AMT

Summary

AMT (aminomethyltransferase, HGNC:473) is a protein-coding gene on chromosome 3p21.31, encoding Aminomethyltransferase, mitochondrial (P48728). The glycine cleavage system catalyzes the degradation of glycine.

This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 275 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycine encephalopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 776 total — 60 pathogenic, 61 likely-pathogenic (top 4% of genes corpus-wide)
• GTEx eGene: eQTL in 48 tissues, sQTL in 6 (q < 0.05)
• Phenotypes (HPO): 10
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.81 (unconstrained)
• MANE Select transcript: NM_000481

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:473
Approved symbol	AMT
Name	aminomethyltransferase
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	GCST, NKH
Ensembl gene	ENSG00000145020
Ensembl biotype	protein_coding
OMIM	238310
Entrez	275

Gene structure

Transcript identifiers

Ensembl transcripts: 81 — 35 retained_intron, 28 protein_coding, 17 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000273588

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 9, TSL 3: 1, TSL 4: 2, TSL 5: 41

ENST00000273588, ENST00000395338, ENST00000399379, ENST00000427987, ENST00000430521, ENST00000458307, ENST00000461210, ENST00000462048, ENST00000465925, ENST00000473163, ENST00000476127, ENST00000476226, ENST00000476828, ENST00000478594, ENST00000480957, ENST00000487589, ENST00000491800, ENST00000493046, ENST00000495436, ENST00000498571, ENST00000538581, ENST00000635772, ENST00000635798, ENST00000635808, ENST00000635889, ENST00000635907, ENST00000635936, ENST00000636023, ENST00000636070, ENST00000636148, ENST00000636188, ENST00000636199, ENST00000636522, ENST00000636587, ENST00000636594, ENST00000636597, ENST00000636725, ENST00000636803, ENST00000636865, ENST00000636871, ENST00000636978, ENST00000636991, ENST00000637059, ENST00000637114, ENST00000637268, ENST00000637291, ENST00000637455, ENST00000637457, ENST00000637527, ENST00000637682, ENST00000637684, ENST00000637821, ENST00000637914, ENST00000637982, ENST00000637994, ENST00000638063, ENST00000638092, ENST00000977341, ENST00000977342, ENST00000977343, ENST00000977344, ENST00000977345, ENST00000977347, ENST00000977348, ENST00000977349, ENST00001054063, ENST00001079327, ENST00001079328, ENST00001079329, ENST00001079330, ENST00001079331, ENST00001079332, ENST00001079334, ENST00001079335, ENST00001094107, ENST00001094108, ENST00001109424, ENST00001119236, ENST00001119237, ENST00001127728, ENST00001143913

RefSeq mRNA: 4 — MANE Select: NM_000481 NM_000481, NM_001164710, NM_001164711, NM_001164712

CCDS: CCDS2797, CCDS54583, CCDS54584, CCDS54585

Canonical transcript exons

ENST00000273588 — 9 exons

Exon	Start	End
ENSE00003482904	49420211	49420342
ENSE00003564602	49417818	49417973
ENSE00003567679	49419710	49419788
ENSE00003593967	49421492	49421572
ENSE00003611044	49418971	49419151
ENSE00003620797	49419260	49419405
ENSE00003656537	49422104	49422271
ENSE00003794373	49422361	49422473
ENSE00003798868	49416778	49417718

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 94.65.

FANTOM5 (CAGE): breadth broad, TPM avg 3.2658 / max 108.5483, expressed in 512 samples.

Highest expression (Bgee): lobe of liver, liver, uterine tube, hemisphere of cerebellum, cerebellar hemisphere.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AMT is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 48 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 54 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	9.9e-114	-0.51	3:49422974:C:T
Cells Cultured fibroblasts	eqtl	4.9e-100	+0.39	3:49330884:A:G
Artery Tibial	eqtl	1.7e-97	-0.43	3:49422974:C:T
Nerve Tibial	eqtl	3.0e-97	-0.44	3:49422974:C:T
Lung	eqtl	1.2e-82	-0.45	3:49422974:C:T
Artery Aorta	eqtl	2.8e-78	-0.48	3:49405115:G:A
Esophagus Muscularis	eqtl	2.8e-72	+0.35	3:49355187:A:G
Adipose Subcutaneous	eqtl	5.7e-72	-0.40	3:49405115:G:A
Esophagus Mucosa	eqtl	6.2e-70	-0.38	3:49390500:G:A
Adipose Visceral Omentum	eqtl	4.5e-69	-0.39	3:49390500:G:A
Muscle Skeletal	eqtl	7.0e-62	-0.32	3:49480235:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.7e-60	-0.42	3:49422974:C:T
Colon Sigmoid	eqtl	3.3e-57	+0.47	3:49351200:T:C
Whole Blood	eqtl	1.1e-54	+0.38	3:49478917:G:A
Skin Sun Exposed Lower leg	eqtl	2.2e-54	-0.37	3:49422974:C:T
Testis	eqtl	1.1e-49	+0.55	3:49355187:A:G
Breast Mammary Tissue	eqtl	5.5e-46	-0.33	3:49405115:G:A
Esophagus Gastroesophageal Junction	eqtl	1.6e-43	-0.38	3:49462981:G:A
Spleen	eqtl	9.4e-39	-0.53	3:49385708:GT:G
Brain Cerebellum	eqtl	1.3e-37	-0.65	3:49462981:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
42263	3.1053	509
42262	0.1605	93

Top tissues by expression

showing 100 of 140 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	94.65	gold quality
liver	UBERON:0002107	93.23	gold quality
right uterine tube	UBERON:0001302	91.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.49	gold quality
cerebellar hemisphere	UBERON:0002245	91.01	gold quality
cerebellar cortex	UBERON:0002129	91.00	gold quality
cerebellum	UBERON:0002037	90.96	gold quality
apex of heart	UBERON:0002098	90.08	gold quality
mucosa of transverse colon	UBERON:0004991	89.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.17	gold quality
pituitary gland	UBERON:0000007	89.07	gold quality
adult mammalian kidney	UBERON:0000082	88.70	gold quality
body of pancreas	UBERON:0001150	88.68	gold quality
left ovary	UBERON:0002119	88.23	gold quality
adenohypophysis	UBERON:0002196	88.09	gold quality
heart left ventricle	UBERON:0002084	88.05	gold quality
fundus of stomach	UBERON:0001160	87.91	gold quality
right atrium auricular region	UBERON:0006631	87.86	gold quality
duodenum	UBERON:0002114	87.69	gold quality
cortex of kidney	UBERON:0001225	87.62	gold quality
transverse colon	UBERON:0001157	87.54	gold quality
ovary	UBERON:0000992	87.45	gold quality
kidney	UBERON:0002113	87.35	gold quality
rectum	UBERON:0001052	87.34	gold quality
heart	UBERON:0000948	87.10	gold quality
right ovary	UBERON:0002118	87.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.06	gold quality
left adrenal gland cortex	UBERON:0035825	86.91	gold quality
right adrenal gland	UBERON:0001233	86.83	gold quality
prostate gland	UBERON:0002367	86.77	gold quality
right adrenal gland cortex	UBERON:0035827	86.62	gold quality
colon	UBERON:0001155	86.48	gold quality
fallopian tube	UBERON:0003889	86.46	gold quality
body of stomach	UBERON:0001161	86.13	gold quality
intestine	UBERON:0000160	86.12	gold quality
small intestine	UBERON:0002108	86.12	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.05	gold quality
mucosa of stomach	UBERON:0001199	85.99	gold quality
left adrenal gland	UBERON:0001234	85.82	gold quality
endocervix	UBERON:0000458	85.80	gold quality
left uterine tube	UBERON:0001303	85.75	gold quality
adrenal gland	UBERON:0002369	85.19	gold quality
body of uterus	UBERON:0009853	85.15	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.12	gold quality
stomach	UBERON:0000945	85.09	gold quality
pancreas	UBERON:0001264	84.98	gold quality
myometrium	UBERON:0001296	84.88	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.83	gold quality
sural nerve	UBERON:0015488	84.68	gold quality
metanephros cortex	UBERON:0010533	84.40	gold quality
ascending aorta	UBERON:0001496	84.21	gold quality
spleen	UBERON:0002106	84.19	gold quality
thoracic aorta	UBERON:0001515	84.13	gold quality
colonic epithelium	UBERON:0000397	84.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.03	gold quality
lower esophagus	UBERON:0013473	84.02	gold quality
tibial nerve	UBERON:0001323	83.85	gold quality
descending thoracic aorta	UBERON:0002345	83.56	gold quality
uterine cervix	UBERON:0000002	83.49	gold quality
tibial artery	UBERON:0007610	83.18	gold quality
popliteal artery	UBERON:0002250	83.16	gold quality
artery	UBERON:0001637	83.01	gold quality
gall bladder	UBERON:0002110	82.96	gold quality
thyroid gland	UBERON:0002046	82.90	gold quality
urinary bladder	UBERON:0001255	82.80	gold quality
vagina	UBERON:0000996	82.71	gold quality
nucleus accumbens	UBERON:0001882	82.71	gold quality
left lobe of thyroid gland	UBERON:0001120	82.70	gold quality
caudate nucleus	UBERON:0001873	82.49	gold quality
ectocervix	UBERON:0012249	82.40	gold quality
putamen	UBERON:0001874	82.19	gold quality
left coronary artery	UBERON:0001626	82.01	gold quality
mammary gland	UBERON:0001911	81.98	gold quality
thoracic mammary gland	UBERON:0005200	81.98	gold quality
anatomical system	UBERON:0000467	81.87	gold quality
right lung	UBERON:0002167	81.85	gold quality
material anatomical entity	UBERON:0000465	81.83	gold quality
multicellular organism	UBERON:0000468	81.83	gold quality
right lobe of thyroid gland	UBERON:0001119	81.78	gold quality
stromal cell of endometrium	CL:0002255	81.73	gold quality
lower esophagus mucosa	UBERON:0035834	81.69	gold quality
adrenal tissue	UBERON:0018303	81.58	gold quality
right coronary artery	UBERON:0001625	81.43	gold quality
muscle tissue	UBERON:0002385	81.41	gold quality
granulocyte	CL:0000094	81.15	gold quality
saliva-secreting gland	UBERON:0001044	81.12	gold quality
muscle of leg	UBERON:0001383	81.07	gold quality
skeletal muscle organ	UBERON:0014892	81.06	gold quality
gastrocnemius	UBERON:0001388	81.02	gold quality
brain	UBERON:0000955	80.82	gold quality
right frontal lobe	UBERON:0002810	80.75	gold quality
skeletal muscle tissue	UBERON:0001134	80.71	gold quality
esophagus	UBERON:0001043	80.63	gold quality
minor salivary gland	UBERON:0001830	80.56	gold quality
uterus	UBERON:0000995	80.54	gold quality
bone marrow	UBERON:0002371	80.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.37	gold quality
skin of abdomen	UBERON:0001416	80.30	gold quality
upper lobe of left lung	UBERON:0008952	80.13	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.04	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.66

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	44.3	high
Kidney	tissue	21.7	high
Heart muscle	tissue	20.2	high
Pancreas	tissue	18.3	high
Pituitary gland	tissue	16.0
Frontal cortex	tissue	14.6
Parathyroid gland	tissue	13.3	high
Duodenum	tissue	12.9	high
Adrenal gland	tissue	12.0	high
Colon	tissue	11.5	high
Small intestine	tissue	11.4	high
Rectum	tissue	11.1	high
Stomach 1	tissue	10.5	high
Caudate putamen	tissue	10.4
Salivary gland	tissue	10.0	high
Fallopian tube	tissue	9.5	high
Cervix	tissue	8.8	high
Vagina	tissue	8.6
Choroid plexus	tissue	8.4
Prostate	tissue	8.4	high
Bone marrow	tissue	8.3	high
Ovary	tissue	8.1	medium
Seminal vesicle	tissue	8.0	high
Epididymis	tissue	7.7	high
Retina	tissue	6.1
Gallbladder	tissue	5.4	high
Cerebellum	tissue	5.3	high
Cerebral cortex	tissue	5.1	high
Thalamus	tissue	5.1
Somatosensory cortex	tissue	5.1
Retrosplenial cortex	tissue	4.6
Occipital cortex	tissue	4.6
Pons	tissue	4.5
Midbrain	tissue	4.4
Hypothalamus	tissue	4.3
Hippocampal formation	tissue	4.3
Retrosplenial and cingulate cortex	tissue	4.3
Temporal cortex	tissue	4.3
Prefrontal cortex	tissue	4.1
Motor cortex	tissue	4.0
Superior colliculi	tissue	4.0
Septum	tissue	4.0
Tongue	tissue	3.9
Entorhinal cortex	tissue	3.9
Olfactory bulb	tissue	3.9
Urinary bladder	tissue	3.8	high
Endometrium 1	tissue	3.8	high
Periaqueductal gray	tissue	3.8
Insular cortex	tissue	3.8
Amygdala	tissue	3.7
Ventral forebrain	tissue	3.7
Thymus	tissue	3.6
Smooth muscle	tissue	3.5	medium
Substantia nigra	tissue	3.5
Medulla oblongata	tissue	3.4
Adipose tissue	tissue	3.3	low
Spinal cord	tissue	3.3
Lung	tissue	3.0	high
Basal ganglia	tissue	2.9	high
Putamen	tissue	2.6

Brain sub-regions (HPA Brain Atlas): detected in 188; highest nTPM — Blood vessel (11.4), Dorsal hippocampus (4.3), Ventral hippocampus (4.3), Subiculum (4.2), Cerebellar cortex (3.7).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting AMT by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 60 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-378A-5P	99.65	66.33	1311

Functional genomics

gnomAD constraint: pLI 0.0001, LOEUF 0.805, missense Z 1 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000273588 — one region, missense o/e 0.93.

Literature-anchored findings (GeneRIF, showing 5)

• The Relish/miR-275/Dredd mediated negative feedback loop is crucial to restoring immune homeostasis of Drosophila Imd pathway. (PMID:37804878)
• x-ray crystallographic structure of human T-protein of glycine cleavage system (PMID:16051266)
• Two unique non-synonymous changes were identified in the AMT gene in patients with neural tube defects. (PMID:22171071)
• 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)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	amt	ENSDARG00000010862
mus_musculus	Amt	ENSMUSG00000032607
rattus_norvegicus	Amt	ENSRNOG00000050214
drosophila_melanogaster	CG6415	FBGN0032287
caenorhabditis_elegans		WBGENE00017765

Paralogs (10): L2HGDH (ENSG00000087299), YPEL3 (ENSG00000090238), PDPR (ENSG00000090857), YPEL1 (ENSG00000100027), FOXRED1 (ENSG00000110074), YPEL5 (ENSG00000119801), SARDH (ENSG00000123453), DMGDH (ENSG00000132837), YPEL4 (ENSG00000166793), YPEL2 (ENSG00000175155)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:3646700) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 24 distinct phenotype terms.

Mouse phenotype (MP)	Records
exencephaly	2
cleft palate	1
incomplete rostral neuropore closure	1
anophthalmia	1
microphthalmia	1
abnormal embryo size	1
prenatal lethality	1
abnormal limb morphology	1
abnormal neural tube morphology	1
short tibia	1
abnormal retina vasculature morphology	1
spina bifida	1
increased erythrocyte cell number	1
abnormal abdominal wall morphology	1
abnormal facial morphology	1
abnormal placenta size	1
decreased lymphocyte cell number	1
increased circulating aspartate transaminase level	1
craniorachischisis	1
facial cleft	1
abnormal retina blood vessel morphology	1
preweaning lethality, complete penetrance	1
abnormal head shape	1
abnormal head size	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Flaveria anomala	O49849	98.8%	Diamond
Flaveria pringlei	P49363	98.8%	Diamond
Flaveria trinervia	O23936	97.5%	Diamond
Canis lupus familiaris	Q9TSZ7	89.8%	Diamond
Bos taurus	P25285	88.7%	Diamond
Arabidopsis thaliana	O65396	88.0%	Diamond
Solanum tuberosum	P54260	87.2%	Diamond
Lathyrus oleraceus	P49364	86.8%	Diamond
Mesembryanthemum crystallinum	P93256	86.4%	Diamond
Gallus gallus	P28337	67.9%	Diamond
Dictyostelium discoideum	Q54DD3	51.7%	Diamond
Schizosaccharomyces pombe 972h-	O14110	47.4%	Diamond
Saccharomyces cerevisiae S288C	P48015	44.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
BSN-DT	ncRNA	100132677
DAG1	protein-coding	1605
TCTA	protein-coding	6988
NICN1	protein-coding	84276
GPX1	protein-coding	2876
RHOA	protein-coding	387
USP4	protein-coding	7375
MIR4271	ncRNA	100422952
C3orf62	protein-coding	375341
APEH	protein-coding	327
BSN	protein-coding	8927

Protein

Protein identifiers

Aminomethyltransferase, mitochondrial — P48728 (reviewed: P48728)

Alternative names: Glycine cleavage system T protein

All UniProt accessions (16): A0A1B0GTA8, A0A1B0GTB6, A0A1B0GTM2, A0A1B0GTV8, A0A1B0GU55, A0A1B0GUK9, A0A1B0GUU7, A0A1B0GV07, A0A1B0GVD0, A0A1B0GVP5, A0A1B0GWC4, B3KTU4, C9JXJ4, P48728, F8WF62, H0Y695

UniProt curated annotations — full annotation on UniProt →

Function. The glycine cleavage system catalyzes the degradation of glycine.

Subunit / interactions. The glycine cleavage system is composed of four proteins: P, T, L and H.

Subcellular location. Mitochondrion.

Disease relevance. Glycine encephalopathy 2 (GCE2) [MIM:620398] A form of glycine encephalopathy, a metabolic disorder characterized by a high concentration of glycine in the body fluids. Affected individuals typically have severe neurological symptoms, including seizure, lethargy, and muscular hypotonia soon after birth. Most of them die within the neonatal period. Atypical cases have later disease onset and less severely affected psychomotor development. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GcvT family.

Isoforms (4)

UniProt ID	Names	Canonical?
P48728-1	1	yes
P48728-2	2
P48728-3	3
P48728-4	4

RefSeq proteins (4): NP_000472, NP_001158182, NP_001158183, NP_001158184 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006222	GCVT_N	Domain
IPR006223	GcvT	Family
IPR013977	GcvT_C	Domain
IPR027266	TrmE/GcvT-like	Homologous_superfamily
IPR028896	GcvT/YgfZ/DmdA	Family
IPR029043	GcvT/YgfZ_C	Homologous_superfamily

Pfam: PF01571, PF08669

Enzyme classification (BRENDA)

• EC 1.4.1.27 — glycine cleavage system (BRENDA: 15 organisms, 4 substrates, 5 inhibitors, 6 Km, 0 kcat entries)
• EC 2.1.2.10 — aminomethyltransferase (BRENDA: 12 organisms, 30 substrates, 2 inhibitors, 21 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
5,10-METHYLENETETRAHYDROFOLATE	0.0677–0.151	5
5,10-METHYLENETETRAHYDROPTEROYLTETRAGLUTAMATE	0.0092–0.0382	5
NH4CL	65.4–256	4
REDUCED H-PROTEIN	0.0007–0.0169	4
GLYCINE	6.6–40	2
TETRAHYDROFOLATE	0.05–0.17	2
LIPOIC ACID	0.83	1
S-AMINOMETHYLDIHYDROLIPOYLPROTEIN	0.0037	1
TETRAHYDROFOLATE	0.17	1

Catalyzed reactions (Rhea)

• N(6)-[(R)-S(8)-aminomethyldihydrolipoyl]-L-lysyl-[protein] + (6S)-5,6,7,8-tetrahydrofolate = N(6)-[(R)-dihydrolipoyl]-L-lysyl-[protein] + (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NH4(+) (RHEA:16945)

UniProt features (57 total): strand 20, helix 13, sequence variant 11, binding site 3, turn 3, splice variant 3, transit peptide 1, chain 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
1WSR	Crystal Structure of Human T-protein of Glycine Cleavage System	X-RAY DIFFRACTION	2
1WSV	Crystal Structure of Human T-protein of Glycine Cleavage System	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48728-F1	93.66	0.91

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; nucleoplasm

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

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

Ligand- & substrate-binding residues (3)

Position	Role
232	substrate
261	substrate
399	substrate

Mutagenesis-validated functional residues (1)

Position	Phenotype
129	loss of aminomethyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-6783984	Glycine degradation	curated
R-HSA-389661	Glyoxylate metabolism and glycine degradation	—
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—

MSigDB gene sets: 148 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, KEGG_ONE_CARBON_POOL_BY_FOLATE, MODULE_66, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, MODULE_294, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_GLYCINE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, MODULE_88, GOBP_AMINO_ACID_CATABOLIC_PROCESS, URS_ADIPOCYTE_DIFFERENTIATION_UP, MODULE_11, MODULE_60

GO Biological Process (3): glycine catabolic process (GO:0006546), glycine decarboxylation via glycine cleavage system (GO:0019464), methylation (GO:0032259)

GO Molecular Function (5): aminomethyltransferase activity (GO:0004047), transaminase activity (GO:0008483), protein binding (GO:0005515), methyltransferase activity (GO:0008168), transferase activity (GO:0016740)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), glycine cleavage complex (GO:0005960)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Glyoxylate metabolism and glycine degradation	1
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

