Iminoglycinuria

Summary

Iminoglycinuria (MONDO:0009448) is a disease with 4 cohort genes. The dominant Reactome pathway is Amino acid transport across the plasma membrane (4 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Europe)
• Cohort genes: 4
• ClinVar variants: 87
• Phenotypes (HPO): 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	6.68	Europe	Not yet validated
Prevalence at birth	1-9 / 100 000	6.67	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0003080	Hydroxyprolinuria	Obligate (100%)
HP:0003108	Hyperglycinuria	Obligate (100%)
HP:0003137	Prolinuria	Obligate (100%)
HP:0002154	Hyperglycinemia	Excluded (0%)
HP:0003260	Hydroxyprolinemia	Excluded (0%)
HP:0008358	Hyperprolinemia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	iminoglycinuria
Mondo ID	MONDO:0009448
MeSH	C536285
OMIM	242600
Orphanet	42062
DOID	DOID:0112265
ICD-11	664428532
SNOMED CT	84121007
UMLS	C0268654
MedGen	124342
GARD	0008424
Is cancer (heuristic)	no

Also known as: iminoglycinuria · iminoglycinuria, digenic

Data availability: 87 ClinVar variants · 3 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 › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of amino acid transport › iminoglycinuria

Related subtypes (18): blue diaper syndrome, ocular cystinosis, juvenile nephropathic cystinosis, cystinuria, hyperdibasic aminoaciduria type 1, lysinuric protein intolerance, dicarboxylic aminoaciduria, Hartnup disease, histidinuria due to a renal tubular defect, oculocerebrorenal syndrome, hypotonia-cystinuria syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, episodic ataxia type 6, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, disorder of neutral amino acid transport, autosomal recessive cerebellar ataxia - pyramidal signs - nystagmus - oculomotor apraxia syndrome, nephropathic infantile cystinosis, undetermined early-onset epileptic encephalopathy

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

87 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 23 likely benign, 18 benign/likely benign, 4 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2019	NM_001003841.3(SLC6A19):c.517G>A (p.Asp173Asn)	SLC6A19	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020	NM_001003841.3(SLC6A19):c.718C>T (p.Arg240Ter)	SLC6A19	Pathogenic	criteria provided, multiple submitters, no conflicts
917714	NM_001003841.3(SLC6A19):c.532C>T (p.Arg178Ter)	SLC6A19	Pathogenic	criteria provided, multiple submitters, no conflicts
1174952	NM_001003841.3(SLC6A19):c.774+1G>A	SLC6A19	Likely pathogenic	criteria provided, single submitter
2052777	NM_181776.3(SLC36A2):c.146AGA[1] (p.Lys50del)	SLC36A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2384	NM_181776.3(SLC36A2):c.260G>T (p.Gly87Val)	SLC36A2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
345394	NM_020208.4(SLC6A20):c.1742G>A (p.Arg581His)	SLC6A20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900867	NM_020208.4(SLC6A20):c.678C>T (p.Tyr226=)	SLC6A20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2385	NM_181776.3(SLC36A2):c.164+1G>A	SLC36A1	Uncertain significance	criteria provided, single submitter
3892479	NM_181776.3(SLC36A2):c.1237G>A (p.Val413Met)	SLC36A2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892480	NM_181776.3(SLC36A2):c.25G>A (p.Gly9Ser)	SLC36A2	Uncertain significance	criteria provided, single submitter
1050258	NM_001003841.3(SLC6A19):c.887+9G>A	SLC6A19	Uncertain significance	criteria provided, single submitter
1348032	NM_001003841.3(SLC6A19):c.697G>A (p.Val233Ile)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1358021	NM_001003841.3(SLC6A19):c.292C>T (p.Arg98Trp)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1371534	NM_001003841.3(SLC6A19):c.767C>T (p.Thr256Met)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1375099	NM_001003841.3(SLC6A19):c.1522G>A (p.Val508Met)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1380307	NM_001003841.3(SLC6A19):c.293G>A (p.Arg98Gln)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1406147	NM_001003841.3(SLC6A19):c.1003G>A (p.Asp335Asn)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1418017	NM_001003841.3(SLC6A19):c.640C>G (p.Arg214Gly)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1474965	NM_001003841.3(SLC6A19):c.125T>C (p.Met42Thr)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1481259	NM_001003841.3(SLC6A19):c.1451T>C (p.Leu484Pro)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1482946	NM_001003841.3(SLC6A19):c.683C>T (p.Thr228Met)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1484107	NM_001003841.3(SLC6A19):c.502A>G (p.Arg168Gly)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1512858	NM_001003841.3(SLC6A19):c.1325C>A (p.Pro442His)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1513911	NM_001003841.3(SLC6A19):c.1244T>C (p.Leu415Pro)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1517264	NM_001003841.3(SLC6A19):c.98C>T (p.Pro33Leu)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
931106	NM_001003841.3(SLC6A19):c.1468G>A (p.Gly490Ser)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
973458	NM_001003841.3(SLC6A19):c.1603C>T (p.Arg535Cys)	SLC6A19	Uncertain significance	criteria provided, multiple submitters, no conflicts
973486	NM_001003841.3(SLC6A19):c.712C>T (p.Leu238Phe)	SLC6A19	Uncertain significance	criteria provided, single submitter
1049972	NM_020208.4(SLC6A20):c.1A>G (p.Met1Val)	SLC6A20	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
SLC36A2	Supportive	Autosomal recessive	iminoglycinuria	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC36A2	Orphanet:42062	Iminoglycinuria
SLC6A19	Orphanet:2116	Hartnup disease
SLC6A19	Orphanet:42062	Iminoglycinuria
SLC6A20	Orphanet:42062	Iminoglycinuria

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC36A2	HGNC:18762	ENSG00000186335	Q495M3	Proton-coupled amino acid transporter 2	gencc,clinvar
SLC36A1	HGNC:18761	ENSG00000123643	Q7Z2H8	Proton-coupled amino acid transporter 1	clinvar
SLC6A19	HGNC:27960	ENSG00000174358	Q695T7	Sodium-dependent neutral amino acid transporter B(0)AT1	clinvar
SLC6A20	HGNC:30927	ENSG00000163817	Q9NP91	Sodium- and chloride-dependent transporter XTRP3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC36A2	Proton-coupled amino acid transporter 2	Electrogenic proton/amino acid symporter with a high selectivity for the small side chains amino acids glycine, alanine and proline, where both L- and D-enantiomers are transported.
SLC36A1	Proton-coupled amino acid transporter 1	Electrogenic proton/amino acid symporter with selectivity for small apolar L-amino acids, their D-enantiomers and selected amino acid derivatives such as 4-aminobutanoate/GABA.
SLC6A19	Sodium-dependent neutral amino acid transporter B(0)AT1	Transporter that mediates resorption of neutral amino acids across the apical membrane of renal and intestinal epithelial cells.
SLC6A20	Sodium- and chloride-dependent transporter XTRP3	Mediates the Na(+)- and Cl(-)-dependent uptake of imino acids such as L-proline, N-methyl-L-proline and pipecolate as well as N-methylated amino acids.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC36A2	Other/Unknown	no		AA_transpt_TM
SLC36A1	Other/Unknown	no		AA_transpt_TM
SLC6A19	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
SLC6A20	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	2
jejunal mucosa	2
gastrocnemius	1
quadriceps femoris	1
skeletal muscle tissue	1
right hemisphere of cerebellum	1
ileal mucosa	1
kidney epithelium	1
choroid plexus epithelium	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC36A2	72	tissue_specific	marker	quadriceps femoris, skeletal muscle tissue, gastrocnemius
SLC36A1	247	ubiquitous	marker	jejunal mucosa, duodenum, right hemisphere of cerebellum
SLC6A19	67	tissue_specific	marker	ileal mucosa, kidney epithelium, jejunal mucosa
SLC6A20	172	tissue_specific	marker	pigmented layer of retina, choroid plexus epithelium, duodenum

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC36A1	1,218
SLC6A19	975
SLC6A20	955
SLC36A2	888

Intra-cohort edges

A	B	Sources
SLC36A1	SLC6A20	string_interaction
SLC36A2	SLC6A19	string_interaction
SLC36A2	SLC6A20	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC6A19	Q695T7	21
SLC6A20	Q9NP91	10

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC36A1	Q7Z2H8	84.95
SLC36A2	Q495M3	84.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Amino acid transport across the plasma membrane	4	300.5×	2e-09	SLC36A2, SLC36A1, SLC6A19, SLC6A20
R-HSA-425393	4	129.8×	2e-08	SLC36A2, SLC36A1, SLC6A19, SLC6A20
Proton-coupled neutral amino acid transporters	2	2855.0×	3e-07	SLC36A2, SLC36A1
SLC-mediated transmembrane transport	4	59.2×	3e-07	SLC36A2, SLC36A1, SLC6A19, SLC6A20
SLC transporter disorders	3	152.9×	1e-06	SLC36A2, SLC6A19, SLC6A20
Disorders of transmembrane transporters	3	104.5×	4e-06	SLC36A2, SLC6A19, SLC6A20
Transport of small molecules	4	25.1×	5e-06	SLC36A2, SLC36A1, SLC6A19, SLC6A20
SLC-mediated transport of neurotransmitters	2	203.9×	7e-05	SLC6A19, SLC6A20
R-HSA-425366	2	90.6×	3e-04	SLC6A19, SLC6A20
Defective SLC36A2 causes iminoglycinuria (IG) and hyperglycinuria (HG)	1	2855.0×	4e-04	SLC36A2
Defective transport of neurotransmitters by SLC6A19 causes Hartnup disorder (HND)	1	2855.0×	4e-04	SLC6A19
Defective transport of amino acids by SLC6A19 causes Hartnup disorder (HND)	1	2855.0×	4e-04	SLC6A19
Variant SLC6A20 affecting neurotransmitter transport contributes towards hyperglycinuria (HG) and iminoglycinuria (IG)	1	1427.5×	8e-04	SLC6A20
Variant SLC6A20 affecting amino acid transport contributes towards hyperglycinuria (HG) and iminoglycinuria (IG)	1	1427.5×	8e-04	SLC6A20
Disease	3	9.8×	0.002	SLC36A2, SLC6A19, SLC6A20

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
amino acid transport	4	312.1×	2e-09	SLC36A2, SLC36A1, SLC6A19, SLC6A20
glycine transport	3	1053.2×	1e-08	SLC36A2, SLC36A1, SLC6A20
proline transport	3	972.2×	1e-08	SLC36A2, SLC36A1, SLC6A20
proline transmembrane transport	2	1685.2×	2e-06	SLC36A2, SLC36A1
L-alanine transport	2	1203.7×	4e-06	SLC36A2, SLC36A1
amino acid import across plasma membrane	2	526.6×	2e-05	SLC36A1, SLC6A20
proton transmembrane transport	2	156.0×	2e-04	SLC36A2, SLC36A1
sodium ion transmembrane transport	2	101.5×	4e-04	SLC6A19, SLC6A20
monoatomic ion transport	2	78.0×	5e-04	SLC36A2, SLC36A1
amino-acid betaine transport	1	2106.5×	8e-04	SLC6A20
L-isoleucine import across plasma membrane	1	2106.5×	8e-04	SLC6A20
proline import across plasma membrane	1	2106.5×	8e-04	SLC6A20
viral life cycle	1	1053.2×	0.001	SLC6A19
L-proline import across plasma membrane	1	842.6×	0.002	SLC6A20
taurine transmembrane transport	1	702.2×	0.002	SLC36A1
alanine transport	1	601.9×	0.002	SLC36A1
glycine import across plasma membrane	1	601.9×	0.002	SLC6A20
neutral amino acid transport	1	221.7×	0.005	SLC6A19
response to nutrient	1	73.9×	0.014	SLC6A19
transport across blood-brain barrier	1	44.8×	0.022	SLC6A20

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
SLC6A19	1	2
SLC36A2	0	0
SLC36A1	0	0
SLC6A20	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CINROMIDE	2	SLC6A19

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC6A19	4	Functional:3, Binding:1
SLC36A1	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
CINROMIDE	2	SLC6A19

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	1	SLC6A19
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SLC36A2, SLC36A1, SLC6A20

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC36A2	0	SLC6A19
SLC36A1	3	—
SLC6A20	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.