TMEM165-congenital disorder of glycosylation

Summary

TMEM165-congenital disorder of glycosylation (MONDO:0013870) is a disease caused by TMEM165 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TMEM165 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 145

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	TMEM165-congenital disorder of glycosylation
Mondo ID	MONDO:0013870
OMIM	614727
Orphanet	314667
DOID	DOID:0070263
SNOMED CT	732252005
UMLS	C3553571
MedGen	766485
GARD	0012413
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type IIk · CDG syndrome type IIk · CDG-IIk · CDG2K · congenital disorder of glycosylation type 2k · congenital disorder of glycosylation type IIk · congenital disorder of glycosylation, type IIk · TMEM165-CDG · TMEM165-CDG (CDG-IIk) · TMEM165-congenital disorder of glycosylation

Data availability: 145 ClinVar variants · 6 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 › TMEM165-congenital disorder of glycosylation

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, SLC39A8-CDG, CCDC115-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

145 retrieved; paginated sample, class counts are floors:

64 likely benign, 61 uncertain significance, 9 benign, 5 pathogenic, 4 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2426476	NC_000004.11:g.(?55124936)(57368027_?)del	KDR	Pathogenic	criteria provided, single submitter
2768393	NM_018475.5(TMEM165):c.747G>A (p.Trp249Ter)	TMEM165	Pathogenic	criteria provided, single submitter
35518	NM_018475.5(TMEM165):c.792+182G>A	TMEM165	Pathogenic	no assertion criteria provided
35519	NM_018475.5(TMEM165):c.377G>A (p.Arg126His)	TMEM165	Pathogenic	no assertion criteria provided
35521	NM_018475.5(TMEM165):c.910G>A (p.Gly304Arg)	TMEM165	Pathogenic	no assertion criteria provided
4845777	NM_018475.5(TMEM165):c.919del (p.Val307fs)	TMEM165	Likely pathogenic	criteria provided, single submitter
349065	NM_018475.5(TMEM165):c.433+15C>A	TMEM165	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
35520	NM_018475.5(TMEM165):c.376C>T (p.Arg126Cys)	TMEM165	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
380191	NM_018475.5(TMEM165):c.294C>T (p.Val98=)	TMEM165	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
905839	NM_018475.5(TMEM165):c.351A>G (p.Ala117=)	TMEM165	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1433363	NC_000004.11:g.(?55124936)(57798318_?)dup	HOPX	Uncertain significance	criteria provided, single submitter
1020581	NM_018475.5(TMEM165):c.207+3G>A	LOC129992613	Uncertain significance	criteria provided, single submitter
1401006	NM_018475.5(TMEM165):c.97G>A (p.Ala33Thr)	LOC129992613	Uncertain significance	criteria provided, single submitter
1422392	NM_018475.5(TMEM165):c.41C>T (p.Pro14Leu)	LOC129992613	Uncertain significance	criteria provided, single submitter
1480813	NM_018475.5(TMEM165):c.191A>G (p.Glu64Gly)	LOC129992613	Uncertain significance	criteria provided, single submitter
1715729	NM_018475.5(TMEM165):c.143C>T (p.Ala48Val)	LOC129992613	Uncertain significance	criteria provided, single submitter
1911342	NM_018475.5(TMEM165):c.163C>G (p.Pro55Ala)	LOC129992613	Uncertain significance	criteria provided, single submitter
2065208	NM_018475.5(TMEM165):c.17_18delinsGG (p.Pro6Arg)	LOC129992613	Uncertain significance	criteria provided, single submitter
2437109	NM_018475.5(TMEM165):c.196G>T (p.Ala66Ser)	LOC129992613	Uncertain significance	criteria provided, single submitter
3674595	NM_018475.5(TMEM165):c.170C>T (p.Pro57Leu)	LOC129992613	Uncertain significance	criteria provided, single submitter
976570	NM_018475.5(TMEM165):c.52C>A (p.Leu18Met)	LOC129992613	Uncertain significance	criteria provided, multiple submitters, no conflicts
976572	NM_018475.5(TMEM165):c.199C>T (p.Arg67Trp)	LOC129992613	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032804	NM_018475.5(TMEM165):c.40C>T (p.Pro14Ser)	TMEM165	Uncertain significance	criteria provided, multiple submitters, no conflicts
1060970	NM_018475.5(TMEM165):c.164C>A (p.Pro55Gln)	TMEM165	Uncertain significance	criteria provided, single submitter
1063540	NM_018475.5(TMEM165):c.952A>G (p.Ile318Val)	TMEM165	Uncertain significance	criteria provided, single submitter
1345250	NM_018475.5(TMEM165):c.690G>C (p.Leu230Phe)	TMEM165	Uncertain significance	criteria provided, single submitter
1349506	NM_018475.5(TMEM165):c.824T>C (p.Val275Ala)	TMEM165	Uncertain significance	criteria provided, multiple submitters, no conflicts
1374146	NM_018475.5(TMEM165):c.833G>A (p.Cys278Tyr)	TMEM165	Uncertain significance	criteria provided, single submitter
1384289	NM_018475.5(TMEM165):c.898+3A>G	TMEM165	Uncertain significance	criteria provided, single submitter
1398878	NM_018475.5(TMEM165):c.226G>C (p.Ala76Pro)	TMEM165	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TMEM165	Definitive	Autosomal recessive	TMEM165-congenital disorder of glycosylation	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM165	Orphanet:314667	TMEM165-CDG
KDR	Orphanet:3303	Tetralogy of Fallot

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM165	HGNC:30760	ENSG00000134851	Q9HC07	Putative divalent cation/proton antiporter TMEM165	gencc,clinvar
HOPX	HGNC:24961	ENSG00000171476	Q9BPY8	Homeodomain-only protein	clinvar
KDR	HGNC:6307	ENSG00000128052	P35968	Vascular endothelial growth factor receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM165	Putative divalent cation/proton antiporter TMEM165	Putative divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane.
HOPX	Homeodomain-only protein	Atypical homeodomain protein which does not bind DNA and is required to modulate cardiac growth and development.
KDR	Vascular endothelial growth factor receptor 2	Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM165	Other/Unknown	no		GDT1-like, GDT1-like_CS
HOPX	Transcription factor	no		HD, Homeodomain-like_sf, HOPX
KDR	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
corpus callosum	1
spinal cord	1
corpus epididymis	1
lower esophagus mucosa	1
upper leg skin	1
germinal epithelium of ovary	1
lower lobe of lung	1
parietal pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM165	282	ubiquitous	marker	corpus callosum, C1 segment of cervical spinal cord, spinal cord
HOPX	285	broad	marker	upper leg skin, corpus epididymis, lower esophagus mucosa
KDR	267	broad	marker	germinal epithelium of ovary, lower lobe of lung, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDR	4,960
HOPX	1,877
TMEM165	1,379

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KDR	P35968	54

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOPX	Q9BPY8	83.57
TMEM165	Q9HC07	76.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
Neuropilin interactions with VEGF and VEGFR	1	1427.5×	0.004	KDR
Signaling by membrane-tethered fusions of PDGFRA or PDGFRB	1	1142.0×	0.004	KDR
VEGF binds to VEGFR leading to receptor dimerization	1	634.4×	0.004	KDR
VEGFR2 mediated cell proliferation	1	285.5×	0.007	KDR
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	139.3×	0.011	HOPX
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.015	KDR
VEGFA-VEGFR2 Pathway	1	69.6×	0.015	KDR
Integrin cell surface interactions	1	67.2×	0.015	KDR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lung alveolus development	2	234.1×	0.002	HOPX, KDR
positive regulation of nitric oxide-cGMP mediated signal transduction	1	5617.3×	0.005	KDR
Golgi calcium ion homeostasis	1	2808.7×	0.005	TMEM165
Golgi calcium ion transport	1	2808.7×	0.005	TMEM165
positive regulation of skeletal muscle tissue regeneration	1	1872.4×	0.005	HOPX
manganese ion transmembrane transport	1	1872.4×	0.005	TMEM165
cellular response to hydrogen sulfide	1	1872.4×	0.005	KDR
bundle of His development	1	1404.3×	0.005	HOPX
post-embryonic camera-type eye morphogenesis	1	1404.3×	0.005	KDR
endocardium development	1	1123.5×	0.005	KDR
blood vessel endothelial cell differentiation	1	1123.5×	0.005	KDR
regulation of hematopoietic progenitor cell differentiation	1	1123.5×	0.005	KDR
regulation of bone development	1	1123.5×	0.005	KDR
vascular endothelial growth factor receptor-2 signaling pathway	1	936.2×	0.006	KDR
positive regulation of striated muscle cell differentiation	1	936.2×	0.006	HOPX
positive regulation of gap junction assembly	1	802.5×	0.006	HOPX
manganese ion transport	1	702.2×	0.006	TMEM165
obsolete regulation of lysosomal lumen pH	1	702.2×	0.006	TMEM165
lymph vessel development	1	624.1×	0.006	KDR
vascular wound healing	1	624.1×	0.006	KDR
positive regulation of mitochondrial depolarization	1	561.7×	0.007	KDR
epithelial cell maturation	1	510.7×	0.007	KDR
positive regulation of positive chemotaxis	1	468.1×	0.007	KDR
endothelium development	1	432.1×	0.007	KDR
positive regulation of vasculogenesis	1	432.1×	0.007	KDR
mesenchymal cell proliferation	1	374.5×	0.008	KDR
endothelial cell differentiation	1	374.5×	0.008	KDR
vascular endothelial growth factor signaling pathway	1	351.1×	0.008	KDR
trophectodermal cell differentiation	1	330.4×	0.008	HOPX
embryonic hemopoiesis	1	330.4×	0.008	KDR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
KDR	VANDETANIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDR	172	4
TMEM165	0	0
HOPX	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VANDETANIB	4	KDR
ERLOTINIB	4	KDR
INDIGOTINDISULFONATE	4	KDR
PONATINIB	4	KDR
SORAFENIB TOSYLATE	4	KDR
PHENYL AMINOSALICYLATE	4	KDR
VEMURAFENIB	4	KDR
FEDRATINIB	4	KDR
TIVOZANIB	4	KDR
LENVATINIB	4	KDR
AXITINIB	4	KDR
SORAFENIB	4	KDR
PIPERAZINE	4	KDR
NICLOSAMIDE	4	KDR
GLAFENINE	4	KDR
SUNITINIB MALATE	4	KDR
AUROTHIOGLUCOSE	4	KDR
ALECTINIB	4	KDR
ESTRAMUSTINE PHOSPHATE	4	KDR
NERATINIB	4	KDR
INFIGRATINIB PHOSPHATE	4	KDR
INFIGRATINIB	4	KDR
IBRUTINIB	4	KDR
REGORAFENIB	4	KDR
ENTRECTINIB	4	KDR
STIRIPENTOL	4	KDR
CABOZANTINIB S-MALATE	4	KDR
QUIZARTINIB DIHYDROCHLORIDE	4	KDR
CABOZANTINIB	4	KDR
TOFACITINIB	4	KDR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KDR	2,687	Binding:2594, Functional:64, ADMET:27, Toxicity:2
TMEM165	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDR	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KDR	2,687

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
VANDETANIB	4	KDR
ERLOTINIB	4	KDR
INDIGOTINDISULFONATE	4	KDR
PONATINIB	4	KDR
SORAFENIB TOSYLATE	4	KDR
PHENYL AMINOSALICYLATE	4	KDR
VEMURAFENIB	4	KDR
FEDRATINIB	4	KDR
TIVOZANIB	4	KDR
LENVATINIB	4	KDR
AXITINIB	4	KDR
SORAFENIB	4	KDR
PIPERAZINE	4	KDR
NICLOSAMIDE	4	KDR
GLAFENINE	4	KDR
SUNITINIB MALATE	4	KDR
AUROTHIOGLUCOSE	4	KDR
ALECTINIB	4	KDR
ESTRAMUSTINE PHOSPHATE	4	KDR
NERATINIB	4	KDR
INFIGRATINIB PHOSPHATE	4	KDR
INFIGRATINIB	4	KDR
IBRUTINIB	4	KDR
REGORAFENIB	4	KDR
ENTRECTINIB	4	KDR
STIRIPENTOL	4	KDR
CABOZANTINIB S-MALATE	4	KDR
QUIZARTINIB DIHYDROCHLORIDE	4	KDR
CABOZANTINIB	4	KDR
TOFACITINIB	4	KDR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDR
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	2	TMEM165, HOPX

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)
TMEM165	1	—
HOPX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.