Is GAMT p.Ala75= (c.225G>A) pathogenic?

GAMT p.Ala75= (c.225G>A) is classified Likely benign in GAMT (ClinVar, Expert panel, 6 submitters; last evaluated 2023-03-09). Rare (popmax 0.317%, eas); Associated with guanidinoacetate methyltransferase deficiency.

What condition is associated with GAMT p.Ala75= (c.225G>A)?

GAMT p.Ala75= (c.225G>A) is associated with guanidinoacetate methyltransferase deficiency, cerebral creatine deficiency syndrome (ClinVar).

How common is GAMT p.Ala75= (c.225G>A) in the general population?

GAMT p.Ala75= (c.225G>A) is rare (popmax 0.317%, eas) (gnomAD).

GAMT p.Ala75=

Q: How is Guanidinoacetate methyltransferase deficiency inherited?

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

c.225G>A · rs202151546 · VCV137433

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.317%, eas)

Conditions

guanidinoacetate methyltransferase deficiency

ClinGen expert panel — Cerebral Creatine Deficiency Syndromes VCEP

Likely Benign for guanidinoacetate methyltransferase deficiency. Applied ACMG criteria (verbatim):

BS1 BP4

Curation rationale (ClinGen, verbatim)

The NM_000156.6(GAMT):c.225G>A (p.Ala75=) variant is a synonymous variant for which splicing prediction algorithms (SpliceAI, varSEAK) predict no impact to the splice consensus sequence nor the creation of a new splice site (BP4); however, the residue altered (Ala75) is conserved through zebrafish. Thus, BP7 is not met. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00117 (21/17954 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). There is a ClinVar entry for this variant (Variation ID: 137433). In summary, this variant meets the crietria to be classified as likely benign for GAMT deficiency. GAMT-specific criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP): BS1, BP4. (Classification approved by the ClinGen CCDS VCEP on March 9, 2023).

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 0.88	GERP -3.1, phastCons 0.99
Overall
CADD	5.803	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.317% East Asian · 142/44,736 alleles

Filtering AF 0.275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.259%

Overall 0.0121% 194/1,608,586 alleles · rare exomes 189/1,456,282 · genomes 5/152,304 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.317%	315
South Asian	0.00667%	14,999
European (non-Finnish)	0.00365%	27,403
Admixed American	0.00336%	29,755
Remaining individualsnot grpmax-eligible	0.00161%	62,288

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.Ala75=
Coding: c.225G>A
MANE Select: NM_000156
dbSNP: rs202151546
Type: single nucleotide variant
Location: chr19:1399895 (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 75: the rmt2 domain; a UniProt-annotated variant site (in ccds2; retains no significant 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.Ala75Val Pathogenic ★★★ same residue
GAMT p.Ala75Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
GAMT p.Ala75Thr 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

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-ala75 (accessed [today's date]).

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