GLDC

Summary

GLDC (glycine decarboxylase, HGNC:4313) is a protein-coding gene on chromosome 9p24.1, encoding Glycine dehydrogenase (decarboxylating), mitochondrial (P23378). The glycine cleavage system catalyzes the degradation of glycine.

Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).

Source: NCBI Gene 2731 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycine encephalopathy (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 26
• Clinical variants (ClinVar): 2,776 total — 289 pathogenic, 232 likely-pathogenic
• Phenotypes (HPO): 20
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000170

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4313
Approved symbol	GLDC
Name	glycine decarboxylase
Location	9p24.1
Locus type	gene with protein product
Status	Approved
Aliases	GCSP, NKH
Ensembl gene	ENSG00000178445
Ensembl biotype	protein_coding
OMIM	238300
Entrez	2731

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 13 protein_coding, 6 protein_coding_CDS_not_defined, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000321612, ENST00000460457, ENST00000463305, ENST00000477960, ENST00000638233, ENST00000638274, ENST00000638654, ENST00000638661, ENST00000638694, ENST00000639020, ENST00000639318, ENST00000639364, ENST00000639443, ENST00000639461, ENST00000639493, ENST00000639639, ENST00000639840, ENST00000639954, ENST00000640208, ENST00000640505, ENST00000640592, ENST00000640703, ENST00000884130, ENST00000920236, ENST00000920237, ENST00000953081

RefSeq mRNA: 1 — MANE Select: NM_000170 NM_000170

CCDS: CCDS34987

Canonical transcript exons

ENST00000321612 — 25 exons

Exon	Start	End
ENSE00001282096	6605131	6605278
ENSE00001488232	6588618	6588702
ENSE00001488255	6536064	6536236
ENSE00001488257	6540051	6540146
ENSE00001488277	6553368	6553509
ENSE00001488288	6554669	6554781
ENSE00001488295	6556153	6556302
ENSE00001488307	6558559	6558684
ENSE00001488311	6565354	6565429
ENSE00001488316	6587141	6587283
ENSE00001488323	6588401	6588442
ENSE00001488339	6589195	6589292
ENSE00001488360	6604588	6604784
ENSE00001488364	6606592	6606669
ENSE00001488369	6610192	6610356
ENSE00001488371	6620184	6620319
ENSE00001488373	6644614	6644692
ENSE00001503843	6550803	6550914
ENSE00001529698	6645245	6645729
ENSE00003506337	6592851	6592990
ENSE00003520932	6595014	6595119
ENSE00003528570	6592143	6592223
ENSE00003584126	6602109	6602205
ENSE00003651670	6534708	6534788
ENSE00003903956	6532467	6533160

Expression profiles

Bgee: expression breadth ubiquitous, 216 present calls, max score 97.90.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2150 / max 124.2109, expressed in 439 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99859	0.4905	240
99858	0.2852	155
99851	0.1693	97
99857	0.1091	36
99853	0.0750	10
99852	0.0503	24
99855	0.0166	7
99854	0.0077	1
99856	0.0059	2
205425	0.0055	1

Top tissues by expression

278 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.90	gold quality
liver	UBERON:0002107	96.94	gold quality
nephron tubule	UBERON:0001231	95.43	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.14	gold quality
adult mammalian kidney	UBERON:0000082	94.06	gold quality
kidney epithelium	UBERON:0004819	92.84	gold quality
ventricular zone	UBERON:0003053	92.74	gold quality
sural nerve	UBERON:0015488	92.68	gold quality
placenta	UBERON:0001987	92.00	gold quality
metanephric glomerulus	UBERON:0004736	90.78	gold quality
renal glomerulus	UBERON:0000074	90.52	gold quality
kidney	UBERON:0002113	90.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.57	gold quality
embryo	UBERON:0000922	88.22	gold quality
ganglionic eminence	UBERON:0004023	88.01	gold quality
anterior cingulate cortex	UBERON:0009835	86.65	gold quality
cingulate cortex	UBERON:0003027	86.56	gold quality
renal medulla	UBERON:0000362	86.34	gold quality
metanephros cortex	UBERON:0010533	86.11	gold quality
tibial nerve	UBERON:0001323	86.08	gold quality
pigmented layer of retina	UBERON:0001782	85.85	gold quality
cortex of kidney	UBERON:0001225	85.75	gold quality
amygdala	UBERON:0001876	83.95	gold quality
right frontal lobe	UBERON:0002810	83.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.40	gold quality
prefrontal cortex	UBERON:0000451	83.18	gold quality
choroid plexus epithelium	UBERON:0003911	83.12	gold quality
neocortex	UBERON:0001950	82.67	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.15	gold quality
sperm	CL:0000019	82.00	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

58 targeting GLDC, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-188-3P	100.00	68.76	1240
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-6731-5P	99.28	67.42	2375

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• Heterozygous GLDC gene mutation in transient neonatal hyperglycinemia. (PMID:12402263)
• Missense and nonsense mutations found in glycine encephalopathy (PMID:14552331)
• Three adults with mild hyperglycinemia, infantile hypotonia, mental retardation, behavioral hyperirritability, and aggressive outbursts were screened for glycine decarboxylase mutations; two novel missense mutations were found. (PMID:15824356)
• The mutation in this nonketotic hyperglycinemia kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. (PMID:15851735)
• Single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is associated with glycine encephalopathy (PMID:15864413)
• the nonketotic hyperglycinemia is due to a novel GLDC mutation. (PMID:16404748)
• forty different gene alterations in the GLDC gene were identified in patients with glycine encephalopathy (PMID:16601880)
• A screening system for GLDC deletions by multiplex ligation-dependent probe amplification identified 14 deletions of different length & Alu-mediated recombination in non-ketotic hyperglycinaemia patients. (PMID:17361008)
• a histidine-to-aspartic acid change at amino acid position 371 (p. His371Asp mutation) in the glycine decarboxylase in a non-ketotic hyperglycemia patient. (PMID:18581728)
• Identification of a splice acceptor site mutation and five different non-synonymous variants in GLDC were found in patients with neural tube defects. (PMID:22171071)
• Study shows that glycine metabolism and the metabolic enzyme glycine decarboxylase (GLDC) drive tumor-initiating cells and tumorigenesis in non-small cell lung cancer. (PMID:22225612)
• study reports a novel mutation, c.2296G>T (p.Gly766Cys), in exon 19 of the glycine decarboxylase (GLDC) gene in a consanguineous Indian couple with a history of 4 neonatal deaths (PMID:23349517)
• Data indicate no mutation was found in glycine cleavage system protein-H (GCSH) and suggest that mutations in both glycine decarboxylase (GLDC) and aminomethyltransferase (AMT) are the main cause of glycine encephalopathy in Malaysian population. (PMID:25231368)
• The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT (PMID:27362913)
• We show that the combination of GLDC and HIF-1alpha expression is an independent prognostic factor in early-stage lung non-small cell cancer (PMID:28062918)
• a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 nonketotic hyperglycinemia patients was performed (PMID:28244183)
• A novel compound heterozygous variant was identified in the GLDC gene in a Chinese family with non-ketotic hyperglycinemia (PMID:29304759)
• Our data indicate that GLDC downregulation decreases reactive oxygen species mediated ubiquitination of cofilin to enhance hepatocellular carcinoma progression and intrahepatic metastasis (PMID:29524606)
• it was concluded that elevated serum GLDC may increase lung cancer risk, and that smoking, GLDC, the miR29 family and DNMT signaling pathways may serve an important role in early malignant transformation during the development of lung cancer. (PMID:29956770)
• Collectively, GLDC regulates cellular antiviral response and orchestrates viral growth. GLDC is a functional susceptibility gene to severe influenza in humans. (PMID:30498026)
• these findings suggest that GLDC-mediated regulation of glycolysis and controlling AGE accumulation is related to maintenance and induction of pluripotency. (PMID:30779965)
• GLDC overexpression significantly induced cell autophagy, whereas GLDC downregulation reduced cell autophagy. Of note, GLDC is the post-transcriptional target of miR-30d-5p. GLDC overexpression could rescue miR-30d-5p-mediated cell metastasis and increase autophagy. (PMID:30804330)
• These findings reveal a critical role of GLDC in sustaining the proliferation of neuroblastoma cells with high-level GLDC expression and suggest that MYCN amplification is a biomarker for GLDC-based therapeutic strategies against high-risk neuroblastoma. (PMID:31444411)
• we identified a new alternative splicing isoform of GLDC, truncated GLDCV1, and demonstrated that GLDCV1 possesses similar biological activities to GLDCfl on regulating CSCs and tumorigenesis. (PMID:31773974)
• Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children. (PMID:35460232)
• GLDC promotes colorectal cancer metastasis through epithelial-mesenchymal transition mediated by Hippo signaling pathway. (PMID:37668829)
• Glycine Decarboxylase (GLDC) Plays a Crucial Role in Regulating Energy Metabolism, Invasion, Metastasis and Immune Escape for Prostate Cancer. (PMID:37781511)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gldc	ENSDARG00000035120
mus_musculus	Gldc	ENSMUSG00000024827
rattus_norvegicus	Gldc	ENSRNOG00000011599
drosophila_melanogaster	CG3999	FBGN0037801
caenorhabditis_elegans		WBGENE00020022

Protein

Protein identifiers

Glycine dehydrogenase (decarboxylating), mitochondrial — P23378 (reviewed: P23378)

Alternative names: Glycine cleavage system P protein, Glycine decarboxylase, Glycine dehydrogenase (aminomethyl-transferring)

All UniProt accessions (10): A0A1W2PP74, A0A1W2PPB1, A0A1W2PPD7, A0A1W2PPE1, A0A1W2PPG0, A0A1W2PPH6, A0A1W2PPK8, A0A1W2PQU6, A0A1W2PQV3, P23378

UniProt curated annotations — full annotation on UniProt →

Function. The glycine cleavage system catalyzes the degradation of glycine. The P protein (GLDC) binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO(2) is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein (GCSH).

Subunit / interactions. Homodimer. Interacts with GCSH. The glycine cleavage system is composed of four proteins: P (GLDC), T (GCST), L (DLD) and H (GCSH).

Subcellular location. Mitochondrion.

Disease relevance. Non-ketotic hyperglycinemia (NKH) [MIM:605899] Autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Stimulated by lipoic acid. Inhibited in presence of methylamine.

Similarity. Belongs to the GcvP family.

RefSeq proteins (1): NP_000161* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001597	ArAA_b-elim_lyase/Thr_aldolase	Domain
IPR003437	GcvP	Family
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR020581	GDC_P	Family
IPR049315	GDC-P_N	Domain
IPR049316	GDC-P_C	Domain

Pfam: PF01212, PF02347, PF21478

Enzyme classification (BRENDA):

• EC 1.4.1.27 — glycine cleavage system (BRENDA: 15 organisms, 4 substrates, 5 inhibitors, 6 Km, 0 kcat entries)
• EC 1.4.4.2 — glycine dehydrogenase (aminomethyl-transferring) (BRENDA: 25 organisms, 27 substrates, 22 inhibitors, 32 Km, 11 kcat entries)

Substrate kinetics (BRENDA)

15 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLYCINE	0.0003–40	19
GLYCINE	6.6–40	2
TETRAHYDROFOLATE	0.05–0.17	2
LIPOYLATED H-APOPROTEIN	0.47–12.3	2
LIPOYLATED HIS-TAGGED H-APOPROTEIN	1–12.6	2
LIPOIC ACID	0.83	1
BICARBONATE	31	1
CO2	3.4	1
H1 PROTEIN	0.0026	1
H2 PROTEIN	0.0037	1
HIS-TAGGED H-APOPROTEIN	12.3	1
LIPOAMIDE	0.043	1
PYRIDOXAL 5’-PHOSPHATE	0.0046	1
RTVH1 PROTEIN	0.0026	1
RTVH2 PROTEIN	0.0037	1

Catalyzed reactions (Rhea), 1 shown:

• N(6)-[(R)-lipoyl]-L-lysyl-[glycine-cleavage complex H protein] + glycine + H(+) = N(6)-[(R)-S(8)-aminomethyldihydrolipoyl]-L-lysyl-[glycine-cleavage complex H protein] + CO2 (RHEA:24304)

UniProt features (125 total): helix 51, strand 29, sequence variant 24, turn 9, modified residue 5, sequence conflict 4, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6I35	X-RAY DIFFRACTION	2
6I34	X-RAY DIFFRACTION	2.1
6I33	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23378-F1	94.50	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 447, 514, 648, 664, 754

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6783984	Glycine degradation

MSigDB gene sets: 210 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, TTGGGAG_MIR150, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, UEDA_PERIFERAL_CLOCK, KLEIN_PRIMARY_EFFUSION_LYMPHOMA_UP, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, DELYS_THYROID_CANCER_DN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_GLYCINE_METABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_UP, GOBP_RESPONSE_TO_LIPID, GOBP_ORGANIC_ACID_METABOLIC_PROCESS

GO Biological Process (7): glycine catabolic process (GO:0006546), glycine decarboxylation via glycine cleavage system (GO:0019464), response to methylamine (GO:0036255), response to lipoic acid (GO:1903442), cellular response to leukemia inhibitory factor (GO:1990830), amino acid metabolic process (GO:0006520), glycine metabolic process (GO:0006544)

GO Molecular Function (8): glycine dehydrogenase (decarboxylating) activity (GO:0004375), electron transfer activity (GO:0009055), glycine binding (GO:0016594), lyase activity (GO:0016829), pyridoxal phosphate binding (GO:0030170), protein homodimerization activity (GO:0042803), pyridoxal binding (GO:0070280), oxidoreductase activity (GO:0016491)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), plasma membrane (GO:0005886), glycine cleavage complex (GO:0005960)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glyoxylate metabolism and glycine degradation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cation binding	2
catalytic activity	2
vitamin B6 binding	2
glycine metabolic process	1
amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
glycine catabolic process	1
response to amine	1
response to fatty acid	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
primary metabolic process	1
proteinogenic amino acid metabolic process	1
oxidoreductase activity, acting on the CH-NH2 group of donors, disulfide as acceptor	1
molecular_function	1
amino acid binding	1
carboxylic acid binding	1
anion binding	1
identical protein binding	1
protein dimerization activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
oxidoreductase complex	1
transferase complex	1

Protein interactions and networks

STRING

2194 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLDC	AMT	P48728	996
GLDC	MYBPH	Q13203	994
GLDC	GCSH	P23434	993
GLDC	OCA2	Q04671	897
GLDC	MTHFD1L	Q6UB35	810
GLDC	DLD	P09622	792
GLDC	MTHFD1	P11586	785
GLDC	MTHFD2	P13995	778
GLDC	SHMT2	P34897	775
GLDC	SHMT1	P34896	774
GLDC	A0A1W2PS29	A0A1W2PS29	763
GLDC	MTHFD2L	Q9H903	763
GLDC	A0A1W2PPQ1	A0A1W2PPQ1	750
GLDC	PSAT1	Q9Y617	687
GLDC	PSPH	P78330	682

IntAct

38 interactions, top by confidence:

A	B	Type	Score
Sh2d5	BCR	psi-mi:“MI:0914”(association)	0.580
CAPN6	UBA6	psi-mi:“MI:0914”(association)	0.530
SOST	KPNA4	psi-mi:“MI:0914”(association)	0.530
FDPS	ZMPSTE24	psi-mi:“MI:0914”(association)	0.530
SPATA13	GLDC	psi-mi:“MI:0914”(association)	0.530
POLG2	GLDC	psi-mi:“MI:0914”(association)	0.530
GCSH	LIAS	psi-mi:“MI:0914”(association)	0.530
NDUFAB1	GLDC	psi-mi:“MI:0914”(association)	0.530
CREG2	GLDC	psi-mi:“MI:0915”(physical association)	0.400
SEMA3E	GLDC	psi-mi:“MI:0915”(physical association)	0.400
	GLDC	psi-mi:“MI:0915”(physical association)	0.370
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
NDUFAB1	SDHB	psi-mi:“MI:0914”(association)	0.350
TNIP3	RNH1	psi-mi:“MI:0914”(association)	0.350
ULK2	PRKAB2	psi-mi:“MI:0914”(association)	0.350
CEP135	MCRIP1	psi-mi:“MI:0914”(association)	0.350
CEP135	WWP2	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350
LINC02872	NMT2	psi-mi:“MI:0914”(association)	0.350
SPATA13	DIRAS1	psi-mi:“MI:0914”(association)	0.350
SEMA3B	HSPA5	psi-mi:“MI:0914”(association)	0.350

BioGRID (327): GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Co-fractionation), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS), GLDC (Affinity Capture-MS)

ESM2 similar proteins: A0A0C1E1D0, A0A0F7CUE9, A0A1U9YHZ6, A0A3G9HRC2, A8X493, B0WSW8, B3MZN7, B3NY19, B8NM72, B9FFD3, B9KHF1, C9K7B8, G5EDZ2, K0E4E5, M1W859, M2XHU6, O64390, O94303, P15505, P23378, Q00706, Q0CS62, Q0JMR0, Q16P87, Q2GLS9, Q39469, Q3UEG6, Q4HXF0, Q5BD67, Q5MNH7, Q5MNI5, Q5PBX6, Q5WUR6, Q5X3A8, Q5ZTI6, Q69TI2, Q6Q887, Q74ZZ1, Q75B12, Q75BA5

Diamond homologs: A0K321, A0M5D4, A1RFY8, A1S965, A1SY74, A1V8N7, A2S6F6, A3D085, A3MQP3, A3NF00, A3P0U7, A3QHI0, A4JA69, A4VRT4, A4YAD8, A4YXQ9, A5EMM2, A5EYY8, A6WSL1, A7N5C4, A9ACU3, A9L330, B1JSZ2, B1YQQ1, B2J427, B2T7I8, B2UG82, B3PP20, B4EF26, B4SS67, B5EUH1, B6ES35, B8EB45, C3JYR1, C3LUU7, O49850, O49852, O49954, O80988, P15505

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GLDC	“form complex”	“Glycine cleavage system”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

2776 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	289
Likely pathogenic	232
Uncertain significance	783
Likely benign	1151
Benign	108

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013034	NM_000170.3(GLDC):c.862-1G>C	Pathogenic
1070375	NC_000009.11:g.(?6602089)(6620339_?)del	Pathogenic
1070376	NC_000009.11:g.(?6587131)(6610366_?)del	Pathogenic
1070377	NC_000009.11:g.(?6587131)(6595129_?)del	Pathogenic
1070959	NM_000170.3(GLDC):c.861+2T>A	Pathogenic
1071227	NM_000170.3(GLDC):c.586del (p.Leu196fs)	Pathogenic
1071673	NM_000170.3(GLDC):c.862-5_883del	Pathogenic
1072388	NC_000009.11:g.(?6533007)(6645509_?)del	Pathogenic
1072389	NC_000009.11:g.(?6610182)(6610366_?)del	Pathogenic
1072390	NC_000009.11:g.(?6587131)(6645509_?)del	Pathogenic
1072611	NM_000170.3(GLDC):c.2T>A (p.Met1Lys)	Pathogenic
1073875	NM_000170.3(GLDC):c.2596G>C (p.Asp866His)	Pathogenic
1073876	NM_000170.3(GLDC):c.2176del (p.Tyr725_Leu726insTer)	Pathogenic
1074244	NC_000009.11:g.(?6550783)(6645519_?)del	Pathogenic
1074245	NC_000009.11:g.(?6604578)(6645509_?)del	Pathogenic
1074246	NC_000009.11:g.(?6533007)(6565439_?)del	Pathogenic
1074247	NC_000009.11:g.(?6550793)(6620329_?)del	Pathogenic
1074248	NC_000009.11:g.(?6610182)(6620329_?)del	Pathogenic
1075327	NM_000170.3(GLDC):c.613del (p.Glu205fs)	Pathogenic
1075468	NM_000170.3(GLDC):c.1789G>T (p.Glu597Ter)	Pathogenic
1075670	NM_000170.3(GLDC):c.1718G>A (p.Trp573Ter)	Pathogenic
1075706	NM_000170.3(GLDC):c.251del (p.Leu84fs)	Pathogenic
1075996	NM_000170.3(GLDC):c.122del (p.Gly41fs)	Pathogenic
1076063	NM_000170.3(GLDC):c.872G>A (p.Cys291Tyr)	Pathogenic
11984	NC_000009.11:g.(?6620184)(6645307_?)del	Pathogenic
11985	NM_000170.3(GLDC):c.1545G>C (p.Arg515Ser)	Pathogenic
11986	NM_000170.3(GLDC):c.2281G>C (p.Gly761Arg)	Pathogenic
11987	NM_000170.3(GLDC):c.2405C>T (p.Ala802Val)	Pathogenic
11988	NM_000170.3(GLDC):c.2T>C (p.Met1Thr)	Pathogenic
11989	NM_000170.3(GLDC):c.1166C>T (p.Ala389Val)	Pathogenic

SpliceAI

4090 predictions. Top by Δscore:

