Atypical glycine encephalopathy

Summary

Atypical glycine encephalopathy (MONDO:0015010) is a disease caused by SLC6A9 (GenCC Strong), with 4 cohort genes. The dominant Reactome pathway is Glycine degradation (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC6A9 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 283

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical glycine encephalopathy
Mondo ID	MONDO:0015010
OMIM	617301
Orphanet	289863
ICD-11	51420481
UMLS	C4310943
MedGen	934910
GARD	0017334
Is cancer (heuristic)	no

Also known as: atypical NKA · atypical non-ketotic hyperglycinemia

Data availability: 283 ClinVar variants · 7 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 › glycine encephalopathy › atypical glycine encephalopathy

Related subtypes (5): neonatal glycine encephalopathy, infantile glycine encephalopathy, multiple mitochondrial dysfunctions syndrome 7, glycine encephalopathy 1, glycine encephalopathy 2

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

283 retrieved; paginated sample, class counts are floors:

155 likely benign, 94 uncertain significance, 16 benign, 6 pathogenic, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2581302	NM_001024845.3(SLC6A9):c.31-764_31-763del	SLC6A9	Pathogenic	criteria provided, single submitter
3659467	NM_001024845.3(SLC6A9):c.941dup (p.Phe315fs)	SLC6A9	Pathogenic	criteria provided, single submitter
374986	NM_001024845.3(SLC6A9):c.1000A>G (p.Ser334Gly)	SLC6A9	Pathogenic	no assertion criteria provided
374987	NM_001024845.3(SLC6A9):c.1498C>T (p.Gln500Ter)	SLC6A9	Pathogenic	no assertion criteria provided
374988	NM_001024845.3(SLC6A9):c.709_713del (p.Lys237fs)	SLC6A9	Pathogenic	no assertion criteria provided
4536025	NM_001024845.3(SLC6A9):c.31-6242G>T	SLC6A9	Pathogenic	criteria provided, single submitter
568191	NM_001024845.3(SLC6A9):c.832C>T (p.Gln278Ter)	SLC6A9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1236206	NM_001024845.3(SLC6A9):c.235C>T (p.Pro79Ser)	SLC6A9	Likely pathogenic	criteria provided, single submitter
1472818	NM_001024845.3(SLC6A9):c.31-6164G>C	SLC6A9	Likely pathogenic	criteria provided, single submitter
2573356	NM_001024845.3(SLC6A9):c.1536+1G>A	SLC6A9	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4697810	NM_001024845.3(SLC6A9):c.31-678G>A	SLC6A9	Likely pathogenic	criteria provided, single submitter
4849494	NM_001024845.3(SLC6A9):c.671C>T (p.Ser224Phe)	SLC6A9	Likely pathogenic	criteria provided, single submitter
1373596	NM_001024845.3(SLC6A9):c.31-6217G>A	SLC6A9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2436072	NM_001024845.3(SLC6A9):c.737C>T (p.Thr246Met)	SLC6A9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
733055	NM_001024845.3(SLC6A9):c.1721C>T (p.Ala574Val)	SLC6A9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
848719	NM_001024845.3(SLC6A9):c.461A>G (p.His154Arg)	SLC6A9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007399	NM_001024845.3(SLC6A9):c.1602C>T (p.Gly534=)	SLC6A9	Uncertain significance	criteria provided, single submitter
1011843	NM_001024845.3(SLC6A9):c.1435G>A (p.Gly479Arg)	SLC6A9	Uncertain significance	criteria provided, single submitter
1015814	NM_001024845.3(SLC6A9):c.1381T>G (p.Phe461Val)	SLC6A9	Uncertain significance	criteria provided, single submitter
1031818	NM_001024845.3(SLC6A9):c.962G>A (p.Arg321Gln)	SLC6A9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031819	NM_001024845.3(SLC6A9):c.31-6241del	SLC6A9	Uncertain significance	criteria provided, single submitter
1031820	NM_001024845.3(SLC6A9):c.407C>T (p.Ser136Leu)	SLC6A9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1352668	NM_001024845.3(SLC6A9):c.490A>C (p.Asn164His)	SLC6A9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1353549	NM_001024845.3(SLC6A9):c.1424T>C (p.Met475Thr)	SLC6A9	Uncertain significance	criteria provided, single submitter
1358489	NM_001024845.3(SLC6A9):c.31-731A>C	SLC6A9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1359347	NM_001024845.3(SLC6A9):c.1835C>T (p.Pro612Leu)	SLC6A9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368935	NM_001024845.3(SLC6A9):c.1780G>A (p.Ala594Thr)	SLC6A9	Uncertain significance	criteria provided, single submitter
1369503	NM_001024845.3(SLC6A9):c.1441C>T (p.Arg481Trp)	SLC6A9	Uncertain significance	criteria provided, single submitter
1374839	NM_001024845.3(SLC6A9):c.229G>A (p.Gly77Arg)	SLC6A9	Uncertain significance	criteria provided, multiple submitters, no conflicts
1376186	NM_001024845.3(SLC6A9):c.508C>G (p.Arg170Gly)	SLC6A9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 29 · Orphanet: 11 · 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
AMT	Definitive	Autosomal recessive	glycine encephalopathy	8
GLDC	Definitive	Autosomal recessive	glycine encephalopathy	8
SLC6A9	Strong	Autosomal recessive	atypical glycine encephalopathy	5
GCSH	Supportive	Autosomal recessive	neonatal glycine encephalopathy	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC6A9	Orphanet:289860	Infantile glycine encephalopathy
SLC6A9	Orphanet:289863	Atypical glycine encephalopathy
GCSH	Orphanet:289857	Neonatal glycine encephalopathy
GCSH	Orphanet:289860	Infantile glycine encephalopathy
GCSH	Orphanet:289863	Atypical glycine encephalopathy
GLDC	Orphanet:289857	Neonatal glycine encephalopathy
GLDC	Orphanet:289860	Infantile glycine encephalopathy
GLDC	Orphanet:289863	Atypical glycine encephalopathy
AMT	Orphanet:289857	Neonatal glycine encephalopathy
AMT	Orphanet:289860	Infantile glycine encephalopathy
AMT	Orphanet:289863	Atypical glycine encephalopathy

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
SLC6A9	HGNC:11056	ENSG00000196517	P48067	Sodium- and chloride-dependent glycine transporter 1	gencc,clinvar
GCSH	HGNC:4208	ENSG00000140905	P23434	Glycine cleavage system H protein, mitochondrial	gencc
GLDC	HGNC:4313	ENSG00000178445	P23378	Glycine dehydrogenase (decarboxylating), mitochondrial	gencc
AMT	HGNC:473	ENSG00000145020	P48728	Aminomethyltransferase, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A9	Sodium- and chloride-dependent glycine transporter 1	Sodium- and chloride-dependent glycine transporter.
GCSH	Glycine cleavage system H protein, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
GLDC	Glycine dehydrogenase (decarboxylating), mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
AMT	Aminomethyltransferase, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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)	3	9.0×	0.004
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A9	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_glycine_GLY1, SNS_sf
GCSH	Enzyme (other)	yes	1.4.1.27	Biotin_lipoyl, GCV_H, 2-oxoA_DH_lipoyl-BS
GLDC	Enzyme (other)	yes	1.4.1.27	ArAA_b-elim_lyase/Thr_aldolase, GcvP, PyrdxlP-dep_Trfase_major
AMT	Enzyme (other)	yes	1.4.1.27	GCVT_N, GcvT, GcvT_C

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	2
liver	2
right lobe of liver	2
skin of leg	1
spinal cord	1
amygdala	1
substantia nigra	1
nephron tubule	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A9	180	ubiquitous	marker	C1 segment of cervical spinal cord, spinal cord, skin of leg
GCSH	134	ubiquitous	marker	C1 segment of cervical spinal cord, substantia nigra, amygdala
GLDC	216	broad	marker	right lobe of liver, liver, nephron tubule
AMT	140	broad	yes	right lobe of liver, liver, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLDC	2,559
GCSH	2,079
AMT	1,716
SLC6A9	1,061

Intra-cohort edges

A	B	Sources
AMT	GCSH	string_interaction
AMT	GLDC	string_interaction
GCSH	GLDC	intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC6A9	P48067	9
GCSH	P23434	3
GLDC	P23378	3
AMT	P48728	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Glycine degradation	3	1223.6×	3e-09	GCSH, GLDC, AMT
Protein lipoylation	1	259.6×	0.012	GCSH
SLC-mediated transport of neurotransmitters	1	102.0×	0.020	SLC6A9
R-HSA-425366	1	45.3×	0.033	SLC6A9
SLC-mediated transmembrane transport	1	14.8×	0.079	SLC6A9
Transport of small molecules	1	6.3×	0.150	SLC6A9

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
glycine decarboxylation via glycine cleavage system	3	4213.0×	7e-11	GCSH, GLDC, AMT
glycine catabolic process	2	4213.0×	3e-07	GLDC, AMT
response to methylamine	1	4213.0×	7e-04	GLDC
regulation of synaptic transmission, glycinergic	1	4213.0×	7e-04	SLC6A9
glycine secretion, neurotransmission	1	4213.0×	7e-04	SLC6A9
response to lipoic acid	1	2106.5×	0.001	GLDC
positive regulation of heme biosynthetic process	1	1404.3×	0.001	SLC6A9
positive regulation of hemoglobin biosynthetic process	1	702.2×	0.002	SLC6A9
glycine import across plasma membrane	1	601.9×	0.003	SLC6A9
neurotransmitter uptake	1	351.1×	0.004	SLC6A9
glycine transport	1	351.1×	0.004	SLC6A9
sodium ion transmembrane transport	1	50.8×	0.023	SLC6A9
transport across blood-brain barrier	1	44.8×	0.024	SLC6A9
cellular response to leukemia inhibitory factor	1	39.8×	0.025	GLDC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
SLC6A9	GLYCINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A9	6	4
GCSH	0	0
GLDC	0	0
AMT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GLYCINE	4	SLC6A9
BITOPERTIN	3	SLC6A9
ICLEPERTIN	3	SLC6A9
SARCOSINE	2	SLC6A9
ORG-25935	2	SLC6A9
PF-03463275	2	SLC6A9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
SLC6A9	88	Binding:83, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCSH	1.4.1.27, 1.4.4.2	glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)
GLDC	1.4.1.27, 1.4.4.2	glycine cleavage system, glycine dehydrogenase (aminomethyl-transferring)
AMT	1.4.1.27, 2.1.2.10	glycine cleavage system, aminomethyltransferase

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

6 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)
GLYCINE	4	SLC6A9
BITOPERTIN	3	SLC6A9
ICLEPERTIN	3	SLC6A9
SARCOSINE	2	SLC6A9
ORG-25935	2	SLC6A9
PF-03463275	2	SLC6A9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC6A9
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	GCSH, GLDC, AMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
GCSH	0	—
GLDC	0	—
AMT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.