TMEM199-CDG

Summary

TMEM199-CDG (MONDO:0014790) is a disease caused by VMA12 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: VMA12 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	TMEM199-CDG
Mondo ID	MONDO:0014790
OMIM	616829
Orphanet	466703
DOID	DOID:0070268
UMLS	C4225190
MedGen	895025
GARD	0017825
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type IIp · CDG syndrome type IIp · CDG-IIp · CDG2P · congenital disorder of glycosylation type 2p · congenital disorder of glycosylation type IIp · congenital disorder of glycosylation, type IIp

Data availability: 7 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 II › TMEM199-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, CCDC115-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

7 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4292339	NM_152464.3(VMA12):c.206_209del (p.Glu69fs)	LOC130060544	Pathogenic	criteria provided, single submitter
218964	NM_152464.3(VMA12):c.92G>C (p.Arg31Pro)	VMA12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223000	NM_152464.3(VMA12):c.40G>C (p.Ala14Pro)	VMA12	Pathogenic	no assertion criteria provided
223001	NM_152464.3(VMA12):c.376-1G>A	VMA12	Pathogenic	no assertion criteria provided
218965	NM_152464.3(VMA12):c.20C>A (p.Ala7Glu)	VMA12	Likely pathogenic	criteria provided, single submitter
773876	NM_152464.3(VMA12):c.156A>G (p.Gln52=)	LOC130060544	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1098426	NM_015077.4(SARM1):c.549= (p.Ser183=)	SARM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
VMA12	Strong	Autosomal recessive	TMEM199-CDG	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VMA12	Orphanet:466703	TMEM199-CDG

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
VMA12	HGNC:18085	ENSG00000244045	Q8N511	Vacuolar ATPase assembly protein VMA12	gencc,clinvar
SARM1	HGNC:17074	ENSG00000004139	Q6SZW1	NAD(+) hydrolase SARM1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VMA12	Vacuolar ATPase assembly protein VMA12	Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis.
SARM1	NAD(+) hydrolase SARM1	NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VMA12	Other/Unknown	no		ATPase_Vma12
SARM1	Other/Unknown	no		TIR_dom, SAM, ARM-like

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
granulocyte	1
leukocyte	1
monocyte	1
body of pancreas	1
cortical plate	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VMA12	197	ubiquitous	marker	monocyte, leukocyte, granulocyte
SARM1	206	ubiquitous	marker	body of pancreas, cortical plate, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SARM1	1,013
VMA12	1,006

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SARM1	Q6SZW1	55

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VMA12	Q8N511	80.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
TRAF6-mediated induction of TAK1 complex within TLR4 complex	1	713.8×	0.003	SARM1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	601.0×	0.003	SARM1
IKK complex recruitment mediated by RIP1	1	496.5×	0.003	SARM1
Toll Like Receptor 3 (TLR3) Cascade	1	193.6×	0.005	SARM1
MyD88-independent TLR4 cascade	1	184.2×	0.005	SARM1

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
negative regulation of MyD88-independent toll-like receptor signaling pathway	1	8426.0×	0.002	SARM1
NAD+ catabolic process	1	1685.2×	0.003	SARM1
vacuolar proton-transporting V-type ATPase complex assembly	1	1404.3×	0.003	VMA12
cellular response to increased oxygen levels	1	1053.2×	0.003	VMA12
regulation of synapse pruning	1	1053.2×	0.003	SARM1
modification of postsynaptic structure	1	936.2×	0.003	SARM1
protein localization to mitochondrion	1	648.1×	0.004	SARM1
nervous system process	1	601.9×	0.004	SARM1
lysosomal protein catabolic process	1	526.6×	0.004	VMA12
regulation of dendrite morphogenesis	1	366.4×	0.005	SARM1
regulation of neuron apoptotic process	1	351.1×	0.005	SARM1
lysosomal lumen acidification	1	337.0×	0.005	VMA12
response to axon injury	1	255.3×	0.006	SARM1
response to glucose	1	127.7×	0.010	SARM1
intracellular iron ion homeostasis	1	122.1×	0.010	VMA12
nervous system development	1	23.0×	0.051	SARM1
innate immune response	1	16.8×	0.066	SARM1
cell differentiation	1	14.6×	0.071	SARM1
signal transduction	1	8.0×	0.121	SARM1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
SARM1	NIACINAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SARM1	7	4
VMA12	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIACINAMIDE	4	SARM1
PHENAZOPYRIDINE HYDROCHLORIDE	4	SARM1
DEXLANSOPRAZOLE	4	SARM1
RABEPRAZOLE	4	SARM1
NITROFURAZONE	4	SARM1
TENATOPRAZOLE	2	SARM1
BERBERINE CHLORIDE	1	SARM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SARM1	25	Binding:25

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

7 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)
NIACINAMIDE	4	SARM1
PHENAZOPYRIDINE HYDROCHLORIDE	4	SARM1
DEXLANSOPRAZOLE	4	SARM1
RABEPRAZOLE	4	SARM1
NITROFURAZONE	4	SARM1
TENATOPRAZOLE	2	SARM1
BERBERINE CHLORIDE	1	SARM1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SARM1
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	VMA12

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)
VMA12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.