ALG9-congenital disorder of glycosylation

Summary

ALG9-congenital disorder of glycosylation (MONDO:0012117) is a disease caused by ALG9 (GenCC Strong), with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALG9 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 806
• Phenotypes (HPO): 86

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

86 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001698	Pericardial effusion	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002652	Skeletal dysplasia	Frequent (30-79%)
HP:0003186	Inverted nipples	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000105	Enlarged kidney	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000154	Wide mouth	Occasional (5-29%)
HP:0000193	Bifid uvula	Occasional (5-29%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000260	Wide anterior fontanel	Occasional (5-29%)
HP:0000270	Delayed cranial suture closure	Occasional (5-29%)
HP:0000308	Microretrognathia	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000319	Smooth philtrum	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000430	Underdeveloped nasal alae	Occasional (5-29%)
HP:0000444	Convex nasal ridge	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000473	Torticollis	Occasional (5-29%)
HP:0000474	Thickened nuchal skin fold	Occasional (5-29%)
HP:0000506	Telecanthus	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000586	Shallow orbits	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000813	Bicornuate uterus	Occasional (5-29%)
HP:0000998	Hypertrichosis	Occasional (5-29%)
HP:0001234	Hitchhiker thumb	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001405	Periportal fibrosis	Occasional (5-29%)
HP:0001407	Hepatic cysts	Occasional (5-29%)
HP:0001539	Omphalocele	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0001762	Talipes equinovarus	Occasional (5-29%)
HP:0001789	Hydrops fetalis	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ALG9-congenital disorder of glycosylation
Mondo ID	MONDO:0012117
MeSH	C535750
OMIM	608776
Orphanet	79328
DOID	DOID:0080564
SNOMED CT	720978005
UMLS	C2931006
MedGen	443955
GARD	0009839
Is cancer (heuristic)	no

Also known as: ALG9-CDG · ALG9-CDG (CDG-IL) · ALG9-congenital disorder of glycosylation · carbohydrate deficient glycoprotein syndrome type 1L · carbohydrate deficient glycoprotein syndrome type IL · CDG 1L · CDG syndrome type IL · CDG-IL · CDG1L · congenital disorder of glycosylation type 1L · congenital disorder of glycosylation type IL · congenital disorder of glycosylation, type IL · mannosyltransferase 7-9 deficiency

Data availability: 806 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

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 › ALG9-congenital disorder of glycosylation

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, ALG6-congenital disorder of glycosylation 1C, 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, 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

Subtypes (1): Gillessen-Kaesbach-Nishimura syndrome

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:

250 uncertain significance, 230 likely benign, 29 pathogenic, 27 conflicting classifications of pathogenicity, 23 benign, 21 likely pathogenic, 15 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1434153	NM_024740.2(ALG9):c.992del (p.Met331fs)	ALG9	Pathogenic	criteria provided, single submitter
1524100	NM_024740.2(ALG9):c.566-1G>A	ALG9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698703	NM_024740.2(ALG9):c.1460T>C (p.Leu487Pro)	ALG9	Pathogenic	no assertion criteria provided
2011582	NM_024740.2(ALG9):c.1296dup (p.Phe433fs)	ALG9	Pathogenic	criteria provided, single submitter
2014762	NM_024740.2(ALG9):c.754_757del (p.Phe252fs)	ALG9	Pathogenic	criteria provided, single submitter
2086914	NM_024740.2(ALG9):c.744G>A (p.Trp248Ter)	ALG9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3656725	NM_024740.2(ALG9):c.1441C>T (p.Arg481Ter)	ALG9	Pathogenic	criteria provided, single submitter
3665027	NM_024740.2(ALG9):c.126del (p.Thr43fs)	ALG9	Pathogenic	criteria provided, single submitter
3749	NM_024740.2(ALG9):c.860A>G (p.Tyr287Cys)	ALG9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074631	NM_012463.4(ATP6V0A2):c.2203C>T (p.Gln735Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2000140	NM_012463.4(ATP6V0A2):c.302T>A (p.Leu101Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2030297	NM_012463.4(ATP6V0A2):c.1926C>A (p.Tyr642Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2133236	NM_012463.4(ATP6V0A2):c.1945_1946del (p.Gln649fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2137448	NM_012463.4(ATP6V0A2):c.390_397dup (p.Arg133delinsThrCysTer)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2137449	NM_012463.4(ATP6V0A2):c.2015T>A (p.Leu672Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
21494	NM_012463.4(ATP6V0A2):c.1324G>T (p.Glu442Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
21501	NM_012463.4(ATP6V0A2):c.732-2A>G	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2687870	NM_012463.4(ATP6V0A2):c.2231_2255dup (p.Tyr753fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2789345	NM_012463.4(ATP6V0A2):c.666G>A (p.Trp222Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2813479	NM_012463.4(ATP6V0A2):c.1604del (p.Pro535fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2829656	NM_012463.4(ATP6V0A2):c.851del (p.Tyr283_Leu284insTer)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2838924	NM_012463.4(ATP6V0A2):c.377_378del (p.Ile126fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2840813	NM_012463.4(ATP6V0A2):c.1994T>A (p.Leu665Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
2991081	NM_012463.4(ATP6V0A2):c.2304del (p.Asp768fs)	ATP6V0A2	Pathogenic	criteria provided, single submitter
3004981	NM_012463.4(ATP6V0A2):c.877G>T (p.Glu293Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
3574387	NM_012463.4(ATP6V0A2):c.130del (p.Asn43_Val44insTer)	ATP6V0A2	Pathogenic	criteria provided, multiple submitters, no conflicts
3574388	NM_012463.4(ATP6V0A2):c.208C>T (p.Gln70Ter)	ATP6V0A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3636993	NM_012463.4(ATP6V0A2):c.112C>T (p.Arg38Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
3658823	NM_012463.4(ATP6V0A2):c.986G>A (p.Trp329Ter)	ATP6V0A2	Pathogenic	criteria provided, single submitter
3674447	NM_012463.4(ATP6V0A2):c.1519_1540dup (p.Ile514delinsLysArgArgTer)	ATP6V0A2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
ALG9	Strong	Autosomal recessive	ALG9-congenital disorder of glycosylation	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG
ATP6V0A2	Orphanet:2834	Wrinkly skin syndrome
ATP6V0A2	Orphanet:357074	Autosomal recessive cutis laxa type 2, classic type
TCTN2	Orphanet:475	Isolated Joubert syndrome
TCTN2	Orphanet:564	Meckel syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALG9	HGNC:15672	ENSG00000086848	Q9H6U8	Alpha-1,2-mannosyltransferase ALG9	gencc,clinvar
ATP6V0A2	HGNC:18481	ENSG00000185344	Q9Y487	V-type proton ATPase 116 kDa subunit a 2	clinvar
ALG10	HGNC:23162	ENSG00000139133	Q5BKT4	Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase A	clinvar
TCTN2	HGNC:25774	ENSG00000168778	Q96GX1	Tectonic-2	clinvar
HSPB2	HGNC:5247	ENSG00000170276	Q16082	Heat shock protein beta-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALG9	Alpha-1,2-mannosyltransferase ALG9	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
ATP6V0A2	V-type proton ATPase 116 kDa subunit a 2	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
ALG10	Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase A	Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
TCTN2	Tectonic-2	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
HSPB2	Heat shock protein beta-2	May regulate the kinase DMPK.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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)	3	7.2×	0.010
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALG9	Enzyme (other)	yes	2.4.1.259	GPI_mannosylTrfase
ATP6V0A2	Enzyme (other)	yes	7.1.2.1	V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
ALG10	Enzyme (other)	yes	2.4.1.256	Alg10
TCTN2	Other/Unknown	no		TCTN1-3_dom, TCTN1-3, TCTN1-3_N
HSPB2	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
endothelial cell	1
ganglionic eminence	1
skin of leg	1
stromal cell of endometrium	1
sural nerve	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
buccal mucosa cell	1
olfactory bulb	1
tendon of biceps brachii	1
apex of heart	1
hindlimb stylopod muscle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALG9	240	ubiquitous	marker	endothelial cell, body of pancreas, ganglionic eminence
ATP6V0A2	239	ubiquitous	marker	skin of leg, sural nerve, stromal cell of endometrium
ALG10	172	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell
TCTN2	218	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, olfactory bulb
HSPB2	134	broad	marker	right atrium auricular region, apex of heart, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB2	2,823
ATP6V0A2	2,076
TCTN2	1,254
ALG9	1,167
ALG10	638

