Is GAMT p.Phe189Ser (c.566T>C) pathogenic?

GAMT p.Phe189Ser (c.566T>C) is classified Uncertain significance in GAMT (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.9546); Absent from gnomAD v4.1; Associated with guanidinoacetate methyltransferase deficiency.

What condition is associated with GAMT p.Phe189Ser (c.566T>C)?

GAMT p.Phe189Ser (c.566T>C) is associated with guanidinoacetate methyltransferase deficiency (ClinVar).

How common is GAMT p.Phe189Ser (c.566T>C) in the general population?

GAMT p.Phe189Ser (c.566T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GAMT p.Phe189Ser (c.566T>C)?

AlphaMissense predicts likely pathogenic (score 0.9546) — an in-silico prediction, not a clinical call.

GAMT p.Phe189Ser

Q: How is Guanidinoacetate methyltransferase deficiency inherited?

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

c.566T>C · VCV4884804

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9546 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

guanidinoacetate methyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.9546	likely pathogenic · top 10% in GAMT
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -14.26	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 11	GERP 1.5, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 4,114 bp · p 0.00031 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GAMT
Protein: p.Phe189Ser
Coding: c.566T>C
MANE Select: NM_000156
Type: single nucleotide variant
Location: chr19:1398920 (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 189: the rmt2 domain; 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

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-phe189ser (accessed [today's date]).

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