ALG6-congenital disorder of glycosylation 1C

Summary

ALG6-congenital disorder of glycosylation 1C (MONDO:0011291) is a disease caused by ALG6 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALG6 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 805
• Phenotypes (HPO): 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		54	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0012379	Abnormal enzyme/coenzyme activity	Obligate (100%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001392	Abnormality of the liver	Occasional (5-29%)
HP:0001929	Reduced factor XI activity	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002243	Protein-losing enteropathy	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002652	Skeletal dysplasia	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0003256	Abnormality of the coagulation cascade	Occasional (5-29%)
HP:0003642	Type I transferrin isoform profile	Occasional (5-29%)
HP:0004855	Reduced protein S activity	Occasional (5-29%)
HP:0005543	Reduced protein C activity	Occasional (5-29%)
HP:0006118	Shortening of all distal phalanges of the fingers	Occasional (5-29%)
HP:0040246	Reduced antithrombin antigen	Occasional (5-29%)
HP:0000510	Rod-cone dystrophy	Very rare (<1-4%)
HP:0000546	Retinal degeneration	Very rare (<1-4%)
HP:0001156	Brachydactyly	Very rare (<1-4%)
HP:0001321	Cerebellar hypoplasia	Very rare (<1-4%)
HP:0002625	Deep venous thrombosis	Very rare (<1-4%)
HP:0003563	Decreased LDL cholesterol concentration	Very rare (<1-4%)
HP:0008373	Puberty and gonadal disorders	Very rare (<1-4%)
HP:0030348	Increased circulating androgen concentration	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALG6-congenital disorder of glycosylation 1C
Mondo ID	MONDO:0011291
MeSH	C535741
OMIM	603147
Orphanet	79320
DOID	DOID:0080555
NCIT	C126869
SNOMED CT	709412006
UMLS	C2930997
MedGen	443952
GARD	0009829
Is cancer (heuristic)	no

Also known as: ALG6 congenital disorder of glycosylation · ALG6-CDG (CDG-Ic) · ALG6-CDG1C · ALG6-congenital disorder of glycosylation 1C · carbohydrate deficient glycoprotein syndrome type Ic · carbohydrate-deficient glycoprotein syndrome type 1C · carbohydrate-deficient glycoprotein syndrome, type 1 with deficient glycosylation of dolichol-linked oligosaccharide (formerly) · carbohydrate-deficient glycoprotein syndrome, type I, with deficient glycosylation of dolichol-linked oligosaccharide · carbohydrate-deficient glycoprotein syndrome, type V (formerly) · CDG 1C · CDG syndrome type Ic · CDG-Ic · CDG1C · CDGIc · CDGS5 (formerly) · congenital disorder of glycosylation caused by mutation in ALG6 · congenital disorder of glycosylation type 1C · congenital disorder of glycosylation type Ic · congenital disorder of glycosylation, type Ic · glucosyltransferase 1 deficiency

Data availability: 805 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

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 I › ALG6-congenital disorder of glycosylation 1C

Related subtypes (27): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, SSR4-congenital disorder of glycosylation, ALG3-congenital disorder of glycosylation, MPI-congenital disorder of glycosylation, ALG12-congenital disorder of glycosylation, ALG2-congenital disorder of glycosylation, DPAGT1-congenital disorder of glycosylation, ALG8-congenital disorder of glycosylation, ALG1-congenital disorder of glycosylation, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-congenital disorder of glycosylation, RFT1-congenital disorder of glycosylation, SRD5A3-congenital disorder of glycosylation, DPM3-congenital disorder of glycosylation, ALG11-congenital disorder of glycosylation, DDOST-congenital disorder of glycosylation, PGM1-congenital disorder of glycosylation, congenital muscular dystrophy with intellectual disability and severe epilepsy, STT3A-congenital disorder of glycosylation, STT3B-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 50, congenital disorder of glycosylation, type IAA, congenital disorder of glycosylation, type ICC, SSR3-CDG

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:

