Is GSS p.Pro413= (c.1239T>C) pathogenic?

GSS p.Pro413= (c.1239T>C) is classified Likely benign in GSS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-02). Very rare (popmax 0.00223%, eas); Associated with glutathione synthetase deficiency with 5-oxoprolinuria.

What condition is associated with GSS p.Pro413= (c.1239T>C)?

GSS p.Pro413= (c.1239T>C) is associated with glutathione synthetase deficiency with 5-oxoprolinuria (ClinVar).

How common is GSS p.Pro413= (c.1239T>C) in the general population?

GSS p.Pro413= (c.1239T>C) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Glutathione synthetase deficiency inherited?

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

GSS p.Pro413=

c.1239T>C · rs201406090 · VCV1578408

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

glutathione synthetase deficiency with 5-oxoprolinuria

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 0.54	GERP -1.2, phastCons 0.79
Overall
CADD	10.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,614,082 alleles · very rare exomes 8/1,461,804 · genomes 1/152,278 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
South Asian	0.0011%	91,072
European (non-Finnish)	0.000593%	168,562

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.Pro413=
Coding: c.1239T>C
MANE Select: NM_000178
dbSNP: rs201406090
Type: single nucleotide variant
Location: chr20:34929463 (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.Pro413Ser 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-pro413 (accessed [today's date]).

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