Is GSS p.Ala48= (c.144C>G) pathogenic?

GSS p.Ala48= (c.144C>G) is classified Likely benign in GSS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-16). Very rare (popmax 0.000255%, nfe); Associated with glutathione synthetase deficiency with 5-oxoprolinuria.

What condition is associated with GSS p.Ala48= (c.144C>G)?

GSS p.Ala48= (c.144C>G) is associated with glutathione synthetase deficiency with 5-oxoprolinuria (ClinVar).

How common is GSS p.Ala48= (c.144C>G) in the general population?

GSS p.Ala48= (c.144C>G) is very rare (popmax 0.000255%, nfe) (gnomAD).

How is Glutathione synthetase deficiency inherited?

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

GSS p.Ala48=

c.144C>G · rs897705346 · VCV2921073

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

glutathione synthetase deficiency with 5-oxoprolinuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP -4.8, phastCons 1
Overall
CADD	7.975	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,178,182 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,459,490 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: GSS
Protein: p.Ala48=
Coding: c.144C>G
MANE Select: NM_000178
dbSNP: rs897705346
Type: single nucleotide variant
Location: chr20:34946084 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB

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

Disease context

glutathione synthetase deficiency with 5-oxoprolinuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glutathione synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GSS p.Ala48Ser Uncertain significance ★ ⚠ same residue
GSS c.130-1G>C Pathogenic/Likely pathogenic ★★ same condition
GSS c.-9+5G>A Pathogenic ★★ same condition
GSS p.Arg125Cys Pathogenic/Likely pathogenic ★★ same condition
GSS p.Arg164Gln Pathogenic ★★ ⚠ same condition
GSS p.Arg164Ter Pathogenic/Likely pathogenic ★★ same condition
GSS p.Arg236Ter Pathogenic/Likely pathogenic ★★ same condition
GSS p.Arg237Ter 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/gss-p-ala48 (accessed [today's date]).

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