SSR4-congenital disorder of glycosylation

Summary

SSR4-congenital disorder of glycosylation (MONDO:0010490) is a disease caused by SSR4 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SSR4 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 22
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Obligate (100%)
HP:0001249	Intellectual disability	Obligate (100%)
HP:0001263	Global developmental delay	Obligate (100%)
HP:0001290	Generalized hypotonia	Obligate (100%)
HP:0001999	Abnormal facial shape	Obligate (100%)
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000400	Macrotia	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000687	Widely spaced teeth	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0002013	Vomiting	Very frequent (80-99%)
HP:0002020	Gastroesophageal reflux	Very frequent (80-99%)
HP:0011024	Abnormality of the gastrointestinal tract	Very frequent (80-99%)
HP:0011339	Abnormality of upper lip vermillion	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0000085	Horseshoe kidney	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0001331	Absent septum pellucidum	Occasional (5-29%)
HP:0001373	Joint dislocation	Occasional (5-29%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0001928	Abnormality of coagulation	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003256	Abnormality of the coagulation cascade	Very rare (<1-4%)
HP:0001643	Patent ductus arteriosus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	SSR4-congenital disorder of glycosylation
Mondo ID	MONDO:0010490
OMIM	300934
Orphanet	370927
DOID	DOID:0080574
SNOMED CT	733115009
UMLS	C4012395
MedGen	860832
GARD	0012405
Is cancer (heuristic)	no

Also known as: carbohydrate deficient glycoprotein syndrome type Iy · CDG Iy · CDG syndrome type Iy · CDG-Iy · CDG1Y · CDGIy · congenital disorder of glycosylation type 1y · congenital disorder of glycosylation type Iy · congenital disorder of glycosylation, type Iy · congenital disorder of glycosylation, type Iy, X-linked recessive · SSR4-CDG · SSR4-congenital disorder of glycosylation

Data availability: 22 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 › SSR4-congenital disorder of glycosylation

Related subtypes (27): PMM2-congenital disorder of glycosylation, developmental and epileptic encephalopathy, 36, 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, RFT1-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

22 retrieved; paginated sample, class counts are floors:

13 pathogenic, 4 likely pathogenic, 4 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1810417	Multiple alleles		Pathogenic	no assertion criteria provided
987741	Single allele	IDH3G	Pathogenic	no assertion criteria provided
1164036	NM_006280.3(SSR4):c.261+2_261+8del	SSR4	Pathogenic	no assertion criteria provided
1333191	NM_006280.3(SSR4):c.269G>A (p.Trp90Ter)	SSR4	Pathogenic	no assertion criteria provided
209110	NM_006280.3(SSR4):c.317del (p.Phe106fs)	SSR4	Pathogenic	no assertion criteria provided
2441661	NM_006280.3(SSR4):c.270G>A (p.Trp90Ter)	SSR4	Pathogenic	criteria provided, single submitter
3392483	NM_006280.3(SSR4):c.68-2A>G	SSR4	Pathogenic	criteria provided, single submitter
372143	NM_006280.3(SSR4):c.187-301_352-15del	SSR4	Pathogenic	no assertion criteria provided
372146	NM_006280.3(SSR4):c.418-1G>A	SSR4	Pathogenic	no assertion criteria provided
4759492	NM_006280.3(SSR4):c.68-322_262-46del	SSR4	Pathogenic	no assertion criteria provided
976747	NM_006280.3(SSR4):c.141dup (p.Val48fs)	SSR4	Pathogenic	criteria provided, single submitter
984389	NM_006280.3(SSR4):c.241C>T (p.Gln81Ter)	SSR4	Pathogenic	no assertion criteria provided
986726	NM_001204526.1:c.1_185del	SSR4	Pathogenic	no assertion criteria provided
1308630	NM_006280.3(SSR4):c.418-2A>G	SSR4	Likely pathogenic	criteria provided, single submitter
2572630	NM_006280.3(SSR4):c.235C>T (p.Arg79Ter)	SSR4	Likely pathogenic	criteria provided, single submitter
372144	NM_006280.3(SSR4):c.358_359del (p.Arg120fs)	SSR4	Likely pathogenic	criteria provided, single submitter
4292876	NM_006280.3(SSR4):c.98del (p.Pro33fs)	SSR4	Likely pathogenic	criteria provided, single submitter
372145	NM_006280.3(SSR4):c.417+1G>A	SSR4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1696447	NM_006280.3(SSR4):c.194C>T (p.Ala65Val)	SSR4	Uncertain significance	criteria provided, single submitter
1805820	NM_006280.3(SSR4):c.482A>G (p.Tyr161Cys)	SSR4	Uncertain significance	criteria provided, single submitter
1806350	NM_006280.3(SSR4):c.429C>A (p.Asn143Lys)	SSR4	Uncertain significance	criteria provided, single submitter
3234963	NM_006280.3(SSR4):c.262-3C>G	SSR4	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
SSR4	Strong	X-linked	SSR4-congenital disorder of glycosylation	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SSR4	Orphanet:370927	SSR4-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
SSR4	HGNC:11326	ENSG00000180879	P51571	Translocon-associated protein subunit delta	gencc,clinvar
IDH3G	HGNC:5386	ENSG00000067829	P51553	Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SSR4	Translocon-associated protein subunit delta	TRAP proteins are part of a complex whose function is to bind calcium to the ER membrane and thereby regulate the retention of ER resident proteins.
IDH3G	Isocitrate dehydrogenase [NAD] subunit gamma, mitochondrial	Regulatory subunit which plays a role in the allosteric regulation of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate.

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)
SSR4	Other/Unknown	no		TRAP-delta
IDH3G	Enzyme (other)	yes	1.1.1.41	Isocitrate_DH_NAD, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom

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
adenohypophysis	1
body of pancreas	1
pituitary gland	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SSR4	295	ubiquitous	marker	pituitary gland, adenohypophysis, body of pancreas
IDH3G	299	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IDH3G	2,794
SSR4	1,891

Intra-cohort edges

A	B	Sources
IDH3G	SSR4	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IDH3G	P51553	12
SSR4	P51571	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Citric acid cycle (TCA cycle)	1	211.5×	0.024	IDH3G
Mitochondrial protein import	1	84.0×	0.030	IDH3G
SRP-dependent cotranslational protein targeting to membrane	1	50.1×	0.033	SSR4
Translation	1	31.0×	0.040	SSR4
Metabolism of proteins	1	6.2×	0.155	SSR4

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
isocitrate metabolic process	1	3370.4×	9e-04	IDH3G
tricarboxylic acid cycle	1	510.7×	0.003	IDH3G
carbohydrate metabolic process	1	135.9×	0.007	IDH3G

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
SSR4	0	0
IDH3G	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
SSR4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IDH3G	1.1.1.41	isocitrate dehydrogenase (NAD+)

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	1	IDH3G
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SSR4

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)
SSR4	2	—
IDH3G	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.