Is GSS p.Pro272= (c.816T>G) pathogenic?

GSS p.Pro272= (c.816T>G) is classified Conflicting classifications of pathogenicity in GSS (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-11). Rare (popmax 0.229%, afr); Associated with inherited glutathione synthetase deficiency.

What condition is associated with GSS p.Pro272= (c.816T>G)?

GSS p.Pro272= (c.816T>G) is associated with inherited glutathione synthetase deficiency, glutathione synthetase deficiency with 5-oxoprolinuria (ClinVar).

How common is GSS p.Pro272= (c.816T>G) in the general population?

GSS p.Pro272= (c.816T>G) is rare (popmax 0.229%, afr) (gnomAD).

How is Glutathione synthetase deficiency inherited?

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

GSS p.Pro272=

c.816T>G · rs35051256 · VCV514272

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.229%, afr)

Conditions

inherited glutathione synthetase deficiency

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 -3.9	GERP -3.9
Overall
CADD	1.638	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.229% African / African-American · 172/75,034 alleles

Filtering AF 0.201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.191%

Overall 0.0121% 195/1,612,692 alleles · rare exomes 91/1,460,354 · genomes 104/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.229%	436
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.016%	6,244
European (non-Finnish)	8.48e-05%	1,178,652

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.Pro272=
Coding: c.816T>G
MANE Select: NM_000178
dbSNP: rs35051256
Type: single nucleotide variant
Location: chr20:34935594 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB
Residue 272: an α-helix

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 with 5-oxoprolinuria

For Glutathione synthetase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

GSS p.Pro272Leu 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-pro272 (accessed [today's date]).

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