Variant	Effect	Δscore
9:6533156:AAGGG:A	acceptor_gain	1.0000
9:6533157:AGGG:A	acceptor_gain	1.0000
9:6533158:GGG:G	acceptor_gain	1.0000
9:6533158:GGGC:G	acceptor_loss	1.0000
9:6533159:GG:G	acceptor_gain	1.0000
9:6533161:C:CC	acceptor_gain	1.0000
9:6533161:C:G	acceptor_loss	1.0000
9:6533162:T:A	acceptor_loss	1.0000
9:6533164:C:CT	acceptor_gain	1.0000
9:6533165:A:T	acceptor_gain	1.0000
9:6534706:A:AC	donor_gain	1.0000
9:6534707:C:CC	donor_gain	1.0000
9:6534786:CAT:C	acceptor_gain	1.0000
9:6536060:GCA:G	donor_loss	1.0000
9:6536061:CACCT:C	donor_loss	1.0000
9:6536062:ACCT:A	donor_loss	1.0000
9:6536063:C:A	donor_loss	1.0000
9:6540044:CACTT:C	donor_loss	1.0000
9:6540045:ACTTA:A	donor_loss	1.0000
9:6540046:CTTA:C	donor_loss	1.0000
9:6540047:TTA:T	donor_loss	1.0000
9:6540048:T:TG	donor_loss	1.0000
9:6540049:ACCA:A	donor_loss	1.0000
9:6550797:ACTT:A	donor_loss	1.0000
9:6550799:TTG:T	donor_loss	1.0000
9:6550800:TGCCT:T	donor_loss	1.0000
9:6550802:C:CA	donor_loss	1.0000
9:6550910:ATCAT:A	acceptor_gain	1.0000
9:6550911:TCAT:T	acceptor_gain	1.0000
9:6550912:CAT:C	acceptor_gain	1.0000

AlphaMissense

6715 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:6558640:A:C	S657R	1.000
9:6558640:A:T	S657R	1.000
9:6558642:T:G	S657R	1.000
9:6558656:C:T	G652E	1.000
9:6602124:G:C	N380K	1.000
9:6602124:G:T	N380K	1.000
9:6602127:G:C	S379R	1.000
9:6602127:G:T	S379R	1.000
9:6602129:T:G	S379R	1.000
9:6602146:C:G	R373P	1.000
9:6602149:A:T	I372N	1.000
9:6602161:C:A	R368M	1.000
9:6533097:C:G	D995H	0.999
9:6533099:C:T	G994E	0.999
9:6533100:C:G	G994R	0.999
9:6533100:C:T	G994R	0.999
9:6533133:A:G	W983R	0.999
9:6533133:A:T	W983R	0.999
9:6536213:A:G	W897R	0.999
9:6536213:A:T	W897R	0.999
9:6540062:A:G	L885P	0.999
9:6540071:G:T	A882D	0.999
9:6554696:C:T	G763D	0.999
9:6554702:C:T	G761E	0.999
9:6554722:C:A	K754N	0.999
9:6554722:C:G	K754N	0.999
9:6554723:T:A	K754M	0.999
9:6554723:T:G	K754T	0.999
9:6554731:A:C	N751K	0.999
9:6554731:A:T	N751K	0.999

dbSNP variants (sampled 300 via entrez): RS1000060801 (9:6533753 G>A,C), RS1000068072 (9:6621848 C>T), RS1000089912 (9:6585767 C>G,T), RS1000105293 (9:6563169 C>G,T), RS1000115133 (9:6563322 T>G), RS1000121520 (9:6622022 A>G), RS1000169775 (9:6594252 C>G,T), RS1000202982 (9:6638505 G>T), RS1000262162 (9:6616596 C>T), RS1000262283 (9:6546061 T>G), RS1000264491 (9:6559236 C>A), RS1000288764 (9:6576364 G>A), RS1000291882 (9:6613692 A>G), RS1000304036 (9:6618005 A>G), RS1000322498 (9:6613939 G>A,C)

Disease associations

OMIM: gene MIM:238300 | disease phenotypes: MIM:605899, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
glycine encephalopathy	Definitive	Autosomal recessive
glycine encephalopathy 1	Definitive	Autosomal recessive
neonatal glycine encephalopathy	Supportive	Autosomal recessive
infantile glycine encephalopathy	Supportive	Autosomal recessive
atypical glycine encephalopathy	Supportive	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
glycine encephalopathy	Definitive	AR

