Is GATM p.Pro74= (c.222C>G) pathogenic?

GATM p.Pro74= (c.222C>G) is classified Likely benign in GATM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). Very rare (popmax 0.00667%, amr); Associated with AGAT deficiency.

What condition is associated with GATM p.Pro74= (c.222C>G)?

GATM p.Pro74= (c.222C>G) is associated with AGAT deficiency (ClinVar).

How common is GATM p.Pro74= (c.222C>G) in the general population?

GATM p.Pro74= (c.222C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

GATM p.Pro74=

Q: How is L-Arginine:glycine amidinotransferase deficiency inherited?

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

c.222C>G · rs774485349 · VCV2052168

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

AGAT deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.5
Overall
CADD	4.846	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,014 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000274% 4/1,461,890 alleles · very rare

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: GATM
Protein: p.Pro74=
Coding: c.222C>G
MANE Select: NM_001482
dbSNP: rs774485349
Type: single nucleotide variant
Location: chr15:45376667 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 11 PDB

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

Disease context

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

For L-Arginine:glycine amidinotransferase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

GATM p.Pro74Leu Uncertain significance ★ ⚠ same residue
GATM p.Pro74Thr Uncertain significance ★ ⚠ same residue
GATM c.484+1G>T Pathogenic ★★★ same condition
GATM p.Ala185Pro Likely pathogenic ★★★ same condition
GATM p.Arg169Ter Pathogenic ★★★ same condition
GATM p.Arg260Ter Likely pathogenic ★★★ same condition
GATM p.Arg413Gln Likely pathogenic ★★★ ⚠ same condition
GATM p.Arg413Trp 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/gatm-p-pro74 (accessed [today's date]).

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