Is GSS p.Ala2fs (c.4del) pathogenic?

GSS p.Ala2fs (c.4del) is classified Pathogenic/Likely pathogenic in GSS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). Very rare (popmax 0.00212%, nfe); Associated with inherited glutathione synthetase deficiency.

What condition is associated with GSS p.Ala2fs (c.4del)?

GSS p.Ala2fs (c.4del) is associated with inherited glutathione synthetase deficiency, glutathione synthetase deficiency without 5-oxoprolinuria, glutathione synthetase deficiency with 5-oxoprolinuria (ClinVar).

How common is GSS p.Ala2fs (c.4del) in the general population?

GSS p.Ala2fs (c.4del) is very rare (popmax 0.00212%, nfe) (gnomAD).

How is Glutathione synthetase deficiency inherited?

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

GSS p.Ala2fs

c.4del · rs752560204 · VCV338302

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Conditions

inherited glutathione synthetase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.8	GERP 0.83, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00212% European (non-Finnish) · 25/1,180,020 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.0115% 185/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.476%	210
Remaining individualsnot grpmax-eligible	0.0288%	3,471
European (non-Finnish)grpmax	0.00212%	47,201
African / African-American	0.00133%	74,936

Ashkenazi Jewish 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.Ala2fs
Coding: c.4del
MANE Select: NM_000178
dbSNP: rs752560204
Type: Deletion
Location: chr20:34951849 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB
Residue 2: a modified residue (n-acetylalanine)

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

Disease context

inherited glutathione synthetase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glutathione synthetase deficiency without 5-oxoprolinuria glutathione synthetase deficiency with 5-oxoprolinuria

For Glutathione synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GSS p.Ala2Thr Uncertain significance ★ ⚠ same residue
GSS p.Ile192fs Pathogenic/Likely pathogenic ★★ same condition
GSS p.Val380_Gln381del Pathogenic/Likely pathogenic ★★ same condition
GSS p.Tyr432fs Uncertain significance ★★ same condition
GSS c.129+9del Benign/Likely benign ★★ same condition
GSS c.275+20del Benign/Likely benign ★★ same condition
GSS c.275+7del Likely benign ★★ same condition
GSS c.1113_1132del20 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-ala2fs (accessed [today's date]).

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