Is GAMT p.Pro40Arg (c.119C>G) pathogenic?

GAMT p.Pro40Arg (c.119C>G) is classified Uncertain significance in GAMT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-10). AlphaMissense: likely pathogenic (0.8012); Very rare (popmax 0.000174%, nfe); Associated with cerebral creatine deficiency syndrome.

What condition is associated with GAMT p.Pro40Arg (c.119C>G)?

GAMT p.Pro40Arg (c.119C>G) is associated with cerebral creatine deficiency syndrome (ClinVar).

How common is GAMT p.Pro40Arg (c.119C>G) in the general population?

GAMT p.Pro40Arg (c.119C>G) is very rare (popmax 0.000174%, nfe) (gnomAD).

What do computational predictors say about GAMT p.Pro40Arg (c.119C>G)?

AlphaMissense predicts likely pathogenic (score 0.8012) — an in-silico prediction, not a clinical call.

GAMT p.Pro40Arg

c.119C>G · rs1222736128 · VCV2136398

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral creatine deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.8012	likely pathogenic
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,147,716 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000131% 2/1,530,032 alleles · very rare exomes 1/1,377,952 · genomes 1/152,080 · joint denominator

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.Pro40Arg
Coding: c.119C>G
MANE Select: NM_000156
dbSNP: rs1222736128
Type: single nucleotide variant
Location: chr19:1401358 (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 40: the rmt2 domain; a β-strand

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

Disease context

cerebral creatine deficiency syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GAMT p.Pro40Ser Uncertain significance ★ ⚠ same residue
GAMT p.Pro40= Likely benign ★ same residue
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

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-pro40arg (accessed [today's date]).

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