APC2	Adenomatous polyposis coli protein 2	Stabilizes microtubules and may regulate actin fiber dynamics through the activation of Rho family GTPases.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A23	Other/Unknown	no		EF_hand_dom, MCP, EF-hand-dom_pair
APC2	Other/Unknown	no		Armadillo, APC_rpt, SAMP

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
buccal mucosa cell	1
caudate nucleus	1
nucleus accumbens	1
cerebellar vermis	1
cortical plate	1
paraflocculus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A23	271	ubiquitous	marker	nucleus accumbens, caudate nucleus, buccal mucosa cell
APC2	199	broad	yes	paraflocculus, cortical plate, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A23	1,383
APC2	963

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A23	Q9BV35	78.93
APC2	O95996	48.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
obsolete regulation of sequestering of calcium ion	1	4213.0×	0.004	SLC25A23
adenine nucleotide transport	1	2106.5×	0.004	SLC25A23
regulation of cellular hyperosmotic salinity response	1	1685.2×	0.004	SLC25A23
ADP transport	1	1053.2×	0.004	SLC25A23
mitochondrial ATP transmembrane transport	1	936.2×	0.004	SLC25A23
positive regulation of mitochondrial calcium ion concentration	1	842.6×	0.004	SLC25A23
ATP transport	1	702.2×	0.004	SLC25A23
regulation of oxidative phosphorylation	1	601.9×	0.004	SLC25A23
calcium import into the mitochondrion	1	601.9×	0.004	SLC25A23
renal system process	1	561.7×	0.004	SLC25A23
mitochondrial calcium ion transmembrane transport	1	495.6×	0.004	SLC25A23
activation of GTPase activity	1	366.4×	0.005	APC2
cell fate specification	1	263.3×	0.006	APC2
negative regulation of microtubule depolymerization	1	247.8×	0.006	APC2
pattern specification process	1	234.1×	0.006	APC2
cellular response to calcium ion	1	100.3×	0.014	SLC25A23
microtubule cytoskeleton organization	1	60.6×	0.021	APC2
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.021	APC2
Wnt signaling pathway	1	49.9×	0.023	APC2
cell migration	1	30.8×	0.035	APC2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.040	APC2
nervous system development	1	23.0×	0.043	APC2

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
SLC25A23	0	0
APC2	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	SLC25A23, APC2

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)
SLC25A23	0	—
APC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.