16 GO namespaces:

Category	Terms
glycine metabolic process	1
amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
glycine catabolic process	1
metabolic process	1
hydroxymethyl-, formyl- and related transferase activity	1
transferase activity, transferring nitrogenous groups	1
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
oxidoreductase complex	1
transferase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
glycine decarboxylation via glycine cleavage system	BP	mutant phenotype
mitochondrion	CC	direct assay
aminomethyltransferase activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,236 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AMT	GCSH	P23434	974
AMT	GLDC	P23378	970
AMT	MYBPH	Q13203	951
AMT	OCA2	Q04671	885
AMT	DLD	P09622	858
AMT	SHMT2	P34897	720
AMT	SHMT1	P34896	666
AMT	A0A1W2PS29	A0A1W2PS29	630
AMT	A0A1W2PPQ1	A0A1W2PPQ1	600
AMT	ATIC	P31939	582
AMT	AGXT	P21549	569
AMT	GCAT	O75600	553
AMT	MTHFD1	P11586	532
AMT	MTHFR	P42898	528
AMT	AASS	Q9UDR5	523

IntAct

BioGRID (12 interactions; top human partners by supporting records): HSPA8 (Affinity Capture-Luminescence; 2 records), DDX58 (Affinity Capture-RNA), MAPT (Proximity Label-MS), PARP10 (Proximity Label-MS), PDLIM4 (Two-hybrid), PNPT1 (Co-fractionation), PSMA2 (Co-fractionation), SPPL3 (Positive Genetic), TRIM71 (Affinity Capture-RNA), VAC14 (Two-hybrid), ZRANB1 (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

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

Disease & clinical

Genetic variants

Variant evidence for AMT: 776 ClinVar records (121 pathogenic / likely pathogenic); 16 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	60
Likely pathogenic	61
Uncertain significance	233
Likely benign	330
Benign	10

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 121 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
11979	NM_000481.4(AMT):c.959G>A (p.Arg320His)	Pathogenic	criteria provided, multiple submitters, no conflicts	20
11981	NM_000481.4(AMT):c.878-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	10
56233	NM_000481.4(AMT):c.471+2T>C	Pathogenic	criteria provided, multiple submitters, no conflicts	8
552860	NM_000481.4(AMT):c.664C>T (p.Arg222Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
557617	NM_000481.4(AMT):c.496C>T (p.Gln166Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
11978	NM_000481.4(AMT):c.826G>C (p.Asp276His)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
552502	NM_000481.4(AMT):c.15_18del (p.Ser6fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
1071418	NM_000481.4(AMT):c.317T>C (p.Ile106Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
962887	NM_000481.4(AMT):c.1107_1108del (p.Tyr369_Ser370delinsTer)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
801971	NM_000481.4(AMT):c.908del (p.Pro303fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1453525	NM_000481.4(AMT):c.59dup (p.Ala21fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1457206	NM_000481.4(AMT):c.2T>C (p.Met1Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
56231	NM_000481.4(AMT):c.434A>T (p.Asn145Ile)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
56241	NM_000481.4(AMT):c.982_983delinsT (p.Ala328fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
552170	NM_000481.4(AMT):c.1034-1dup	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3

Per-variant reference — Sugi Variant

Explore AMT’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 42 predictions of 784):

Position(s)	Effect	Δscore	Sites
3:49417719–49417720	acceptor_loss	1.0000	6
3:49419275	donor_gain	1.0000
3:49421490–49421491	donor_loss	1.0000	5
3:49421506	donor_gain	1.0000
3:49421573–49421574	acceptor_loss	1.0000	6
3:49417803	donor_gain	0.9900
3:49418969–49418970	donor_loss	0.9900	6
3:49419152–49419153	acceptor_loss	0.9900	6
3:49419258–49419259	donor_loss	0.9900	5
3:49419708–49419709	donor_loss	0.9900	5

AlphaMissense

930 missense substitutions predicted likely pathogenic (of 2,618 scored), across 250 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M84	9	0.905	0.991
D128	8	0.987	0.995
D129	8	0.983	0.993
D80	8	0.968	0.982
F79	8	0.966	0.995
D276	8	0.955	0.993
D262	8	0.946	0.985
F204	8	0.940	0.995
N145	8	0.938	0.994
D229	8	0.938	0.982
H83	8	0.934	0.982
F52	8	0.933	0.997
F394	8	0.909	0.974
H42	8	0.896	0.970
H69	8	0.884	0.977
S349	8	0.884	0.995
D152	8	0.855	0.970
E267	7	0.973	0.989
W290	7	0.968	0.989
E232	7	0.963	0.977