Intra-cohort edges

A	B	Sources
ALG9	TCTN2	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALG9	Q9H6U8	2
HSPB2	Q16082	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALG10	Q5BKT4	93.51
ATP6V0A2	Q9Y487	81.94
TCTN2	Q96GX1	74.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ALG9 causes CDG-1l	1	2284.0×	0.004	ALG9
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	2	83.0×	0.004	ALG9, ALG10
Asparagine N-linked glycosylation	2	24.0×	0.018	ALG9, ALG10
Diseases associated with N-glycosylation of proteins	1	126.9×	0.031	ALG9
Attenuation phase	1	81.6×	0.031	HSPB2
HSF1 activation	1	76.1×	0.031	HSPB2
Insulin receptor recycling	1	76.1×	0.031	ATP6V0A2
Transferrin endocytosis and recycling	1	73.7×	0.031	ATP6V0A2
ROS and RNS production in phagocytes	1	67.2×	0.031	ATP6V0A2
HSF1-dependent transactivation	1	63.4×	0.031	HSPB2
Post-translational protein modification	2	7.7×	0.044	ALG9, ALG10
Regulation of HSF1-mediated heat shock response	1	27.9×	0.058	HSPB2
Diseases of glycosylation	1	26.2×	0.058	ALG9
Anchoring of the basal body to the plasma membrane	1	22.6×	0.060	TCTN2
Cilium Assembly	1	21.8×	0.060	TCTN2
Ion channel transport	1	19.2×	0.064	ATP6V0A2
Metabolism of proteins	2	5.0×	0.065	ALG9, ALG10
Diseases of metabolism	1	16.1×	0.067	ALG9
Organelle biogenesis and maintenance	1	13.2×	0.077	TCTN2
Disease	1	2.6×	0.328	ALG9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dolichol-linked oligosaccharide biosynthetic process	2	337.0×	2e-04	ALG9, ALG10
protein N-linked glycosylation	2	105.3×	0.001	ALG9, ALG10
somatic muscle development	1	842.6×	0.007	HSPB2
protein localization to ciliary transition zone	1	481.5×	0.008	TCTN2
cellular response to increased oxygen levels	1	421.3×	0.008	ATP6V0A2
Golgi lumen acidification	1	337.0×	0.008	ATP6V0A2
vacuolar acidification	1	146.5×	0.017	ATP6V0A2
protein refolding	1	124.8×	0.017	HSPB2
response to heat	1	84.3×	0.022	HSPB2
proton transmembrane transport	1	62.4×	0.024	ATP6V0A2
response to unfolded protein	1	60.2×	0.024	HSPB2
regulation of macroautophagy	1	59.1×	0.024	ATP6V0A2
intracellular iron ion homeostasis	1	48.9×	0.027	ATP6V0A2
smoothened signaling pathway	1	36.2×	0.033	TCTN2
cilium assembly	1	14.7×	0.075	TCTN2
immune response	1	9.4×	0.108	ATP6V0A2
negative regulation of apoptotic process	1	7.0×	0.136	HSPB2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
ALG9	0	0
ATP6V0A2	0	0
ALG10	0	0
TCTN2	0	0
HSPB2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALG9	2.4.1.259, 2.4.1.261	dolichyl-P-Man:Man6GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase, dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase
ATP6V0A2	7.1.2.1	P-type H+-exporting transporter
ALG10	2.4.1.256	dolichyl-P-Glc:Glc2Man9GlcNAc2-PP-dolichol alpha-1,2-glucosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	ALG9
D	Druggable family + AlphaFold only, no drug	2	ATP6V0A2, ALG10
E	Difficult family or no structure, no drug	2	TCTN2, HSPB2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ALG9	0	—
ATP6V0A2	0	—
ALG10	0	—
TCTN2	0	—
HSPB2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.