Is GAMT p.Phe149fs (c.444_448del) pathogenic?

GAMT p.Phe149fs (c.444448del) is classified Likely pathogenic in GAMT (ClinVar, Expert panel, 3 submitters; last evaluated 2026-04-24). No gnomAD frequency available for this variant; Associated with guanidinoacetate methyltransferase deficiency.

How common is GAMT p.Phe149fs (c.444_448del) in the general population?

GAMT p.Phe149fs (c.444_448del) is no gnomAD frequency available for this variant (gnomAD).

GAMT p.Phe149fs

Q: What condition is associated with GAMT p.Phe149fs (c.444_448del)?

GAMT p.Phe149fs (c.444_448del) is associated with guanidinoacetate methyltransferase deficiency, cerebral creatine deficiency syndrome (ClinVar).

Q: How is Guanidinoacetate methyltransferase deficiency inherited?

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

c.444_448del · rs2512224776 · VCV2831012

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

guanidinoacetate methyltransferase deficiency

ClinGen expert panel — Cerebral Creatine Deficiency Syndromes VCEP

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

PVS1_Strong PM2_Supporting PP4 PM3

Curation rationale (ClinGen, verbatim)

The NM_000156.6:c.444_448del (p.Phe149LeufsTer40) variant in GAMT is a frameshift variant that is predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. About 20% of the protein is predicted to be removed (PVS1_Strong). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). One patient with clinical symptoms consistent with GAMT deficiency has been reported with elevated guanidinoacetate and low creatine in dried blood spot, and improvement in seizure frequency after 3 years of creatine treatment (PMID: 35588794) (PP4). This individual is compound heterozygous for the variant and another variant in GAMT that has been classified as likely pathogenic for GAMT deficiency by the CCDS VCEP, c.520T>C (p.Trp174Arg) (ClinVar Variation ID: 1420866), confirmed in trans by parental DNA testing (PMID: 35588794),1 point. (PM3). There is a ClinVar entry for this variant (Variation ID: 2831012). In summary, this variant meets the criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase deficiency. GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specification Version 2.0.0.): PVS1_Strong, PM3, PP4, PM2_Supporting (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 24, 2026)

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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.47	GERP -2.7, phastCons 0.15

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GAMT
Protein: p.Phe149fs
Coding: c.444_448del
MANE Select: NM_000156
dbSNP: rs2512224776
Type: Deletion
Location: chr19:1399139 (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 149: 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

Also linked: cerebral creatine deficiency syndrome

For Guanidinoacetate methyltransferase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

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GAMT p.Ala103fs Pathogenic/Likely pathogenic ★★ same condition
GAMT p.Asp101fs Pathogenic/Likely pathogenic ★★ same condition
GAMT p.Gln97fs Pathogenic ★★ same condition
GAMT p.Ile111fs Pathogenic/Likely pathogenic ★★ same condition
GAMT p.Leu159fs Pathogenic/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-phe149fs (accessed [today's date]).

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