CCDC115-CDG

Summary

CCDC115-CDG (MONDO:0014789) is a disease caused by VMA22 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VMA22 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	CCDC115-CDG
Mondo ID	MONDO:0014789
OMIM	616828
Orphanet	468684
DOID	DOID:0070267
UMLS	C4225191
MedGen	906792
GARD	0017845
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type IIo · CDG syndrome type IIo · CDG-IIo · CDG2O · congenital disorder of glycosylation type 2o · congenital disorder of glycosylation type IIo · congenital disorder of glycosylation, type IIo

Data availability: 10 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 glycosylation › congenital disorder of glycosylation type II › CCDC115-CDG

Related subtypes (25): MGAT2-congenital disorder of glycosylation, leukocyte adhesion deficiency type II, SLC35A2-congenital disorder of glycosylation, SLC35A1-congenital disorder of glycosylation, MOGS-congenital disorder of glycosylation, B4GALT1-congenital disorder of glycosylation, COG7-congenital disorder of glycosylation, COG8-congenital disorder of glycosylation, COG1-congenital disorder of glycosylation, COG4-congenital disorder of glycosylation, COG5-congenital disorder of glycosylation, COG6-congenital disorder of glycosylation, TMEM165-congenital disorder of glycosylation, SLC39A8-CDG, TMEM199-CDG, congenital disorder of glycosylation, type IIr, congenital disorder of glycosylation, type iit, congenital disorder of glycosylation, type 2v, congenital disorder of glycosylation, type IIw, congenital disorder of glycosylation, type IIq, congenital disorder of glycosylation, type IIy, congenital disorder of glycosylation, type IIz, congenital disorder of glycosylation, type IIaa, congenital disorder of glycosylation, type IIbb, congenital disorder of glycosylation, type IIcc

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

10 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
218963	NM_032357.4(CCDC115):c.31G>T (p.Asp11Tyr)	CCDC115	Pathogenic	no assertion criteria provided
4537444	NM_032357.4(VMA22):c.19C>T (p.Arg7Ter)	LOC129934769	Pathogenic	no assertion criteria provided
218967	NM_032357.4(VMA22):c.92T>C (p.Leu31Ser)	VMA22	Pathogenic	criteria provided, multiple submitters, no conflicts
3772685	NM_032357.4(VMA22):c.227del (p.Glu76fs)	VMA22	Pathogenic	criteria provided, single submitter
3391371	NM_032357.4(CCDC115):c.425G>A (p.Arg142Gln)	CCDC115	Uncertain significance	criteria provided, single submitter
3391372	NM_032357.4(CCDC115):c.470G>A (p.Arg157His)	CCDC115	Uncertain significance	criteria provided, single submitter
1805385	NM_032357.4(VMA22):c.305G>A (p.Arg102Gln)	VMA22	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439785	NM_032357.4(VMA22):c.469C>T (p.Arg157Cys)	VMA22	Uncertain significance	criteria provided, single submitter
4056494	NM_032357.4(VMA22):c.451A>T (p.Ile151Leu)	VMA22	Uncertain significance	criteria provided, single submitter
4529500	NM_032357.4(VMA22):c.108G>T (p.Glu36Asp)	VMA22	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
VMA22	Definitive	Autosomal recessive	CCDC115-CDG	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VMA22	Orphanet:468684	CCDC115-CDG

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VMA22	HGNC:28178	ENSG00000136710	Q96NT0	Vacuolar ATPase assembly protein VMA22	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VMA22	Vacuolar ATPase assembly protein VMA22	Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VMA22	Other/Unknown	no		Vma22/CCDC115

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
ileal mucosa	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VMA22	258	ubiquitous	marker	kidney epithelium, ileal mucosa, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VMA22	1,501

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VMA22	Q96NT0	83.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHOA GTPase cycle	1	74.6×	0.037	VMA22
RHO GTPase cycle	1	60.1×	0.037	VMA22
Signaling by Rho GTPases	1	34.2×	0.037	VMA22
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.037	VMA22
Signal Transduction	1	10.2×	0.098	VMA22

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vacuolar proton-transporting V-type ATPase complex assembly	1	2808.7×	0.001	VMA22
cellular response to increased oxygen levels	1	2106.5×	0.001	VMA22
lysosomal protein catabolic process	1	1053.2×	0.002	VMA22
lysosomal lumen acidification	1	674.1×	0.002	VMA22
intracellular iron ion homeostasis	1	244.2×	0.004	VMA22

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
VMA22	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	VMA22

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)
VMA22	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.