Is GSS p.Arg330Cys (c.988C>T) pathogenic?

GSS p.Arg330Cys (c.988C>T) is classified Conflicting classifications of pathogenicity in GSS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-04-28). AlphaMissense: likely benign (0.2436); Rare (popmax 0.235%, amr); Associated with glutathione synthetase deficiency with 5-oxoprolinuria.

What condition is associated with GSS p.Arg330Cys (c.988C>T)?

GSS p.Arg330Cys (c.988C>T) is associated with glutathione synthetase deficiency with 5-oxoprolinuria, inherited glutathione synthetase deficiency (ClinVar).

How common is GSS p.Arg330Cys (c.988C>T) in the general population?

GSS p.Arg330Cys (c.988C>T) is rare (popmax 0.235%, amr) (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.Arg330Cys (c.988C>T)?

AlphaMissense predicts likely benign (score 0.2436) — an in-silico prediction, not a clinical call.

GSS p.Arg330Cys

c.988C>T · rs148640446 · VCV897215

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2436 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.235%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glutathione synthetase deficiency with 5-oxoprolinuria

Computational evidence

Protein change
AlphaMissense	0.2436	likely benign
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -14.33	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 23 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	31.0	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 0.235% Admixed American · 141/60,022 alleles

Filtering AF 0.203% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.191%

Overall 0.0988% 1,594/1,614,144 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.423%	236
Admixed Americangrpmax	0.235%	426
European (non-Finnish)	0.0961%	1,041
Remaining individualsnot grpmax-eligible	0.056%	1,786
African / African-American	0.0173%	5,773

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg330Cys
Coding: c.988C>T
MANE Select: NM_000178
dbSNP: rs148640446
Type: single nucleotide variant
Location: chr20:34931980 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB
Residue 330: a UniProt-annotated variant site (in cnsha6; uncertain significance); 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

Also linked: inherited glutathione synthetase deficiency

For Glutathione synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GSS p.Arg330His Uncertain significance ★ ⚠ same residue
GSS p.Arg330= Likely benign ★ 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

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-arg330cys (accessed [today's date]).

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