GAMT p.Trp20Ser
c.59G>C · rs80338734 · VCV8303
ClinGen expert panel — Cerebral Creatine Deficiency Syndromes VCEP
Pathogenic for guanidinoacetate methyltransferase deficiency. Applied ACMG criteria (verbatim):
PS3_Supporting PP4_Strong PM3_Strong PP3
Curation rationale (ClinGen, verbatim)
The NM_000156.6:c.59G>C variant in GAMT is a missense variant predicted to cause substitution of tryptophan by serine at amino acid 20 (p.Trp20Ser). This variant has been detected in at least 9 unrelated individuals with GAMT deficiency (PMID: 15651030, PMID: 16855203, PMID: 15108290). Of those individuals, one was compound heterozygous for the variant and a pathogenic variant, c.521G>A (p.Trp174*, in trans (PMID: 16855203) and eight individuals were homozygous for the variant (PMID: 15651030, PMID: 16855203, PMID: 15108290) (2 points total) (PM3_Strong). These individuals showed elevated plasma GAA and urine GAA (PMID: 15651030, PMID: 16855203, PMID: 15108290), three also showed deficient (<5% wild-type) GAMT enzyme activity in lymphoblasts (PMID: 15651030), and one also showed deficient (<5% wild-type) GAMT enzyme activity in fibroblasts and reduced creatine signal on brain MRS (PMID: 16855203, PMID: 21140503) (PP4_Strong). Expression of the variant in HeLa cells resulted in 3% wild type GAMT activity indicating that this variant may impact protein function (PMID: 17336114)(PS3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001 (3/27420 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004); however, as this variant is covered in <50% of individuals in gnomAD v2.1.1, allele frequency estimates may not be reliable and thus PM2_Supporting is not met. The computational predictor REVEL gives a score of 0.94 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 8303, 2 star review status) with 9 submitters classifying the variant as pathogenic and 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PS3_Supporting, PM3_Strong, PP3, PP4_Strong. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9056 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.94 | strongly pathogenic-leaning |
| SaProt | LLR -11.43 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 7.4 | GERP 1.5, phastCons 1 |
| Regional constraint | o/e 1.19 | unconstrained · MANE · 4,114 bp · p 0.00031 · regional, not allelic |
| Overall | ||
| CADD | 31.0 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0228% | 4,382 |
| Admixed American | 0.0223% | 4,481 |
| South Asian | 0.00542% | 18,465 |
| Remaining individualsnot grpmax-eligible | 0.00539% | 18,551 |
| European (non-Finnish) | 0.00317% | 31,509 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- GAMT
- Protein
- p.Trp20Ser
- Coding
- c.59G>C
- MANE Select
- NM_000156
- dbSNP
- rs80338734
- Type
- single nucleotide variant
- Location
- chr19:1401418 (GRCh38)
- Gene constraint
- LOEUF 1.536 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 96.73 · 1 PDB
- Residue 20
- a UniProt-annotated variant site (in ccds2); the rmt2 domain; a binding site; an α-helix
Disease context
guanidinoacetate methyltransferase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: cerebral creatine deficiency syndrome
For Guanidinoacetate methyltransferase deficiency (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Childhood, Infancy
Similar variants
- GAMT p.Trp20Leu Uncertain significance ★★★ ⚠ same residue
- GAMT p.Trp20Ter Pathogenic/Likely pathogenic ★★ same residue
- GAMT p.Trp20fs Pathogenic ★★★ same residue
- GAMT c.327+43G>A Likely pathogenic ★★★ same condition
- GAMT c.328-1G>A Pathogenic ★★★ same condition
- GAMT c.328-2A>G Pathogenic ★★★ same condition
- GAMT c.391+15G>T Likely pathogenic ★★★ same condition
- GAMT c.391+1G>C Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gamt-p-trp20ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown