GAMT

Chr 19AR

guanidinoacetate N-methyltransferase

Also known as: CCDS2, HEL-S-20, PIG2, TP53I2

NCBI Gene: 2593ENSG00000130005UniProt: Q14353

The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

Primary Disease Associations & Inheritance

Cerebral creatine deficiency syndrome 2MIM #612736
AR
595
ClinVar variants
128
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— GAMT
🧬
Gene-Disease Validity (ClinGen)
guanidinoacetate methyltransferase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
128 Pathogenic / Likely Pathogenic· 218 VUS of 595 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.26LOEUF
pLI 0.009
Z-score 1.11
OE 0.55 (0.27–1.26)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.09Z-score
OE missense 1.02 (0.89–1.17)
153 obs / 150.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.27–1.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.02 (0.89–1.17)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 4 / 7.2Missense obs/exp: 153 / 150.0Syn Z: 0.02

ClinVar Variant Classifications

595 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic63
VUS218
Likely Benign235
Benign12
Conflicting2
65
Pathogenic
63
Likely Pathogenic
218
VUS
235
Likely Benign
12
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
13
27
0
65
Likely Pathogenic
29
20
13
1
63
VUS
1
179
30
8
218
Likely Benign
1
11
91
132
235
Benign
0
3
9
0
12
Conflicting
—2
Total56226170141595

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GAMT · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GAMT-related guanidinoacetate methyltransferase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cerebral creatine deficiency syndrome 2

MIM #612736

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GAMT
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Creatine deficiency syndromes.
Schulze A·Mol Cell Biochem
2003Review
Creatine deficiency syndromes.
Schulze A·Handb Clin Neurol
2013Review
GAMT Deficiency: Clinical Presentation, Treatment, Diagnosis, Animal Models, Preclinical and Clinical Developments.
Biagiotti S et al.·Int J Mol Sci
2025Review
Electro-clinical features and long-term outcomes in guanidinoacetate methyltransferase (GAMT) deficiency.
Yıldız Y et al.·Eur J Paediatr Neurol
2024
Muscle phenotype of AGAT- and GAMT-deficient mice after simvastatin exposure.
Sasani A et al.·Amino Acids
2020
Current and potential new treatment strategies for creatine deficiency syndromes.
Fernandes-Pires G et al.·Mol Genet Metab
2022Review
Overexpression of GAMT restores GAMT activity in primary GAMT-deficient fibroblasts.
Almeida LS et al.·Mol Genet Metab
2006
Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency.
Dhar SU et al.·Mol Genet Metab
2009
ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.
Goldstein J et al.·Mol Genet Metab
2024
Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders.
Stockler-Ipsiroglu S et al.·Semin Neurol
2014Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools