Intellectual disability, autosomal dominant 34

Summary

Intellectual disability, autosomal dominant 34 (MONDO:0014599) is a disease caused by CERT1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: CERT1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 38

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 34
Mondo ID	MONDO:0014599
OMIM	616351
DOID	DOID:0070064
UMLS	C4225156
MedGen	907277
GARD	0025006
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 34 · autosomal dominant non-syndromic intellectual disability caused by mutation in COL4A3BP · COL4A3BP autosomal dominant non-syndromic intellectual disability · intellectual developmental disorder, autosomal dominant 34 · intellectual disability, autosomal dominant 34 · intellectual disability, autosomal dominant type 34 · mental retardation, autosomal dominant 34 · mental retardation, autosomal dominant type 34 · MRD34

Data availability: 38 ClinVar variants · 2 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 dominant non-syndromic intellectual disability › intellectual disability, autosomal dominant 34

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

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

38 retrieved; paginated sample, class counts are floors:

21 uncertain significance, 6 likely pathogenic, 5 pathogenic, 4 conflicting classifications of pathogenicity, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3387779	CERT1, SER135PRO	CERT1	Pathogenic	no assertion criteria provided
3387780	CERT1, SER138CYS	CERT1	Pathogenic	no assertion criteria provided
3387781	CERT1, THR166ALA	CERT1	Pathogenic	no assertion criteria provided
3387782	CERT1, GLY243ARG	CERT1	Pathogenic	no assertion criteria provided
548566	NM_001379029.1(CERT1):c.-114G>T	CERT1	Pathogenic	criteria provided, single submitter
2580916	NM_001379029.1(CERT1):c.728G>C (p.Gly243Ala)	CERT1	Likely pathogenic	criteria provided, single submitter
3376829	NM_001379029.1(CERT1):c.1742C>T (p.Ala581Val)	CERT1	Likely pathogenic	criteria provided, single submitter
3775396	NM_001379029.1(CERT1):c.887C>G (p.Thr296Arg)	CERT1	Likely pathogenic	criteria provided, single submitter
4532002	NM_001379029.1(CERT1):c.191G>T (p.Gly64Val)	CERT1	Likely pathogenic	criteria provided, single submitter
977354	NM_001379029.1(CERT1):c.496A>G (p.Thr166Ala)	CERT1	Likely pathogenic	criteria provided, single submitter
985122	NM_001379029.1(CERT1):c.404C>T (p.Ser135Phe)	CERT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2504168	NM_001379029.1(CERT1):c.1367A>G (p.His456Arg)	CERT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
419654	NM_001379029.1(CERT1):c.395C>T (p.Ser132Leu)	CERT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
996805	NM_001379029.1(CERT1):c.413C>T (p.Ser138Phe)	CERT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3893067	NM_001379029.1(CERT1):c.-236C>A	POLK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1199412	NM_001379029.1(CERT1):c.905C>A (p.Ser302Tyr)	CERT1	Uncertain significance	criteria provided, single submitter
1683632	NM_001379029.1(CERT1):c.1439T>C (p.Val480Ala)	CERT1	Uncertain significance	criteria provided, single submitter
1707616	NM_001130105.1(CERT1):c.67G>A (p.Val23Ile)	CERT1	Uncertain significance	no assertion criteria provided
1710195	NM_001379029.1(CERT1):c.1637G>A (p.Arg546His)	CERT1	Uncertain significance	no assertion criteria provided
2439921	NM_001379029.1(CERT1):c.-41A>T	CERT1	Uncertain significance	criteria provided, single submitter
2439923	NM_001379029.1(CERT1):c.238G>A (p.Asp80Asn)	CERT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2440316	NM_001379029.1(CERT1):c.1073C>G (p.Ala358Gly)	CERT1	Uncertain significance	criteria provided, single submitter
2440317	NM_001379029.1(CERT1):c.734C>T (p.Ala245Val)	CERT1	Uncertain significance	criteria provided, single submitter
2672255	NM_001379029.1(CERT1):c.1300G>A (p.Val434Ile)	CERT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2688766	NM_001379029.1(CERT1):c.1201G>T (p.Val401Leu)	CERT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068266	NM_001379029.1(CERT1):c.1212C>G (p.His404Gln)	CERT1	Uncertain significance	criteria provided, single submitter
3234988	NM_001379029.1(CERT1):c.853A>G (p.Arg285Gly)	CERT1	Uncertain significance	criteria provided, single submitter
3491070	NM_001379029.1(CERT1):c.1516G>A (p.Val506Ile)	CERT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4078250	NM_001379029.1(CERT1):c.1018-1G>T	CERT1	Uncertain significance	criteria provided, single submitter
4081864	NM_001379029.1(CERT1):c.380T>C (p.Leu127Ser)	CERT1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
CERT1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 34	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CERT1	Orphanet:528084	Non-specific 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
CERT1	HGNC:2205	ENSG00000113163	Q9Y5P4	Ceramide transfer protein	gencc,clinvar
POLK	HGNC:9183	ENSG00000122008	Q9UBT6	DNA polymerase kappa	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CERT1	Ceramide transfer protein	Shelters ceramides inside its steroidogenic acute regulatory lipid transfer (START) domain and mediates their intracellular trafficking in a non-vesicular manner from the endoplasmic reticulum to the Golgi apparatus for conversion to sphin…
POLK	DNA polymerase kappa	DNA polymerase specifically involved in DNA repair.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	8.6×	0.160
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CERT1	Scaffold/PPI	no	2.7.11.9	PH_domain, START_lipid-bd_dom, PH-like_dom_sf
POLK	Enzyme (other)	yes	2.7.7.7	UmuC, Rad18_UBZ4, DNA_pol_Y-fam_little_finger

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
cerebellar vermis	1
male germ cell	1
sperm	1
adrenal tissue	1
calcaneal tendon	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CERT1	290	ubiquitous	marker	sperm, male germ cell, cerebellar vermis
POLK	255	ubiquitous	marker	calcaneal tendon, adrenal tissue, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLK	1,873
CERT1	1,306

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CERT1	Q9Y5P4	27
POLK	Q9UBT6	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Translesion synthesis by POLK	1	317.2×	0.012	POLK
Gap-filling DNA repair synthesis and ligation in GG-NER	1	219.6×	0.012	POLK
Termination of translesion DNA synthesis	1	173.0×	0.012	POLK
Sphingolipid de novo biosynthesis	1	142.8×	0.012	CERT1
Dual Incision in GG-NER	1	129.8×	0.012	POLK
HDR through Homologous Recombination (HRR)	1	95.2×	0.012	POLK
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.012	POLK
Dual incision in TC-NER	1	86.5×	0.012	POLK

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
intermembrane sphingolipid transfer	1	8426.0×	0.003	CERT1
ER to Golgi ceramide transport	1	2808.7×	0.004	CERT1
nucleotide-excision repair, DNA gap filling	1	1404.3×	0.006	POLK
ceramide transport	1	766.0×	0.006	CERT1
error-prone translesion synthesis	1	766.0×	0.006	POLK
sphingomyelin biosynthetic process	1	702.2×	0.006	CERT1
intermembrane lipid transfer	1	601.9×	0.006	CERT1
translesion synthesis	1	468.1×	0.006	POLK
ceramide metabolic process	1	401.2×	0.006	CERT1
DNA biosynthetic process	1	401.2×	0.006	POLK
endoplasmic reticulum organization	1	210.7×	0.011	CERT1
heart morphogenesis	1	187.2×	0.011	CERT1
lipid homeostasis	1	168.5×	0.011	CERT1
cellular response to UV	1	147.8×	0.012	POLK
muscle contraction	1	104.0×	0.016	CERT1
response to endoplasmic reticulum stress	1	83.4×	0.017	CERT1
DNA replication	1	82.6×	0.017	POLK
cell morphogenesis	1	78.8×	0.017	CERT1
mitochondrion organization	1	75.9×	0.017	CERT1
cell population proliferation	1	51.4×	0.024	CERT1
in utero embryonic development	1	36.0×	0.033	CERT1
DNA repair	1	31.9×	0.035	POLK
DNA damage response	1	26.8×	0.040	POLK
immune response	1	23.5×	0.044	CERT1
signal transduction	1	8.0×	0.121	CERT1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
POLK	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLK	1	4
CERT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	POLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
POLK	22	Binding:20, Functional:2
CERT1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CERT1	2.7.11.9	Goodpasture-antigen-binding protein kinase
POLK	2.7.7.7	DNA-directed DNA polymerase

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

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)
CANDESARTAN CILEXETIL	4	POLK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLK
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	1	CERT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CERT1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.