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.84e-08
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	3.97e-07
Lung Adenocarcinoma (TCGA)	favorable	9.19e-05
Rectum Adenocarcinoma (TCGA)	favorable	0.000259

Disease associations

OMIM: gene MIM:238310 | disease phenotypes: MIM:605899, MIM:620398, MIM:212138, MIM:613818, MIM:616538

GenCC curated gene-disease

6 curated gene-disease records:

Disease	Classification	Inheritance	Records
glycine encephalopathy	Definitive	Autosomal recessive	4
glycine encephalopathy 2	Definitive	Autosomal recessive
glycine encephalopathy 1	Strong	Autosomal recessive
neonatal glycine encephalopathy	Supportive	Autosomal recessive
infantile glycine encephalopathy	Supportive	Autosomal recessive
atypical glycine encephalopathy	Supportive	Unknown

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
glycine encephalopathy	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (10 panels, 10 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

10 panels:

Panel	Rating
DDG2P	green
Early onset or syndromic epilepsy	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (9): glycine encephalopathy (MONDO:0011612), glycine encephalopathy 2 (MONDO:0958192), glycine encephalopathy 1 (MONDO:0958179), carnitine-acylcarnitine translocase deficiency (MONDO:0008918), autosomal recessive limb-girdle muscular dystrophy type 2P (MONDO:0013440), muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9 (MONDO:0014683), neonatal glycine encephalopathy (MONDO:0017353), infantile glycine encephalopathy (MONDO:0017354), atypical glycine encephalopathy (MONDO:0015010)

Orphanet (5): Glycine encephalopathy (Orphanet:407), Carnitine-acylcarnitine translocase deficiency (Orphanet:159), Alpha-dystroglycan-related limb-girdle muscular dystrophy R16 (Orphanet:280333), Muscle-eye-brain disease with bilateral multicystic leucodystrophy (Orphanet:370997), Walker-Warburg syndrome (Orphanet:899)

HPO phenotypes

10 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0002878	Respiratory failure
HP:0003623	Neonatal onset
HP:0008288	Nonketotic hyperglycinemia
HP:0010851	EEG with burst suppression
HP:0010864	Severe intellectual disability
HP:0011342	Mild global developmental delay
HP:0011463	Childhood onset
HP:0500230	Increased CSF glycine concentration

GWAS associations

16 associations:

Study	Trait	p-value
GCST004131_23	Inflammatory bowel disease	1e-33
GCST010698_7	Subcortical volume (min-P)	3e-24
GCST004132_111	Crohn’s disease	3e-23
GCST004133_74	Ulcerative colitis	8e-20
GCST010701_11	Cortical surface area (MOSTest)	1e-16
GCST010703_214	Brain morphology (MOSTest)	2e-13
GCST010702_18	Subcortical volume (MOSTest)	1e-10
GCST008840_1	Depressive symptom (depressed mood) (binary trait)	8e-10
GCST008849_2	Depressive symptoms (binary sum-score)	7e-9
GCST005196_234	Coronary artery disease	1e-8
GCST006922_9	Regular attendance at a religious group	3e-8
GCST007559_12	Sleep duration (short sleep)	3e-8
GCST007044_11	Extremely high intelligence	4e-8
GCST010699_3	Brain morphology (min-P)	4e-8
GCST003854_32	Gut microbiota (functional units)	4e-6
GCST002774_6	Cognitive function	8e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0007874	gut microbiome measurement
EFO:0009592	social interaction measurement
EFO:0007006	depressive symptom measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C562812	Carnitine-Acylcarnitine Translocase Deficiency *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression	2
Fluorouracil	increases expression	2
Nickel	decreases expression	2
Valproic Acid	affects expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
methylselenic acid	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	affects expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Plant Oils	decreases expression	1
Polychlorinated Biphenyls	affects expression	1
Quercetin	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tunicamycin	increases expression	1
Urethane	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

6 trials:

NCT	Phase	Status	Title
NCT02214160	Phase 2	COMPLETED	Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Extension Study for Subjects Previously Enrolled in Triheptanoin Studies
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT03655223	Not specified	ACTIVE_NOT_RECRUITING	Early Check: Expanded Screening in Newborns
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments