RFT1-congenital disorder of glycosylation

Summary

RFT1-congenital disorder of glycosylation (MONDO:0012783) is a disease caused by RFT1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RFT1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 524
• Phenotypes (HPO): 22

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

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Obligate (100%)
HP:0001252	Hypotonia	Obligate (100%)
HP:0001263	Global developmental delay	Obligate (100%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0002804	Arthrogryposis multiplex congenita	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0001928	Abnormality of coagulation	Frequent (30-79%)
HP:0001977	Abnormal thrombosis	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0003186	Inverted nipples	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000932	Abnormality of the posterior cranial fossa	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002401	Stroke-like episode	Occasional (5-29%)
HP:0007146	Bilateral basal ganglia lesions	Occasional (5-29%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	RFT1-congenital disorder of glycosylation
Mondo ID	MONDO:0012783
MeSH	C567437
OMIM	612015
Orphanet	244310
DOID	DOID:0080566
SNOMED CT	733084000
UMLS	C2677590
MedGen	383145
GARD	0012394
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type In · CDG syndrome type In · CDG-In · CDG1N · CDGIN · congenital disorder of glycosylation type 1n · congenital disorder of glycosylation type In · congenital disorder of glycosylation, type In · Man5GlcNAc2-PP-Dol flippase deficiency · RFT1-CDG · RFT1-CDG (CDG-In) · RFT1-congenital disorder of glycosylation

Data availability: 524 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 I › RFT1-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, ALG9-congenital disorder of glycosylation, congenital disorder of glycosylation type 1E, MPDU1-congenital disorder of glycosylation, DK1-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

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

524 retrieved; paginated sample, class counts are floors:

257 uncertain significance, 201 likely benign, 24 benign, 23 conflicting classifications of pathogenicity, 8 likely pathogenic, 5 pathogenic, 4 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
207986	NM_052859.4(RFT1):c.454A>G (p.Lys152Glu)	RFT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207987	NM_052859.4(RFT1):c.892G>A (p.Glu298Lys)	RFT1	Pathogenic	no assertion criteria provided
207988	NM_052859.4(RFT1):c.887T>A (p.Ile296Lys)	RFT1	Pathogenic	no assertion criteria provided
207989	NM_052859.4(RFT1):c.887T>G (p.Ile296Arg)	RFT1	Pathogenic	no assertion criteria provided
207990	NM_052859.4(RFT1):c.1222A>G (p.Met408Val)	RFT1	Pathogenic	no assertion criteria provided
785	NM_052859.4(RFT1):c.199C>T (p.Arg67Cys)	RFT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807671	NM_052859.4(RFT1):c.775G>A (p.Gly259Ser)	RFT1	Pathogenic	criteria provided, single submitter
1350291	NM_052859.4(RFT1):c.1195G>T (p.Glu399Ter)	RFT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
207991	NM_052859.4(RFT1):c.1325G>A (p.Arg442Gln)	RFT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572513	NM_052859.4(RFT1):c.229C>T (p.Arg77Ter)	RFT1	Likely pathogenic	criteria provided, single submitter
3254892	NM_052859.4(RFT1):c.1208+1G>T	RFT1	Likely pathogenic	criteria provided, single submitter
3393040	NM_052859.4(RFT1):c.306G>A (p.Trp102Ter)	RFT1	Likely pathogenic	criteria provided, single submitter
3572861	NM_052859.4(RFT1):c.775+1G>C	RFT1	Likely pathogenic	no assertion criteria provided
495320	NM_052859.4(RFT1):c.902A>G (p.Tyr301Cys)	RFT1	Likely pathogenic	criteria provided, single submitter
931309	NM_052859.4(RFT1):c.740dup (p.Lys248fs)	RFT1	Likely pathogenic	criteria provided, single submitter
725196	NM_052859.4(RFT1):c.23G>A (p.Gly8Asp)	LOC129936883	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195396	NM_052859.4(RFT1):c.136G>A (p.Val46Ile)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2144279	NM_052859.4(RFT1):c.208T>C (p.Cys70Arg)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2582408	NM_052859.4(RFT1):c.1154A>G (p.Asn385Ser)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346189	NM_052859.4(RFT1):c.831G>A (p.Val277=)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346190	NM_052859.4(RFT1):c.827-14T>C	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346198	NM_052859.4(RFT1):c.303C>G (p.Gly101=)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
346201	NM_052859.4(RFT1):c.47C>G (p.Ser16Cys)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372948	NM_052859.4(RFT1):c.200G>A (p.Arg67His)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
380593	NM_052859.4(RFT1):c.826+7T>C	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4629118	NM_052859.4(RFT1):c.1397A>G (p.His466Arg)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
524109	NM_052859.4(RFT1):c.1198del (p.Glu400fs)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
697945	NM_052859.4(RFT1):c.5G>A (p.Gly2Asp)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
715287	NM_052859.4(RFT1):c.821A>G (p.Asp274Gly)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
719646	NM_052859.4(RFT1):c.1356C>T (p.Arg452=)	RFT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
RFT1	Strong	Autosomal recessive	RFT1-congenital disorder of glycosylation	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RFT1	Orphanet:244310	RFT1-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
RFT1	HGNC:30220	ENSG00000163933	Q96AA3	Man(5)GlcNAc(2)-PP-dolichol translocation protein RFT1	gencc,clinvar
PPM1M	HGNC:26506	ENSG00000164088	Q96MI6	Protein phosphatase 1M	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RFT1	Man(5)GlcNAc(2)-PP-dolichol translocation protein RFT1	Intramembrane glycolipid transporter that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RFT1	Other/Unknown	no		RFT1
PPM1M	Phosphatase	yes		PPM-type_phosphatase-like_dom, PP2C, PPM-type-like_dom_sf

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
body of pancreas	1
islet of Langerhans	1
primordial germ cell in gonad	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RFT1	205	ubiquitous	marker	primordial germ cell in gonad, body of pancreas, islet of Langerhans
PPM1M	212	ubiquitous	marker	granulocyte, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RFT1	685
PPM1M	539

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RFT1	Q96AA3	90.46
PPM1M	Q96MI6	86.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Defective RFT1 causes CDG-1n	1	11420.0×	2e-04	RFT1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.005	RFT1

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
glycolipid translocation	1	8426.0×	5e-04	RFT1
dolichol-linked oligosaccharide biosynthetic process	1	421.3×	0.005	RFT1
protein N-linked glycosylation	1	131.7×	0.009	RFT1
protein dephosphorylation	1	110.9×	0.009	PPM1M

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
RFT1	0	0
PPM1M	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RFT1	1	Binding:1

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	PPM1M
E	Difficult family or no structure, no drug	1	RFT1

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)
RFT1	1	—
PPM1M	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.