Is GSS p.Val45= (c.135G>A) pathogenic?

GSS p.Val45= (c.135G>A) is classified Likely benign in GSS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-13). Very rare (popmax 0.00267%, afr); Associated with glutathione synthetase deficiency with 5-oxoprolinuria.

What condition is associated with GSS p.Val45= (c.135G>A)?

GSS p.Val45= (c.135G>A) is associated with glutathione synthetase deficiency with 5-oxoprolinuria (ClinVar).

How common is GSS p.Val45= (c.135G>A) in the general population?

GSS p.Val45= (c.135G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Glutathione synthetase deficiency inherited?

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

GSS p.Val45=

c.135G>A · rs1452277210 · VCV2180783

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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	<0.2	all four deltas below 0.2 · C>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.2	GERP 1.5, phastCons 1
Overall
CADD	14.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,820 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000249% 4/1,609,076 alleles · very rare exomes 3/1,456,920 · genomes 1/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,410
Remaining individualsnot grpmax-eligible	0.00161%	62,212
European (non-Finnish)	8.5e-05%	1,176,121

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.Val45=
Coding: c.135G>A
MANE Select: NM_000178
dbSNP: rs1452277210
Type: single nucleotide variant
Location: chr20:34946093 (GRCh38)
Gene constraint: LOEUF 0.819 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.25 · 2 PDB
Residue 45: a β-strand

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 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
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-val45 (accessed [today's date]).

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