Is GAMT p.Pro40Ser (c.118C>T) pathogenic?

GAMT p.Pro40Ser (c.118C>T) is classified Uncertain significance in GAMT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely pathogenic (0.6626); Very rare (popmax 0.00427%, afr); Associated with cerebral creatine deficiency syndrome.

What condition is associated with GAMT p.Pro40Ser (c.118C>T)?

GAMT p.Pro40Ser (c.118C>T) is associated with cerebral creatine deficiency syndrome (ClinVar).

How common is GAMT p.Pro40Ser (c.118C>T) in the general population?

GAMT p.Pro40Ser (c.118C>T) is very rare (popmax 0.00427%, afr) (gnomAD).

What do computational predictors say about GAMT p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely pathogenic (score 0.6626) — an in-silico prediction, not a clinical call.

GAMT p.Pro40Ser

c.118C>T · rs11551914 · VCV1448647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6626 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00427%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral creatine deficiency syndrome

Computational evidence

Protein change
AlphaMissense	0.6626	likely pathogenic
REVEL	0.694	pathogenic-leaning
SaProt	LLR -8.55	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	32.0	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 0.00427% African / African-American · 3/70,238 alleles

Filtering AF 0.00113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000614%

Overall 0.000327% 5/1,529,588 alleles · very rare exomes 2/1,377,508 · genomes 3/152,080 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00427%	23,413
East Asian	0.00265%	37,804
Admixed American	0.00192%	52,196

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.Pro40Ser
Coding: c.118C>T
MANE Select: NM_000156
dbSNP: rs11551914
Type: single nucleotide variant
Location: chr19:1401359 (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.Pro40Arg 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-pro40ser (accessed [today's date]).

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