congenital disorder of glycosylation, type Iw, autosomal dominant

Summary

congenital disorder of glycosylation, type Iw, autosomal dominant (MONDO:0859223) is a disease caused by STT3A (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: STT3A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of glycosylation, type Iw, autosomal dominant
Mondo ID	MONDO:0859223
OMIM	619714
UMLS	C5562068
MedGen	1794278
GARD	0026670
Is cancer (heuristic)	no

Data availability: 19 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › congenital disorder of glycosylation › congenital disorder of glycosylation, type Iw, autosomal dominant

Related subtypes (24): congenital disorder of glycosylation type I, congenital disorder of glycosylation type II, Larsen-like syndrome, B3GAT3 type, Ehlers-Danlos syndrome, musculocontractural type, temtamy preaxial brachydactyly syndrome, progressive myoclonic epilepsy type 3, autosomal recessive limb-girdle muscular dystrophy type 2P, seizures-scoliosis-macrocephaly syndrome, disorder of protein N-glycosylation, disorder of protein O-glycosylation, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of multiple glycosylation, XYLT1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability, congenital disorder of glycosylation syndrome type 4, congenital disorder of glycosylation with defective fucosylation, SLC10A7-congenital disorder of glycosylation, ALG14-congenital disorder of glycosylation, B3GALT6-congenital disorder of glycosylation, A4GALT-congenital disorder of glycosylation, FAM20B-congenital disorder of glycosylation, ALG10-congenital disorder of glycosylation, congenital disorder of glycosylation, type Ibb, congenital disorder of glycosylation, type 1DD

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

19 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 benign/likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2691773	NM_001128840.3(CACNA1D):c.2239T>C (p.Phe747Leu)	CACNA1D	Pathogenic	no assertion criteria provided
1334780	NM_152713.5(STT3A):c.1213C>T (p.Arg405Cys)	STT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334781	NM_152713.5(STT3A):c.1214G>A (p.Arg405His)	STT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334779	NM_152713.5(STT3A):c.479G>A (p.Arg160Gln)	STT3A	Likely pathogenic	criteria provided, single submitter
1895409	NM_152713.5(STT3A):c.251T>C (p.Ile84Thr)	STT3A	Likely pathogenic	criteria provided, single submitter
2431752	NM_152713.5(STT3A):c.1213C>A (p.Arg405Ser)	STT3A	Likely pathogenic	criteria provided, single submitter
1334778	NM_152713.5(STT3A):c.137A>G (p.His46Arg)	STT3A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1334776	NM_152713.5(STT3A):c.1637C>T (p.Thr546Ile)	STT3A	Uncertain significance	criteria provided, single submitter
1334777	NM_152713.5(STT3A):c.1589A>C (p.Tyr530Ser)	STT3A	Uncertain significance	criteria provided, single submitter
1334782	NM_152713.5(STT3A):c.985C>T (p.Arg329Cys)	STT3A	Uncertain significance	criteria provided, single submitter
1703171	NM_152713.5(STT3A):c.961G>A (p.Gly321Arg)	STT3A	Uncertain significance	criteria provided, single submitter
2481235	NM_152713.5(STT3A):c.691C>T (p.Arg231Cys)	STT3A	Uncertain significance	criteria provided, single submitter
2582505	NM_152713.5(STT3A):c.1841A>G (p.Glu614Gly)	STT3A	Uncertain significance	criteria provided, single submitter
2664988	NM_152713.5(STT3A):c.1193A>G (p.Tyr398Cys)	STT3A	Uncertain significance	criteria provided, single submitter
2691772	NM_152713.5(STT3A):c.1631A>G (p.Asn544Ser)	STT3A	Uncertain significance	criteria provided, single submitter
3376796	NM_152713.5(STT3A):c.1099C>T (p.Leu367Phe)	STT3A	Uncertain significance	criteria provided, single submitter
3382851	NM_152713.5(STT3A):c.1005T>A (p.Asp335Glu)	STT3A	Uncertain significance	criteria provided, single submitter
4849499	NM_152713.5(STT3A):c.740G>C (p.Gly247Ala)	STT3A	Uncertain significance	criteria provided, single submitter
1287809	NM_152713.5(STT3A):c.1775-8dup	STT3A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
STT3A	Definitive	Autosomal dominant	congenital disorder of glycosylation, type Iw, autosomal dominant	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STT3A	Orphanet:370921	STT3A-CDG
CACNA1D	Orphanet:324321	Sinoatrial node dysfunction and deafness
CACNA1D	Orphanet:369929	Primary hyperaldosteronism-seizures-neurological abnormalities 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
STT3A	HGNC:6172	ENSG00000134910	P46977	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A	gencc,clinvar
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STT3A	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A	Catalytic subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within a…
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	55.8×	0.036
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STT3A	Enzyme (other)	yes	2.4.99.18	Oligo_trans_STT3, STT3_N, AglB-like_core
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu

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
body of pancreas	1
islet of Langerhans	1
stromal cell of endometrium	1
adrenal tissue	1
buccal mucosa cell	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STT3A	262	ubiquitous	marker	stromal cell of endometrium, body of pancreas, islet of Langerhans
CACNA1D	219	broad	marker	buccal mucosa cell, adrenal tissue, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1D	2,318
STT3A	2,266

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1D	Q01668	6
STT3A	P46977	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	1	259.6×	0.022	STT3A
Translation of Structural Proteins	1	203.9×	0.022	STT3A
Adrenaline,noradrenaline inhibits insulin secretion	1	196.9×	0.022	CACNA1D
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	167.9×	0.022	STT3A
Sensory processing of sound	1	154.3×	0.022	CACNA1D
Late SARS-CoV-2 Infection Events	1	146.4×	0.022	STT3A
NCAM signaling for neurite out-growth	1	135.9×	0.022	CACNA1D
Maturation of spike protein	1	132.8×	0.022	STT3A
NCAM1 interactions	1	124.1×	0.022	CACNA1D
Regulation of insulin secretion	1	109.8×	0.022	CACNA1D
Maturation of DENV proteins	1	105.7×	0.022	STT3A
Integration of energy metabolism	1	87.8×	0.024	CACNA1D
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.024	CACNA1D
Sensory Perception	1	47.6×	0.039	CACNA1D
SARS-CoV-2 Infection	1	40.2×	0.043	STT3A
Asparagine N-linked glycosylation	1	30.1×	0.054	STT3A
SARS-CoV Infections	1	27.7×	0.055	STT3A
Axon guidance	1	22.6×	0.063	CACNA1D
Nervous system development	1	21.5×	0.063	CACNA1D
Viral Infection Pathways	1	15.4×	0.083	STT3A
Infectious disease	1	12.4×	0.098	STT3A
Post-translational protein modification	1	9.6×	0.120	STT3A
Developmental Biology	1	7.2×	0.151	CACNA1D
Disease	1	6.5×	0.159	STT3A
Metabolism of proteins	1	6.2×	0.161	STT3A
Metabolism	1	5.8×	0.165	CACNA1D

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
positive regulation of adenylate cyclase activity	1	1685.2×	0.005	CACNA1D
membrane depolarization during SA node cell action potential	1	1685.2×	0.005	CACNA1D
regulation of atrial cardiac muscle cell membrane repolarization	1	1203.7×	0.005	CACNA1D
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.006	CACNA1D
calcium ion import	1	401.2×	0.006	CACNA1D
cardiac muscle cell action potential involved in contraction	1	351.1×	0.006	CACNA1D
obsolete protein N-linked glycosylation via asparagine	1	337.0×	0.006	STT3A
regulation of potassium ion transmembrane transport	1	312.1×	0.006	CACNA1D
positive regulation of calcium ion transport	1	290.6×	0.006	CACNA1D
calcium ion import across plasma membrane	1	271.8×	0.006	CACNA1D
post-translational protein modification	1	210.7×	0.007	STT3A
regulation of heart rate by cardiac conduction	1	187.2×	0.008	CACNA1D
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	168.5×	0.008	CACNA1D
protein N-linked glycosylation	1	131.7×	0.009	STT3A
calcium ion transmembrane transport	1	105.3×	0.011	CACNA1D
calcium ion transport	1	90.6×	0.012	CACNA1D
sensory perception of sound	1	50.5×	0.020	CACNA1D

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
CACNA1D	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1D	48	4
STT3A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1D
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2
STT3A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
STT3A	2.4.99.18	dolichyl-diphosphooligosaccharide-protein glycotransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CACNA1D	233

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

30 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)
BEPRIDIL	4	CACNA1D
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1D
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	STT3A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
STT3A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.