GAMT p.Val110Phe
c.328G>T · rs753198836 · VCV205580
ClinGen expert panel — Cerebral Creatine Deficiency Syndromes VCEP
Likely Pathogenic for guanidinoacetate methyltransferase deficiency. Applied ACMG criteria (verbatim):
PP3_Moderate PM3_Supporting PM2_Supporting PS3_Supporting PP4_Strong
Curation rationale (ClinGen, verbatim)
The NM_000156.6:c.328G>T variant in GAMT is a missense variant predicted to cause substitution of valine by phenylalanine at amino acid 110 (p.Val110Phe). Two patient(s) with this variant had elevated guanidinoacetate in urine and decreased creatine peak on MRS (PMID: 24415674; CreatineInfo Registry) (PP4_Strong). Both individuals with GAMT deficiency were heterozygous for the variant and another variant in GAMT that has been classified as pathogenic (c.327G>A, PMID: 24415674) or likely pathogenic (CreatineInfo Registry data) by the ClinGen CCDS VCEP. The phase was unconfirmed in both cases (PM3_Supporting). The variant has also been reported in an individual with neurodevelopmental disorder/epilepsy but further details are unavailable, and it is unknown if this case may overlap with either of the other 2 cases (PMID: 29655203). Expression of the variant in GAMT-deficient fibroblasts resulted in extremely low GAMT activity, and no detectable expression of the protein (Figure 1, PMID 24415674) indicating that this variant may impact protein function (PS3_Supporting). The computational predictor REVEL gives a score of 0.928 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level. Furthermore, SpliceAI predicts that this variant, which alters the first nucleotide of exon 3, impacts normal splicing (score = 0.4 for acceptor loss) (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000009326 (11/1179478 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 205580. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_strong, PP3_Moderate, PS3_Supporting, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 18, 2025).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.7978 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.928 | moderately pathogenic-leaning |
| SaProt | LLR -14.43 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | Δ0.39 | acceptor loss · deltas |
| Pangolin | Δ0.38 | loss · gain 0.03 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 7.5 | GERP 1.5, phastCons 1 |
| Regional constraint | o/e 1.19 | unconstrained · MANE · 4,114 bp · p 0.00031 · regional, not allelic |
| Overall | ||
| CADD | 26.5 | 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 |
|---|---|---|
| Finnishnot grpmax-eligible | 0.00158% | 63,250 |
| European (non-Finnish)grpmax | 0.000933% | 107,225 |
Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Val110Phe
- Coding
- c.328G>T
- MANE Select
- NM_000156
- dbSNP
- rs753198836
- Type
- single nucleotide variant
- Location
- chr19:1399587 (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 110
- the rmt2 domain; a UniProt-annotated variant site (in ccds2; retains no significant activity); a β-strand
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 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
- GAMT c.391+5G>C Likely pathogenic ★★★ same condition
- GAMT p.Ala156Asp Likely pathogenic ★★★ same condition
- GAMT p.Ala54Pro Likely 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-val110phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown