Is GATM p.Pro320Ser (c.958C>T) pathogenic?

GATM p.Pro320Ser (c.958C>T) is classified Pathogenic in GATM (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-11). AlphaMissense: ambiguous (0.5362); Absent from gnomAD v4.1; Associated with Fanconi renotubular syndrome 1.

What condition is associated with GATM p.Pro320Ser (c.958C>T)?

GATM p.Pro320Ser (c.958C>T) is associated with Fanconi renotubular syndrome 1 (ClinVar).

How common is GATM p.Pro320Ser (c.958C>T) in the general population?

GATM p.Pro320Ser (c.958C>T) is absent from gnomAD v4.1 (gnomAD).

How is Primary Fanconi renotubular syndrome inherited?

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

What do computational predictors say about GATM p.Pro320Ser (c.958C>T)?

AlphaMissense predicts ambiguous (score 0.5362) — an in-silico prediction, not a clinical call.

GATM p.Pro320Ser

c.958C>T · rs1889443535 · VCV917493

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5362 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Fanconi renotubular syndrome 1

ClinGen expert panel — Cerebral Creatine Deficiency Syndromes VCEP

Uncertain Significance for AGAT deficiency. Applied ACMG criteria (verbatim):

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_001482.3:c.958C>T variant in GATM is a missense variant that is predicted to result in the substitution of proline by serine at amino acid 320 (p.Pro320Ser). It is absent in gnomAD v2.1.1. (PM2_Supporting). The computational predictor REVEL gives a score of 0.356 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. To our knowledge, this variant has not been reported in an individual with phenotypic features of AGAT deficiency. It has been reported as a single heterozygous variant segregating in a family autosomal dominant renal Fanconi syndrome and kidney failure (PMID: 29654216). However, classification with respect to this alternative disorder is outside the scope of this curation. There is a ClinVar entry for this variant (Variation ID: 917493). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.5362	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -12.09	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 15 kb · p 1.8e-10 · regional, not allelic
Overall
CADD	27.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GATM
Protein: p.Pro320Ser
Coding: c.958C>T
MANE Select: NM_001482
dbSNP: rs1889443535
Type: single nucleotide variant
Location: chr15:45366066 (GRCh38)
Gene constraint: LOEUF 0.597 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 90.24 · 11 PDB
Residue 320: a UniProt-annotated variant site (in frts1; results in gatm protein aggregation; gatm deposits affect mitochondrial morphology leading to abnormal and elongated mitochondria)

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

Disease context

Fanconi renotubular syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary Fanconi renotubular syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy

Similar variants

GATM p.Pro320Ala Uncertain significance ★ ⚠ same residue
GATM c.484+1G>T Pathogenic ★★★ same condition
GATM p.Arg169Ter Pathogenic ★★★ same condition
GATM p.Pro320fs Likely pathogenic ★★★ same residue
GATM p.Arg189Cys Uncertain significance ★★★ ⚠ same condition
GATM p.Arg282His Uncertain significance ★★★ ⚠ same condition
GATM p.Asp411Asn Uncertain significance ★★★ ⚠ same condition
GATM p.Pro341Leu Uncertain significance ★★★ ⚠ 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-pro320ser (accessed [today's date]).

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