303 likely benign, 168 uncertain significance, 42 likely pathogenic, 39 pathogenic, 20 pathogenic/likely pathogenic, 16 benign, 9 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076049	NM_013339.4(ALG6):c.409G>T (p.Glu137Ter)	ALG6	Pathogenic	criteria provided, single submitter
1338460	NM_013339.4(ALG6):c.796_799dup (p.Asp267delinsGlyTer)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363248	NM_013339.4(ALG6):c.789_790del (p.Phe264fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1370628	NM_013339.4(ALG6):c.1326+1G>T	ALG6	Pathogenic	criteria provided, single submitter
1405663	NM_013339.4(ALG6):c.171T>G (p.Tyr57Ter)	ALG6	Pathogenic	criteria provided, single submitter
1407854	NM_013339.4(ALG6):c.506_507del (p.Val169fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411147	NM_013339.4(ALG6):c.723del (p.Phe242fs)	ALG6	Pathogenic	criteria provided, single submitter
1414979	NM_013339.4(ALG6):c.835del (p.Trp279fs)	ALG6	Pathogenic	criteria provided, single submitter
1415838	NM_013339.4(ALG6):c.1171_1172del (p.Val391fs)	ALG6	Pathogenic	criteria provided, single submitter
1421154	NC_000001.10:g.(?63867905)(63902691_?)del	ALG6	Pathogenic	criteria provided, single submitter
1423464	NM_013339.4(ALG6):c.1249del (p.Gln417fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1431177	NM_013339.4(ALG6):c.574del (p.Ala192fs)	ALG6	Pathogenic	criteria provided, single submitter
1450339	NM_013339.4(ALG6):c.920T>A (p.Leu307Ter)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1450530	NM_013339.4(ALG6):c.791del (p.Phe264fs)	ALG6	Pathogenic	criteria provided, single submitter
1453538	NM_013339.4(ALG6):c.484_485insA (p.Gly162fs)	ALG6	Pathogenic	criteria provided, single submitter
1454278	NM_013339.4(ALG6):c.684del (p.Phe228fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456351	NC_000001.10:g.(?63836649)(63836750_?)del	ALG6	Pathogenic	criteria provided, single submitter
1456612	NM_013339.4(ALG6):c.254_255del (p.Tyr85fs)	ALG6	Pathogenic	criteria provided, single submitter
1456617	NM_013339.4(ALG6):c.428del (p.Lys143fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457700	NM_013339.4(ALG6):c.510del (p.Gly172fs)	ALG6	Pathogenic	criteria provided, single submitter
1457885	NM_013339.4(ALG6):c.121C>T (p.Gln41Ter)	ALG6	Pathogenic	criteria provided, single submitter
1458787	NC_000001.10:g.(?63885021)(63885131_?)del	ALG6	Pathogenic	criteria provided, single submitter
1460456	NM_013339.4(ALG6):c.634del (p.Cys212fs)	ALG6	Pathogenic	criteria provided, single submitter
1522702	NM_013339.4(ALG6):c.680+1G>A	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1524712	NM_013339.4(ALG6):c.988-1G>A	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2004426	NM_013339.4(ALG6):c.493C>T (p.Gln165Ter)	ALG6	Pathogenic	criteria provided, single submitter
2029354	NM_013339.4(ALG6):c.1029dup (p.His344fs)	ALG6	Pathogenic	criteria provided, single submitter
2045342	NM_013339.4(ALG6):c.100_101del (p.Met34fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2118725	NM_013339.4(ALG6):c.663dup (p.Gly222fs)	ALG6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2167373	NM_013339.4(ALG6):c.889C>T (p.Gln297Ter)	ALG6	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
ALG6	Definitive	Autosomal recessive	ALG6-congenital disorder of glycosylation 1C	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG6	Orphanet:79320	ALG6-CDG
DOCK7	Orphanet:411986	Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism 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
ALG6	HGNC:23157	ENSG00000088035	Q9Y672	Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase	gencc,clinvar
DOCK7	HGNC:19190	ENSG00000116641	Q96N67	Dedicator of cytokinesis protein 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG6	Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase	Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
DOCK7	Dedicator of cytokinesis protein 7	Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG6	Enzyme (other)	yes	2.4.1.267	Glyco_trans_ALG6/ALG8
DOCK7	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain

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
primordial germ cell in gonad	1
secondary oocyte	1
upper leg skin	1
calcaneal tendon	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG6	268	ubiquitous	yes	secondary oocyte, primordial germ cell in gonad, upper leg skin
DOCK7	260	ubiquitous	marker	ventricular zone, calcaneal tendon, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DOCK7	1,934
ALG6	965

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DOCK7	Q96N67	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG6	Q9Y672	93.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Defective ALG6 causes CDG-1c	1	5710.0×	0.002	ALG6
MET activates RAP1 and RAC1	1	519.1×	0.013	DOCK7
Diseases associated with N-glycosylation of proteins	1	317.2×	0.014	ALG6
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.031	ALG6
Diseases of glycosylation	1	65.6×	0.039	ALG6
Diseases of metabolism	1	40.2×	0.043	ALG6
CDC42 GTPase cycle	1	36.1×	0.043	DOCK7
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.043	DOCK7
RAC1 GTPase cycle	1	30.5×	0.043	DOCK7
Asparagine N-linked glycosylation	1	30.1×	0.043	ALG6
Post-translational protein modification	1	9.6×	0.120	ALG6
Disease	1	6.5×	0.155	ALG6
Metabolism of proteins	1	6.2×	0.155	ALG6

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
establishment of neuroblast polarity	1	2106.5×	0.004	DOCK7
interkinetic nuclear migration	1	1685.2×	0.004	DOCK7
positive regulation of vascular associated smooth muscle cell migration	1	495.6×	0.007	DOCK7
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.007	ALG6
Rac protein signal transduction	1	280.9×	0.008	DOCK7
regulation of Rho protein signal transduction	1	255.3×	0.008	DOCK7
regulation of neurogenesis	1	200.6×	0.009	DOCK7
negative regulation of cold-induced thermogenesis	1	172.0×	0.009	DOCK7
protein N-linked glycosylation	1	131.7×	0.010	ALG6
axonogenesis	1	80.2×	0.015	DOCK7
neuron projection development	1	61.1×	0.016	DOCK7
microtubule cytoskeleton organization	1	60.6×	0.016	DOCK7

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
ALG6	0	0
DOCK7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG6	2.4.1.267	dolichyl-P-Glc:Man9GlcNAc2-PP-dolichol alpha-1,3-glucosyltransferase

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	1	ALG6
E	Difficult family or no structure, no drug	1	DOCK7

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)
ALG6	0	—
DOCK7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.