AGAT deficiency

Summary

AGAT deficiency (MONDO:0012996) is a disease caused by GATM (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GATM (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 604
• Phenotypes (HPO): 17
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:6000572	Reduced tissue arginine:glycine amidinotransferase activity	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0012101	Decreased serum creatinine	Frequent (30-79%)
HP:0025051	Reduced brain creatine level by MRS	Frequent (30-79%)
HP:0034292	Reduced circulating creatine concentration	Frequent (30-79%)
HP:0034597	Decreased CSF creatinine concentration	Frequent (30-79%)
HP:0034888	Decreased urine guanidinoacetic acid level	Frequent (30-79%)
HP:6000115	Decreased urine creatinine level	Frequent (30-79%)
HP:6000748	Decreased urinary creatine level	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	AGAT deficiency
Mondo ID	MONDO:0012996
MeSH	C567192
OMIM	612718
Orphanet	35704
DOID	DOID:0050712
SNOMED CT	702440000
UMLS	C2675179
MedGen	436367
GARD	0010323
Is cancer (heuristic)	no

Also known as: AGAT deficiency · arginine:glycine amidinotransferase deficiency · CCDS3 · cerebral creatine deficiency syndrome 3 · cerebral creatine deficiency syndrome type 3 · creatine deficiency syndrome due to AGAT deficiency · disorder of glycine amidinotransferase activity · GATM deficiency · glycine amidinotransferase activity disease · L-arginine:glycine amidinotransferase deficiency

Data availability: 604 ClinVar variants · 56 ClinGen variant curations · 6 GenCC gene-disease records · 2 cell lines.

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 › cerebral creatine deficiency syndrome › AGAT deficiency

Related subtypes (2): creatine transporter deficiency, guanidinoacetate methyltransferase deficiency

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

600 retrieved; paginated sample, class counts are floors:

275 uncertain significance, 256 likely benign, 23 benign, 17 pathogenic, 16 likely pathogenic, 6 conflicting classifications of pathogenicity, 6 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1387616	NM_001482.3(GATM):c.724_725del (p.Gly242fs)	GATM	Pathogenic	criteria provided, single submitter
1456298	NM_001482.3(GATM):c.401T>G (p.Leu134Ter)	GATM	Pathogenic	criteria provided, single submitter
2004921	NM_001482.3(GATM):c.580C>T (p.Arg194Ter)	GATM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21299	NM_001482.3(GATM):c.484+1G>T	GATM	Pathogenic	reviewed by expert panel
2446450	NM_001482.3(GATM):c.629G>A (p.Trp210Ter)	GATM	Pathogenic	reviewed by expert panel
2799740	NM_001482.3(GATM):c.41_48dup (p.Val17fs)	GATM	Pathogenic	criteria provided, single submitter
2836363	NM_001482.3(GATM):c.76C>T (p.Arg26Ter)	GATM	Pathogenic	criteria provided, single submitter
2842677	NM_001482.3(GATM):c.551del (p.Met184fs)	GATM	Pathogenic	criteria provided, single submitter
2844980	NM_001482.3(GATM):c.1079dup (p.Met360fs)	GATM	Pathogenic	criteria provided, single submitter
2850245	NM_001482.3(GATM):c.207C>A (p.Tyr69Ter)	GATM	Pathogenic	criteria provided, single submitter
3243810	NC_000015.9:g.(?45661504)(45670651_?)del	GATM	Pathogenic	criteria provided, single submitter
3638018	NM_001482.3(GATM):c.92G>A (p.Trp31Ter)	GATM	Pathogenic	criteria provided, single submitter
3638316	NM_001482.3(GATM):c.964C>T (p.Arg322Ter)	GATM	Pathogenic	criteria provided, single submitter
3721886	NM_001482.3(GATM):c.5_33del (p.Leu2fs)	GATM	Pathogenic	criteria provided, single submitter
4734408	NM_001482.3(GATM):c.141dup (p.Asn48fs)	GATM	Pathogenic	criteria provided, single submitter
55918	NM_001482.3(GATM):c.1111dup (p.Met371fs)	GATM	Pathogenic	reviewed by expert panel
55919	NM_001482.3(GATM):c.505C>T (p.Arg169Ter)	GATM	Pathogenic	reviewed by expert panel
7302	NM_001482.3(GATM):c.446G>A (p.Trp149Ter)	GATM	Pathogenic	reviewed by expert panel
1478699	NM_001482.3(GATM):c.553G>C (p.Ala185Pro)	GATM	Likely pathogenic	reviewed by expert panel
205617	NM_001482.3(GATM):c.778C>T (p.Arg260Ter)	GATM	Likely pathogenic	reviewed by expert panel
2446451	NM_001482.3(GATM):c.1238G>A (p.Arg413Gln)	GATM	Likely pathogenic	reviewed by expert panel
2699241	NM_001482.3(GATM):c.288+2_288+11del	GATM	Likely pathogenic	criteria provided, single submitter
2709818	NM_001482.3(GATM):c.70-2A>C	GATM	Likely pathogenic	criteria provided, single submitter
2709887	NM_001482.3(GATM):c.979-1_979insT	GATM	Likely pathogenic	criteria provided, single submitter
2747701	NM_001482.3(GATM):c.1043-1G>C	GATM	Likely pathogenic	criteria provided, single submitter
2751845	NM_001482.3(GATM):c.676-1G>C	GATM	Likely pathogenic	criteria provided, single submitter
2760560	NM_001482.3(GATM):c.289-1_292del	GATM	Likely pathogenic	criteria provided, single submitter
3000694	NM_001482.3(GATM):c.69+1G>A	GATM	Likely pathogenic	criteria provided, single submitter
3577235	NM_001482.3(GATM):c.217_250dup (p.Glu84fs)	GATM	Likely pathogenic	criteria provided, single submitter
3716750	NM_001482.3(GATM):c.608A>G (p.Tyr203Cys)	GATM	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
GATM	Definitive	Autosomal recessive	AGAT deficiency	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GATM	Orphanet:3337	Primary Fanconi renotubular syndrome
GATM	Orphanet:35704	L-Arginine:glycine amidinotransferase deficiency
DUOX2	Orphanet:226316	Genetic transient congenital hypothyroidism
DUOX2	Orphanet:95716	Familial thyroid dyshormonogenesis
AFG2B	Orphanet:659975	Sensorineural hearing loss-spastic quadriplegia-intellectual disability syndrome
AFG2B	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
GATM	HGNC:4175	ENSG00000171766	P50440	Glycine amidinotransferase, mitochondrial	gencc,clinvar
DUOX2	HGNC:13273	ENSG00000140279	Q9NRD8	Dual oxidase 2	clinvar
AFG2B	HGNC:28762	ENSG00000171763	Q9BVQ7	ATPase family gene 2 protein homolog B	clinvar
COXFA4L3	HGNC:29898	ENSG00000166920	Q9C002	Cytochrome c oxidase associated subunit FA4L3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GATM	Glycine amidinotransferase, mitochondrial	Transamidinase that catalyzes the transfer of the amidino group of L-arginine onto the amino moiety of acceptor metabolites such as glycine, beta-alanine, gamma-aminobutyric acid (GABA) and taurine yielding the corresponding guanidine deri…
DUOX2	Dual oxidase 2	Generates hydrogen peroxide which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO.
AFG2B	ATPase family gene 2 protein homolog B	ATP-dependent chaperone part of the 55LCC heterohexameric ATPase complex which is chromatin-associated and promotes replisome proteostasis to maintain replication fork progression and genome stability.
COXFA4L3	Cytochrome c oxidase associated subunit FA4L3	Mitochondrial small peptide that orchestrates a two-pronged immunoregulatory mechanism in response to inflammatory stimuli.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GATM	Enzyme (other)	yes	2.1.4.1	AmidinoTrfase
DUOX2	Enzyme (other)	yes	1.6.3.1	EF_hand_dom, Haem_peroxidase_sf, EF-hand-dom_pair
AFG2B	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
COXFA4L3	Other/Unknown	no		B12D

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
adult organism	1
body of pancreas	1
right lobe of liver	1
gall bladder	1
nasal cavity epithelium	1
palpebral conjunctiva	1
buccal mucosa cell	1
esophagus squamous epithelium	1
lower esophagus mucosa	1
mucosa of transverse colon	1
rectum	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GATM	289	ubiquitous	marker	body of pancreas, adult organism, right lobe of liver
DUOX2	191	tissue_specific	marker	gall bladder, nasal cavity epithelium, palpebral conjunctiva
AFG2B	272	ubiquitous	marker	lower esophagus mucosa, esophagus squamous epithelium, buccal mucosa cell
COXFA4L3	130	broad	marker	mucosa of transverse colon, rectum, right testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AFG2B	3,341
GATM	2,658
DUOX2	1,639
COXFA4L3	980

Intra-cohort edges

A	B	Sources
AFG2B	GATM	string_interaction
DUOX2	GATM	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GATM	P50440	11
AFG2B	Q9BVQ7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COXFA4L3	Q9C002	89.97
DUOX2	Q9NRD8	84.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Creatine metabolism	1	519.1×	0.002	GATM
Thyroxine biosynthesis	1	407.9×	0.002	DUOX2

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
creatine biosynthetic process	1	2106.5×	0.004	GATM
muscle atrophy	1	2106.5×	0.004	GATM
cuticle development	1	1404.3×	0.004	DUOX2
mitotic spindle disassembly	1	1404.3×	0.004	AFG2B
creatine metabolic process	1	1053.2×	0.005	GATM
hormone biosynthetic process	1	351.1×	0.010	DUOX2
hydrogen peroxide biosynthetic process	1	351.1×	0.010	DUOX2
thyroid hormone generation	1	247.8×	0.011	DUOX2
retrograde protein transport, ER to cytosol	1	247.8×	0.011	AFG2B
positive regulation of cell motility	1	191.5×	0.012	DUOX2
superoxide anion generation	1	168.5×	0.012	DUOX2
hydrogen peroxide catabolic process	1	168.5×	0.012	DUOX2
positive regulation of wound healing	1	131.7×	0.013	DUOX2
response to cAMP	1	127.7×	0.013	DUOX2
ribosomal large subunit biogenesis	1	110.9×	0.014	AFG2B
autophagosome maturation	1	87.8×	0.017	AFG2B
learning or memory	1	60.2×	0.023	GATM
defense response	1	54.0×	0.025	DUOX2
response to bacterium	1	48.4×	0.026	COXFA4L3
positive regulation of cold-induced thermogenesis	1	40.9×	0.029	GATM
response to virus	1	36.0×	0.031	DUOX2
response to oxidative stress	1	32.7×	0.032	DUOX2
cytokine-mediated signaling pathway	1	32.7×	0.032	DUOX2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	13.0×	0.074	AFG2B

Therapeutics

Drug target analysis

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

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
GATM	0	0
DUOX2	0	0
AFG2B	0	0
COXFA4L3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
DUOX2	1	Binding:1
AFG2B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GATM	2.1.4.1	glycine amidinotransferase
DUOX2	1.6.3.1	NAD(P)H oxidase (H2O2-forming)

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

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	GATM
D	Druggable family + AlphaFold only, no drug	1	DUOX2
E	Difficult family or no structure, no drug	2	AFG2B, COXFA4L3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GATM	0	—
DUOX2	1	—
AFG2B	1	—
COXFA4L3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns