Congenital disorder of deglycosylation 2

Summary

Congenital disorder of deglycosylation 2 (MONDO:0030770) is a disease caused by MAN2C1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MAN2C1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 26

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital disorder of deglycosylation 2
Mondo ID	MONDO:0030770
OMIM	619775
DOID	DOID:0060990
UMLS	C5676931
MedGen	1809253
GARD	0025635
Is cancer (heuristic)	no

Also known as: CDDG2 · congenital disorder of deglycosylation 2

Data availability: 26 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 › inborn errors of metabolism › congenital disorder of deglycosylation › congenital disorder of deglycosylation 2

Related subtypes (1): congenital disorder of deglycosylation 1

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

26 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 11 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4847124	NM_006715.4(MAN2C1):c.2568_2571del (p.Met856fs)	MAN2C1	Pathogenic	criteria provided, single submitter
4845880	NM_006715.4(MAN2C1):c.76_80del (p.Phe26fs)	LOC112272617	Likely pathogenic	criteria provided, single submitter
4686036	NM_006715.4(MAN2C1):c.2791_2792del (p.Leu931fs)	LOC121847958	Likely pathogenic	criteria provided, single submitter
1342928	NM_006715.4(MAN2C1):c.2612G>C (p.Cys871Ser)	MAN2C1	Likely pathogenic	criteria provided, single submitter
1342930	NM_006715.4(MAN2C1):c.607G>A (p.Gly203Arg)	MAN2C1	Likely pathogenic	criteria provided, single submitter
3366544	NM_006715.4(MAN2C1):c.2109_2141+4delinsAGT	MAN2C1	Likely pathogenic	criteria provided, single submitter
3375098	NM_006715.4(MAN2C1):c.600+1del	MAN2C1	Likely pathogenic	criteria provided, single submitter
3384737	NM_006715.4(MAN2C1):c.351+1G>A	MAN2C1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779828	NM_006715.4(MAN2C1):c.1235G>A (p.Trp412Ter)	MAN2C1	Likely pathogenic	criteria provided, single submitter
4072347	NM_006715.4(MAN2C1):c.2569del (p.Asp857fs)	MAN2C1	Likely pathogenic	criteria provided, single submitter
4820271	NM_006715.4(MAN2C1):c.2221G>A (p.Val741Ile)	MAN2C1	Likely pathogenic	criteria provided, single submitter
1342929	NM_006715.4(MAN2C1):c.2733_2734del (p.His911fs)	NEIL1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342926	NM_006715.4(MAN2C1):c.601-2A>G	MAN2C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803699	NM_006715.4(MAN2C1):c.1825G>A (p.Ala609Thr)	MAN2C1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1687395	NM_006715.4(MAN2C1):c.52_54del (p.Glu18del)	LOC112272617	Uncertain significance	criteria provided, single submitter
1342927	NM_006715.4(MAN2C1):c.2303G>A (p.Arg768Gln)	MAN2C1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1687203	NM_006715.4(MAN2C1):c.2997-1G>T	MAN2C1	Uncertain significance	criteria provided, single submitter
1805966	NM_006715.4(MAN2C1):c.2702G>A (p.Arg901His)	MAN2C1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2370363	NM_006715.4(MAN2C1):c.685G>A (p.Glu229Lys)	MAN2C1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2580926	NM_006715.4(MAN2C1):c.1167C>G (p.Ile389Met)	MAN2C1	Uncertain significance	criteria provided, single submitter
2582393	NM_006715.4(MAN2C1):c.833G>A (p.Arg278Gln)	MAN2C1	Uncertain significance	criteria provided, single submitter
3065612	NM_006715.4(MAN2C1):c.2197C>T (p.Pro733Ser)	MAN2C1	Uncertain significance	criteria provided, single submitter
3362290	NM_006715.4(MAN2C1):c.346G>A (p.Val116Ile)	MAN2C1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4056596	NM_006715.4(MAN2C1):c.1792+11C>A	MAN2C1	Uncertain significance	criteria provided, single submitter
4079238	NM_006715.4(MAN2C1):c.1445C>T (p.Thr482Met)	MAN2C1	Uncertain significance	criteria provided, single submitter
4537417	NM_006715.4(MAN2C1):c.634G>A (p.Ala212Thr)	MAN2C1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
MAN2C1	Strong	Autosomal recessive	congenital disorder of deglycosylation 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAN2C1	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
MAN2C1	HGNC:6827	ENSG00000140400	Q9NTJ4	Alpha-mannosidase 2C1	gencc,clinvar
NEIL1	HGNC:18448	ENSG00000140398	Q96FI4	Endonuclease 8-like 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAN2C1	Alpha-mannosidase 2C1	Cleaves alpha 1,2-, alpha 1,3-, and alpha 1,6-linked mannose residues on cytoplasmic free oligosaccharides generated by N-glycoprotein degradation pathways.
NEIL1	Endonuclease 8-like 1	Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents.

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)
MAN2C1	Enzyme (other)	yes	3.2.1.24	Glyco_hydro_38_N, Gal_mutarotase_sf_dom, Glyco_hydro/deAcase_b/a-brl
NEIL1	Other/Unknown	no		Ribosomal_uS13-like_H2TH, FPG_cat, Endonuclease-VIII_DNA-bd

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
right uterine tube	2
adenohypophysis	1
right lobe of thyroid gland	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAN2C1	230	ubiquitous	marker	right lobe of thyroid gland, adenohypophysis, right uterine tube
NEIL1	244	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAN2C1	1,887
NEIL1	1,346

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NEIL1	Q96FI4	27

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAN2C1	Q9NTJ4	94.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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 Base Excision Repair Associated with NEIL1	1	5710.0×	0.003	NEIL1
Diseases of Base Excision Repair	1	2855.0×	0.003	NEIL1
Lysosomal oligosaccharide catabolism	1	1427.5×	0.004	MAN2C1
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	815.7×	0.005	NEIL1
Resolution of Abasic Sites (AP sites)	1	571.0×	0.005	NEIL1
Depyrimidination	1	475.8×	0.005	NEIL1
Base-Excision Repair, AP Site Formation	1	439.2×	0.005	NEIL1
Base Excision Repair	1	356.9×	0.005	NEIL1
Diseases of DNA repair	1	285.5×	0.006	NEIL1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.015	NEIL1
Cleavage of the damaged pyrimidine	1	92.1×	0.015	NEIL1
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.021	MAN2C1
DNA Repair	1	49.2×	0.023	NEIL1
Disease	1	6.5×	0.158	NEIL1
Metabolism	1	5.8×	0.165	MAN2C1

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
obsolete negative regulation of nuclease activity	1	8426.0×	8e-04	NEIL1
mannose metabolic process	1	1053.2×	0.002	MAN2C1
depyrimidination	1	936.2×	0.002	NEIL1
oligosaccharide catabolic process	1	766.0×	0.002	MAN2C1
base-excision repair, gap-filling	1	561.7×	0.002	NEIL1
base-excision repair	1	234.1×	0.005	NEIL1
response to oxidative stress	1	65.3×	0.015	NEIL1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAN2C1	0	0
NEIL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NEIL1	6	Binding:5, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAN2C1	3.2.1.24	alpha-mannosidase

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	MAN2C1
E	Difficult family or no structure, no drug	1	NEIL1

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)
MAN2C1	0	—
NEIL1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.