Mondo (10): glycine encephalopathy (MONDO:0011612), glycine encephalopathy 1 (MONDO:0958179), retinitis pigmentosa (MONDO:0019200), obesity disorder (MONDO:0011122), generalized epilepsy (MONDO:0100574), intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092), neonatal glycine encephalopathy (MONDO:0017353), infantile glycine encephalopathy (MONDO:0017354), atypical glycine encephalopathy (MONDO:0015010)

Orphanet (5): Glycine encephalopathy (Orphanet:407), Retinitis pigmentosa (Orphanet:791), Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

20 total (21 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000711	Restlessness
HP:0000718	Aggressive behavior
HP:0000737	Irritability
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001265	Hyporeflexia
HP:0001274	Agenesis of corpus callosum
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0001522	Death in infancy
HP:0002154	Hyperglycinemia
HP:0003108	Hyperglycinuria
HP:0100247	Recurrent singultus
HP:0100710	Impulsivity
HP:0001513	Obesity

GWAS associations

26 associations (top):

Study	Trait	p-value
GCST001588_15	Periodontal microbiota	3.000000e-06
GCST005158_1	Overall survival in osteosarcoma	5.000000e-08
GCST005998_18	Alanine transaminase levels	2.000000e-08
GCST007563_22	Allergic disease (asthma, hay fever or eczema)	2.000000e-08
GCST007564_17	Asthma or allergic disease (pleiotropy)	2.000000e-10
GCST007564_32	Asthma or allergic disease (pleiotropy)	4.000000e-22
GCST007638_39	Glycine levels	2.000000e-40
GCST007836_9	Glycine levels	8.000000e-121
GCST007837_5	Glycine levels	1.000000e-42
GCST007838_8	Glycine levels	3.000000e-85
GCST008839_224	Height	8.000000e-08
GCST008916_26	Asthma	3.000000e-64
GCST008916_47	Asthma	2.000000e-08
GCST008916_5	Asthma	7.000000e-17
GCST008916_83	Asthma	1.000000e-08
GCST008916_9	Asthma	4.000000e-18
GCST009391_1192	Metabolite levels	9.000000e-06
GCST009391_463	Metabolite levels	9.000000e-06
GCST009733_152	Urinary metabolite levels in chronic kidney disease	3.000000e-22
GCST009733_154	Urinary metabolite levels in chronic kidney disease	2.000000e-19
GCST009733_156	Urinary metabolite levels in chronic kidney disease	2.000000e-18
GCST011352_32	Alanine aminotransferase levels	1.000000e-08
GCST012020_403	Serum metabolite levels	2.000000e-34
GCST012020_404	Serum metabolite levels	3.000000e-50
GCST012489_37	Heel bone mineral density x serum urate levels interaction	4.000000e-13
GCST90011898_120	Alanine aminotransferase levels	2.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0000638	overall survival
EFO:0009767	glycine measurement
EFO:0021575	adipic acid measurement
EFO:0010522	phosphoenolpyruvic acid measurement
EFO:0005116	urinary metabolite measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10975641	Efficacy	3	citalopram;escitalopram	Major Depressive Disorder

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10975641	GLDC	3	3.50	1	citalopram;escitalopram

CTD chemical–gene interactions

76 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	6
Benzo(a)pyrene	affects methylation, decreases expression	5
Tetrachlorodibenzodioxin	decreases expression	4
bisphenol A	affects expression, decreases expression, increases methylation	3
Acetaminophen	decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression, increases methylation	3
Aflatoxin B1	affects expression, affects methylation, decreases expression	3
sodium arsenite	decreases expression	2
Decitabine	decreases expression, decreases reaction, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Carbamazepine	affects expression	2
Estradiol	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
Tunicamycin	decreases expression	2
Thapsigargin	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
sotorasib	decreases expression, affects cotreatment	1
methyleugenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases reaction, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
tobacco tar	increases expression	1
potassium chromate(VI)	increases expression	1
HC toxin	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1WL	Abcam A-549 GLDC KO	Cancer cell line	Male
CVCL_D2AZ	Abcam HCT 116 GLDC KO	Cancer cell line	Male
CVCL_WT15	UAMi005-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

296 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients
NCT00694811	PHASE4	COMPLETED	Effects of Re-Feeding Duration on Weight Maintenance After Weight Loss With Very-Low-Energy Diets (VLEDs)
NCT00699413	PHASE4	TERMINATED	Supplements for Controlling Resistance to Insulin