Intellectual disability, autosomal dominant 9

Summary

Intellectual disability, autosomal dominant 9 (MONDO:0013656) is a disease caused by KIF1A (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KIF1A (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 2,746

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		45	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 9
Mondo ID	MONDO:0013656
OMIM	614255
Orphanet	662367
DOID	DOID:0070039
NCIT	C133742
UMLS	C5393830
MedGen	1714250
GARD	0016459
Is cancer (heuristic)	no

Also known as: autosomal dominant non-syndromic intellectual disability caused by mutation in KIF1A · intellectual disability, autosomal dominant 9 · intellectual disability, autosomal dominant type 9 · KIF1A autosomal dominant non-syndromic intellectual disability · mental retardation, autosomal dominant 9 · mental retardation, autosomal dominant type 9 · MRD9 · NESCAV syndrome

Data availability: 2,746 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › intellectual disability, autosomal dominant › intellectual disability, autosomal dominant 9

Related subtypes (28): intellectual disability, autosomal dominant 1, intellectual disability, autosomal dominant 3, intellectual disability, autosomal dominant 4, intellectual disability, autosomal dominant 5, intellectual disability, autosomal dominant 6, intellectual disability, autosomal dominant 2, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, intellectual disability, autosomal dominant 10, intellectual disability, autosomal dominant 11, intellectual disability, autosomal dominant 24, intellectual disability, autosomal dominant 38, intellectual disability, autosomal dominant 39, intellectual disability, autosomal dominant 40, intellectual disability, autosomal dominant 42, autosomal dominant non-syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 65, intellectual developmental disorder, autosomal dominant 69, intellectual developmental disorder, autosomal dominant 66, intellectual developmental disorder, autosomal dominant 64, intellectual developmental disorder, autosomal dominant 67, intellectual developmental disorder, autosomal dominant 68, autosomal dominant syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 70, intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, intellectual developmental disorder, autosomal dominant 72, intellectual developmental disorder, autosomal dominant 74, intellectual developmental disorder, autosomal dominant 75, intellectual developmental disorder, autosomal dominant 76

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:

242 likely benign, 237 uncertain significance, 68 conflicting classifications of pathogenicity, 19 benign, 16 pathogenic, 12 likely pathogenic, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1411455	NC_000002.11:g.(?238233417)(242801596_?)del	ATG4B	Pathogenic	criteria provided, single submitter
1004912	NM_001244008.2(KIF1A):c.934A>C (p.Thr312Pro)	KIF1A	Pathogenic	criteria provided, single submitter
1058331	NM_001244008.2(KIF1A):c.467A>T (p.Asp156Val)	KIF1A	Pathogenic	criteria provided, single submitter
1076894	NC_000002.11:g.(?_241656771)_241759735del	KIF1A	Pathogenic	criteria provided, single submitter
1320162	NM_001244008.2(KIF1A):c.3073del (p.Glu1025fs)	KIF1A	Pathogenic	criteria provided, single submitter
1349128	NM_001244008.2(KIF1A):c.173C>G (p.Ser58Trp)	KIF1A	Pathogenic	criteria provided, single submitter
1395436	NM_001244008.2(KIF1A):c.785_798+1del	KIF1A	Pathogenic	criteria provided, single submitter
1413300	NM_001244008.2(KIF1A):c.361C>T (p.Gln121Ter)	KIF1A	Pathogenic	criteria provided, single submitter
1439490	NM_001244008.2(KIF1A):c.4529del (p.Pro1510fs)	KIF1A	Pathogenic	criteria provided, single submitter
1451452	NM_001244008.2(KIF1A):c.2389G>T (p.Glu797Ter)	KIF1A	Pathogenic	criteria provided, single submitter
1451736	NM_001244008.2(KIF1A):c.864+1del	KIF1A	Pathogenic	criteria provided, single submitter
1452132	NM_001244008.2(KIF1A):c.1031C>T (p.Thr344Met)	KIF1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1454352	NM_001244008.2(KIF1A):c.919C>T (p.Arg307Ter)	KIF1A	Pathogenic	criteria provided, single submitter
1456633	NM_001244008.2(KIF1A):c.2270_2271del (p.Gln757fs)	KIF1A	Pathogenic	criteria provided, single submitter
1459290	NM_001244008.2(KIF1A):c.4624del (p.Leu1542fs)	KIF1A	Pathogenic	criteria provided, single submitter
1460332	NC_000002.11:g.(?241676460)(241686758_?)del	KIF1A	Pathogenic	criteria provided, single submitter
1001813	NM_001244008.2(KIF1A):c.32G>T (p.Arg11Leu)	KIF1A	Likely pathogenic	criteria provided, single submitter
1023002	NM_001244008.2(KIF1A):c.748G>T (p.Ala250Ser)	KIF1A	Likely pathogenic	criteria provided, single submitter
1032200	NM_001244008.2(KIF1A):c.839A>G (p.Lys280Arg)	KIF1A	Likely pathogenic	criteria provided, single submitter
1320263	NM_001244008.2(KIF1A):c.812T>G (p.Ile271Ser)	KIF1A	Likely pathogenic	criteria provided, single submitter
1467822	NM_001244008.2(KIF1A):c.1037+1G>C	KIF1A	Likely pathogenic	criteria provided, single submitter
1472010	NM_001244008.2(KIF1A):c.958+1G>C	KIF1A	Likely pathogenic	criteria provided, single submitter
1477424	NM_001244008.2(KIF1A):c.760C>G (p.Arg254Gly)	KIF1A	Likely pathogenic	criteria provided, single submitter
1486265	NM_001244008.2(KIF1A):c.759G>C (p.Glu253Asp)	KIF1A	Likely pathogenic	criteria provided, single submitter
1505292	NM_001244008.2(KIF1A):c.79A>T (p.Ile27Phe)	KIF1A	Likely pathogenic	criteria provided, single submitter
1507070	NM_001244008.2(KIF1A):c.773C>A (p.Thr258Lys)	KIF1A	Likely pathogenic	criteria provided, single submitter
1513283	NM_001244008.2(KIF1A):c.3374+2T>G	KIF1A	Likely pathogenic	criteria provided, single submitter
1524644	NM_001244008.2(KIF1A):c.1578-2A>G	KIF1A	Likely pathogenic	criteria provided, single submitter
1003221	NM_001244008.2(KIF1A):c.4391G>T (p.Gly1464Val)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005458	NM_001244008.2(KIF1A):c.3776G>A (p.Arg1259His)	KIF1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 5 · 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
KIF1A	Definitive	Autosomal dominant	syndromic intellectual disability	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KIF1A	Orphanet:101010	Autosomal spastic paraplegia type 30
KIF1A	Orphanet:662367	NESCAV syndrome
KIF1A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
POLR1A	Orphanet:1200	Burn-McKeown syndrome
AGXT	Orphanet:93598	Primary hyperoxaluria type 1

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIF1A	HGNC:888	ENSG00000130294	Q12756	Kinesin-like protein KIF1A	gencc,clinvar
POLR1A	HGNC:17264	ENSG00000068654	O95602	DNA-directed RNA polymerase I subunit RPA1	clinvar
ATG4B	HGNC:20790	ENSG00000168397	Q9Y4P1	Cysteine protease ATG4B	clinvar
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KIF1A	Kinesin-like protein KIF1A	Kinesin motor with a plus-end-directed microtubule motor activity.
POLR1A	DNA-directed RNA polymerase I subunit RPA1	Catalytic core component of RNA polymerase I (Pol I), a DNA-dependent RNA polymerase which synthesizes ribosomal RNA precursors using the four ribonucleoside triphosphates as substrates.
ATG4B	Cysteine protease ATG4B	Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins.
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	9.2×	0.392
Scaffold/PPI	1	4.3×	0.392
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF1A	Scaffold/PPI	no	5.6.1.3	FHA_dom, Kinesin_motor_dom, PH_domain
POLR1A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3
ATG4B	Protease	yes		Peptidase_C54, Papain-like_cys_pep_sf, Peptidase_C54_cat
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parietal lobe	1
postcentral gyrus	1
right frontal lobe	1
stromal cell of endometrium	1
sural nerve	1
tibialis anterior	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
endometrium epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF1A	198	broad	marker	right frontal lobe, postcentral gyrus, parietal lobe
POLR1A	198	ubiquitous	marker	sural nerve, tibialis anterior, stromal cell of endometrium
ATG4B	289	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR1A	4,620
KIF1A	2,833
AGXT	2,648
ATG4B	2,076

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF1A	Q12756	21
AGXT	P21549	17
POLR1A	O95602	7
ATG4B	Q9Y4P1	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glyoxylate metabolism and glycine degradation	1	190.3×	0.054	AGXT
Positive epigenetic regulation of rRNA expression	1	86.5×	0.054	POLR1A
RNA Polymerase I Transcription Termination	1	81.6×	0.054	POLR1A
RNA Polymerase I Promoter Clearance	1	73.2×	0.054	POLR1A
RNA Polymerase I Transcription	1	71.4×	0.054	POLR1A
Negative epigenetic regulation of rRNA expression	1	64.9×	0.054	POLR1A
RNA Polymerase I Transcription Initiation	1	56.0×	0.054	POLR1A
Protein localization	1	47.6×	0.054	AGXT
Kinesins	1	44.6×	0.054	KIF1A
Peroxisomal protein import	1	43.3×	0.054	AGXT
Autophagy	1	37.1×	0.054	ATG4B
Golgi-to-ER retrograde transport	1	33.2×	0.054	KIF1A
B-WICH complex positively regulates rRNA expression	1	30.4×	0.054	POLR1A
RNA Polymerase I Promoter Escape	1	30.4×	0.054	POLR1A
Macroautophagy	1	28.8×	0.054	ATG4B
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.054	KIF1A
NoRC negatively regulates rRNA expression	1	26.2×	0.054	POLR1A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.054	KIF1A
Epigenetic regulation of gene expression	1	17.8×	0.073	POLR1A
Metabolism of amino acids and derivatives	1	16.9×	0.073	AGXT
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.073	KIF1A
Membrane Trafficking	1	9.3×	0.119	KIF1A
Hemostasis	1	9.0×	0.119	KIF1A
Vesicle-mediated transport	1	8.7×	0.119	KIF1A
Gene expression (Transcription)	1	4.5×	0.214	POLR1A
Metabolism	1	2.9×	0.302	AGXT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
otolith mineralization completed early in development	1	4213.0×	0.003	ATG4B
microautophagy	1	1404.3×	0.003	ATG4B
obsolete glycine biosynthetic process, by transamination of glyoxylate	1	1404.3×	0.003	AGXT
oxalic acid secretion	1	1404.3×	0.003	AGXT
negative regulation of protein localization to nucleolus	1	1404.3×	0.003	POLR1A
glyoxylate catabolic process	1	1053.2×	0.003	AGXT
L-cysteine catabolic process	1	1053.2×	0.003	AGXT
L-alanine catabolic process	1	1053.2×	0.003	AGXT
dense core granule cytoskeletal transport	1	1053.2×	0.003	KIF1A
anterograde neuronal dense core vesicle transport	1	1053.2×	0.003	KIF1A
nucleolar large rRNA transcription by RNA polymerase I	1	842.6×	0.003	POLR1A
protein delipidation	1	842.6×	0.003	ATG4B
retrograde neuronal dense core vesicle transport	1	842.6×	0.003	KIF1A
glyoxylate metabolic process	1	702.2×	0.003	AGXT
L-serine metabolic process	1	421.3×	0.004	AGXT
aggrephagy	1	421.3×	0.004	ATG4B
regulation of dendritic spine development	1	421.3×	0.004	KIF1A
transcription by RNA polymerase I	1	351.1×	0.005	POLR1A
protein localization to phagophore assembly site	1	247.8×	0.007	ATG4B
piecemeal microautophagy of the nucleus	1	234.1×	0.007	ATG4B
regulation of dendritic spine morphogenesis	1	210.7×	0.007	KIF1A
anterograde axonal transport	1	145.3×	0.010	KIF1A
mitophagy	1	79.5×	0.017	ATG4B
macroautophagy	1	60.2×	0.021	ATG4B
autophagosome assembly	1	56.2×	0.022	ATG4B
protein processing	1	42.6×	0.028	ATG4B
Notch signaling pathway	1	35.4×	0.032	AGXT
autophagy	1	27.5×	0.040	ATG4B
vesicle-mediated transport	1	24.1×	0.044	KIF1A
protein transport	1	11.0×	0.091	ATG4B

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATG4B	TIOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATG4B	7	4
POLR1A	1	2
KIF1A	0	0
AGXT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TIOCONAZOLE	4	ATG4B
BIFONAZOLE	4	ATG4B
HYPERICIN	3	ATG4B
EBSELEN	3	ATG4B
MOLIBRESIB	2	POLR1A
TOLFENAMIC ACID	2	ATG4B
FENTICLOR	2	ATG4B
ELLAGIC ACID	2	ATG4B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ATG4B	63	Binding:61, Functional:2
POLR1A	16	Binding:16
AGXT	8	Binding:8
KIF1A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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)
TIOCONAZOLE	4	ATG4B
BIFONAZOLE	4	ATG4B
HYPERICIN	3	ATG4B
EBSELEN	3	ATG4B
MOLIBRESIB	2	POLR1A
TOLFENAMIC ACID	2	ATG4B
FENTICLOR	2	ATG4B
ELLAGIC ACID	2	ATG4B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATG4B
B	Phased (≥1) drug, not yet approved	1	POLR1A
C	Druggable family + PDB, no drug	1	AGXT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KIF1A

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)
KIF1A	2	—
AGXT	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.