Is GAMT p.Ser76= (c.228A>T) pathogenic?

GAMT p.Ser76= (c.228A>T) is classified Uncertain significance in GAMT (ClinVar, Expert panel, 3 submitters; last evaluated 2024-10-08). Ultra-rare (popmax 0.0101%, amr); Associated with guanidinoacetate methyltransferase deficiency.

What condition is associated with GAMT p.Ser76= (c.228A>T)?

GAMT p.Ser76= (c.228A>T) is associated with guanidinoacetate methyltransferase deficiency, cerebral creatine deficiency syndrome (ClinVar).

How common is GAMT p.Ser76= (c.228A>T) in the general population?

GAMT p.Ser76= (c.228A>T) is ultra-rare (popmax 0.0101%, amr) (gnomAD).

GAMT p.Ser76=

Q: How is Guanidinoacetate methyltransferase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.228A>T · rs752364729 · VCV1552732

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, amr)

Conditions

guanidinoacetate methyltransferase deficiency

ClinGen expert panel — Cerebral Creatine Deficiency Syndromes VCEP

Uncertain Significance for guanidinoacetate methyltransferase deficiency. Applied ACMG criteria (verbatim):

PM2_Supporting BP7 BP4

Curation rationale (ClinGen, verbatim)

The NM_000156.6:c.228A>T (p.Ser76=) variant in GAMT is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by phyloP (score -0.250) (BP4, BP7). To our knowledge, this variant has not been reported among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001008 (6/59514 alleles) in the Admixed American 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: 1552732). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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 2.0.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.1	GERP -3.1
Overall
CADD	0.566	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0101% Admixed American · 6/59,514 alleles

Filtering AF 0.00431% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00297%

Overall 0.000497% 8/1,608,564 alleles · ultra-rare exomes 7/1,456,400 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0101%	9,919
European (non-Finnish)	0.00017%	589,202

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.Ser76=
Coding: c.228A>T
MANE Select: NM_000156
dbSNP: rs752364729
Type: single nucleotide variant
Location: chr19:1399892 (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 76: the rmt2 domain; a UniProt-annotated variant site (no effect on enzymatic activity); an α-helix

Full GAMT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

guanidinoacetate methyltransferase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral creatine deficiency syndrome

For Guanidinoacetate methyltransferase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

GAMT p.Ser76Leu Uncertain significance ★★ ⚠ same residue
GAMT p.Ser76Pro Uncertain significance ★ ⚠ 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
GAMT c.391+5G>C 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-ser76 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown