Intellectual disability, autosomal dominant 5

Summary

Intellectual disability, autosomal dominant 5 (MONDO:0012960) is a disease caused by SYNGAP1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SYNGAP1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,493
• Phenotypes (HPO): 41

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		57	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0002197	Generalized-onset seizure	Very frequent (80-99%)
HP:0010832	Abnormality of pain sensation	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002370	Poor coordination	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0020208	Eating-induced seizure	Frequent (30-79%)
HP:0100738	Abnormal eating behavior	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000233	Thin vermilion border	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000325	Triangular face	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000490	Deeply set eye	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001344	Absent speech	Occasional (5-29%)
HP:0008770	Obsessive-compulsive trait	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0011150	Myoclonic absence	Occasional (5-29%)
HP:0012703	Abnormal subarachnoid space morphology	Occasional (5-29%)
HP:0012760	Reduced social responsiveness	Occasional (5-29%)
HP:0030810	Abnormal tongue physiology	Occasional (5-29%)
HP:0040080	Anteverted ears	Occasional (5-29%)
HP:0100023	Recurrent hand flapping	Occasional (5-29%)
HP:0100259	Postaxial polydactyly	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 5
Mondo ID	MONDO:0012960
MeSH	C567234
OMIM	612621
Orphanet	544254
DOID	DOID:0070035
UMLS	C2675473
MedGen	382611
GARD	0012558
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 5 · autosomal dominant non-syndromic intellectual disability caused by mutation in SYNGAP1 · epilepsy due to SYNGAP mutations · intellectual disability, autosomal dominant 5 · intellectual disability, autosomal dominant type 5 · mental retardation, autosomal dominant 5 · mental retardation, autosomal dominant type 5 · MRD5 · SYNGAP1 autosomal dominant non-syndromic intellectual disability · SYNGAP1 gene mutation linked to intellectual disability, schizophrenia and autism · SYNGAP1 syndrome · SYNGAP1-related developmental and epileptic encephalopathy · SYNGAP1-related non-syndromic intellectual disability · SYNGAP1-related NSID

Data availability: 1,493 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome › infantile epilepsy syndrome › intellectual disability, autosomal dominant 5

Related subtypes (8): benign partial infantile seizures, infant epilepsy with migrant focal crisis, infantile spasms-broad thumbs syndrome, progressive myoclonic epilepsy with dystonia, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, undetermined early-onset epileptic encephalopathy, idiopathic hemiconvulsion-hemiplegia syndrome, myoclonic epilepsy in infancy

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

600 retrieved; paginated sample, class counts are floors:

237 likely benign, 157 uncertain significance, 72 pathogenic, 52 conflicting classifications of pathogenicity, 44 benign, 25 likely pathogenic, 8 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030154	NM_006772.3(SYNGAP1):c.654_655del (p.Phe218fs)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070521	NM_006772.3(SYNGAP1):c.91C>T (p.Arg31Ter)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071251	NM_006772.3(SYNGAP1):c.2234del (p.Pro745fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1071936	NM_006772.3(SYNGAP1):c.2387dup (p.Pro797fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1072360	NM_006772.3(SYNGAP1):c.1534G>T (p.Glu512Ter)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1073426	NM_006772.3(SYNGAP1):c.2717del (p.Leu906fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1075175	NM_006772.3(SYNGAP1):c.190-2A>C	SYNGAP1	Pathogenic	criteria provided, single submitter
1075709	NM_006772.3(SYNGAP1):c.1022_1023del (p.Gly341fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1076713	NM_006772.3(SYNGAP1):c.1136C>A (p.Ser379Ter)	SYNGAP1	Pathogenic	criteria provided, single submitter
1172661	NM_006772.3(SYNGAP1):c.2782C>T (p.Gln928Ter)	SYNGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1176818	NM_006772.3(SYNGAP1):c.1641_1642del (p.Cys547_Glu548delinsTer)	SYNGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184918	NM_006772.3(SYNGAP1):c.3138del (p.Ser1047fs)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1216291	NM_006772.3(SYNGAP1):c.2197C>T (p.Gln733Ter)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1285474	NM_006772.3(SYNGAP1):c.3269dup (p.Asn1090fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
130525	NM_006772.3(SYNGAP1):c.1783del (p.Leu595fs)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
130528	NM_006772.3(SYNGAP1):c.2602del (p.Asp868fs)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1338772	NM_006772.3(SYNGAP1):c.1676+1G>A	SYNGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386516	NM_006772.3(SYNGAP1):c.3369_3380del (p.Gly1125_Gly1128del)	SYNGAP1	Pathogenic	criteria provided, single submitter
1393302	NM_006772.3(SYNGAP1):c.3516dup (p.Ile1173fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1401359	NM_006772.3(SYNGAP1):c.3685C>T (p.Gln1229Ter)	SYNGAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1401645	NM_006772.3(SYNGAP1):c.3303del (p.Ala1102fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1404191	NM_006772.3(SYNGAP1):c.1640G>A (p.Cys547Tyr)	SYNGAP1	Pathogenic	criteria provided, single submitter
1425584	NM_006772.3(SYNGAP1):c.2516dup (p.Ser840fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1432487	NM_006772.3(SYNGAP1):c.1712C>A (p.Ser571Ter)	SYNGAP1	Pathogenic	criteria provided, single submitter
1433397	NM_006772.3(SYNGAP1):c.3452_3453del (p.Ala1150_Ser1151insTer)	SYNGAP1	Pathogenic	criteria provided, single submitter
1441002	NM_006772.3(SYNGAP1):c.1564del (p.Glu522fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1444585	NM_006772.3(SYNGAP1):c.1902del (p.Asn635fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1451486	NM_006772.3(SYNGAP1):c.3133del (p.Ala1045fs)	SYNGAP1	Pathogenic	criteria provided, single submitter
1453923	NM_006772.3(SYNGAP1):c.2450C>G (p.Ser817Ter)	SYNGAP1	Pathogenic	criteria provided, single submitter
1455263	NM_006772.3(SYNGAP1):c.883_884del (p.Thr295fs)	SYNGAP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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
SYNGAP1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 5	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYNGAP1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SYNGAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SYNGAP1	Orphanet:544254	SYNGAP1-related developmental and epileptic encephalopathy

Cohort genes → proteins

5 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	gencc,clinvar
MIR5004	HGNC:43532	ENSG00000284256		microRNA 5004	clinvar
SYNGAP1-AS1	HGNC:53831	ENSG00000274259		SYNGAP1 antisense RNA 1	clinvar
B3GALT4	HGNC:919	ENSG00000235863	O96024	Beta-1,3-galactosyltransferase 4	clinvar
BAK1	HGNC:949	ENSG00000030110	Q16611	Bcl-2 homologous antagonist/killer	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.
B3GALT4	Beta-1,3-galactosyltransferase 4	Involved in GM1/GD1B/GA1 ganglioside biosynthesis.
BAK1	Bcl-2 homologous antagonist/killer	Plays a role in the mitochondrial apoptotic process.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	3.5×	0.530
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
MIR5004	Other/Unknown	no
SYNGAP1-AS1	Other/Unknown	no
B3GALT4	Enzyme (other)	yes	2.4.1.62	Glyco_trans_31
BAK1	Other/Unknown	no		Bcl2-like, Bcl2_BH1_motif_CS, Bcl2_BH2_motif_CS

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
lower esophagus mucosa	2
mucosa of transverse colon	2
adenohypophysis	1
pituitary gland	1
right uterine tube	1
adrenal tissue	1
blood	1
olfactory segment of nasal mucosa	1
primordial germ cell in gonad	1
sural nerve	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYNGAP1	137	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis
MIR5004	87		yes	olfactory segment of nasal mucosa, adrenal tissue, blood
SYNGAP1-AS1	133	broad	yes	thymus, sural nerve, primordial germ cell in gonad
B3GALT4	170	ubiquitous	yes	lower esophagus mucosa, mucosa of transverse colon, granulocyte
BAK1	193	ubiquitous	marker	mucosa of transverse colon, granulocyte, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BAK1	2,273
SYNGAP1	2,175
B3GALT4	831
MIR5004	0
SYNGAP1-AS1	0

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BAK1	Q16611	55

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GALT4	O96024	84.89
SYNGAP1	Q96PV0	60.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation and oligomerization of BAK protein	1	1903.3×	0.011	BAK1
Release of apoptotic factors from the mitochondria	1	543.8×	0.015	BAK1
Blood group systems biosynthesis	1	380.7×	0.015	B3GALT4
Apoptotic factor-mediated response	1	292.8×	0.015	BAK1
Regulated Necrosis	1	237.9×	0.015	BAK1
Lewis blood group biosynthesis	1	223.9×	0.015	B3GALT4
Glycosphingolipid biosynthesis	1	200.3×	0.015	B3GALT4
Pyroptosis	1	141.0×	0.019	BAK1
Glycosphingolipid metabolism	1	100.2×	0.021	B3GALT4
Intrinsic Pathway for Apoptosis	1	97.6×	0.021	BAK1
Regulation of RAS by GAPs	1	64.5×	0.029	SYNGAP1
Apoptosis	1	56.0×	0.029	BAK1
Sphingolipid metabolism	1	56.0×	0.029	B3GALT4
Programmed Cell Death	1	48.8×	0.031	BAK1
MAPK1/MAPK3 signaling	1	43.8×	0.032	SYNGAP1
Metabolism of carbohydrates and carbohydrate derivatives	1	40.1×	0.032	B3GALT4
MAPK family signaling cascades	1	34.3×	0.036	SYNGAP1
RAF/MAP kinase cascade	1	20.4×	0.056	SYNGAP1
Metabolism of lipids	1	10.5×	0.102	B3GALT4
Metabolism	1	3.9×	0.248	B3GALT4
Signal Transduction	1	3.4×	0.267	SYNGAP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
B cell negative selection	1	2808.7×	0.008	BAK1
response to mycotoxin	1	1872.4×	0.008	BAK1
maintenance of postsynaptic specialization structure	1	1872.4×	0.008	SYNGAP1
response to fungus	1	1404.3×	0.008	BAK1
post-embryonic camera-type eye morphogenesis	1	1404.3×	0.008	BAK1
establishment or maintenance of transmembrane electrochemical gradient	1	936.2×	0.008	BAK1
negative regulation of endoplasmic reticulum calcium ion concentration	1	936.2×	0.008	BAK1
regulation of synapse structure or activity	1	936.2×	0.008	SYNGAP1
apoptotic process involved in blood vessel morphogenesis	1	936.2×	0.008	BAK1
myeloid cell homeostasis	1	702.2×	0.008	BAK1
positive regulation of IRE1-mediated unfolded protein response	1	702.2×	0.008	BAK1
positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	624.1×	0.008	BAK1
response to UV-C	1	561.7×	0.008	BAK1
fibroblast apoptotic process	1	510.7×	0.008	BAK1
vagina development	1	510.7×	0.008	BAK1
B cell apoptotic process	1	468.1×	0.008	BAK1
regulation of mitochondrial membrane permeability	1	468.1×	0.008	BAK1
thymocyte apoptotic process	1	468.1×	0.008	BAK1
negative regulation of axonogenesis	1	432.1×	0.008	SYNGAP1
positive regulation of calcium ion transport into cytosol	1	401.2×	0.008	BAK1
calcium ion transport into cytosol	1	401.2×	0.008	BAK1
ganglioside biosynthetic process	1	374.5×	0.008	B3GALT4
limb morphogenesis	1	351.1×	0.008	BAK1
negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway	1	351.1×	0.008	BAK1
cellular response to unfolded protein	1	330.4×	0.008	BAK1
regulation of long-term neuronal synaptic plasticity	1	330.4×	0.008	SYNGAP1
endocrine pancreas development	1	312.1×	0.008	BAK1
regulation of intracellular signal transduction	1	295.6×	0.008	SYNGAP1
mitochondrial fusion	1	280.9×	0.008	BAK1
endoplasmic reticulum calcium ion homeostasis	1	280.9×	0.008	BAK1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BAK1	1	1
SYNGAP1	0	0
MIR5004	0	0
SYNGAP1-AS1	0	0
B3GALT4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ABT 737	1	BAK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BAK1	28	Binding:27, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALT4	2.4.1.62	ganglioside galactosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
ABT 737	1	BAK1

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	1	BAK1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	B3GALT4
E	Difficult family or no structure, no drug	3	SYNGAP1, MIR5004, SYNGAP1-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYNGAP1	0	—
MIR5004	0	—
SYNGAP1-AS1	0	—
B3GALT4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.