Is GAMT p.Pro217= (c.651G>A) pathogenic?

GAMT p.Pro217= (c.651G>A) is classified Likely benign in GAMT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-23). Ultra-rare (popmax 0.0147%, afr); Associated with cerebral creatine deficiency syndrome.

What condition is associated with GAMT p.Pro217= (c.651G>A)?

GAMT p.Pro217= (c.651G>A) is associated with cerebral creatine deficiency syndrome (ClinVar).

How common is GAMT p.Pro217= (c.651G>A) in the general population?

GAMT p.Pro217= (c.651G>A) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

GAMT p.Pro217=

c.651G>A · rs745327521 · VCV1052866

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

cerebral creatine deficiency syndrome

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 -20	GERP -3.3
Overall
CADD	0.156	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,904 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00211% 34/1,611,480 alleles · ultra-rare exomes 27/1,459,312 · genomes 7/152,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,809
Admixed American	0.005%	19,997
European (non-Finnish)	0.00161%	62,098
South Asian	0.0011%	91,086

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.Pro217=
Coding: c.651G>A
MANE Select: NM_000156
dbSNP: rs745327521
Type: single nucleotide variant
Location: chr19:1397419 (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 217: the rmt2 domain; an α-helix

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.Pro217Leu Uncertain significance ★★★ ⚠ same residue
GAMT p.Pro217Ala Uncertain significance ★★ ⚠ same residue
GAMT p.Pro217Gln Uncertain significance ★★ ⚠ same residue
GAMT p.Pro217Ser Uncertain significance ★ ⚠ 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

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-pro217 (accessed [today's date]).

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