Is GSS p.Pro325Ser (c.973C>T) pathogenic?

GSS p.Pro325Ser (c.973C>T) is classified Conflicting classifications of pathogenicity in GSS (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0835); Rare (popmax 0.488%, afr); Associated with glutathione synthetase deficiency with 5-oxoprolinuria.

What condition is associated with GSS p.Pro325Ser (c.973C>T)?

GSS p.Pro325Ser (c.973C>T) is associated with glutathione synthetase deficiency with 5-oxoprolinuria (ClinVar).

How common is GSS p.Pro325Ser (c.973C>T) in the general population?

GSS p.Pro325Ser (c.973C>T) is rare (popmax 0.488%, afr) (gnomAD).

How is Glutathione synthetase deficiency inherited?

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

What do computational predictors say about GSS p.Pro325Ser (c.973C>T)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

GSS p.Pro325Ser

c.973C>T · rs11905938 · VCV698137

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.488%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glutathione synthetase deficiency with 5-oxoprolinuria

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.247	benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -0.91, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 23 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	21.3	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

Grpmax group 0.488% African / African-American · 366/75,052 alleles

Filtering AF 0.446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.43%

Overall 0.0269% 434/1,614,208 alleles · rare exomes 194/1,461,868 · genomes 240/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.488%	205
Admixed American	0.0766%	1,305
Remaining individualsnot grpmax-eligible	0.0352%	2,841

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.Pro325Ser
Coding: c.973C>T
MANE Select: NM_000178
dbSNP: rs11905938
Type: single nucleotide variant
Location: chr20:34931995 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB
Residue 325: an α-helix

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

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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
GSS p.Arg267Trp 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-pro325ser (accessed [today's date]).

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