Is GSR p.Pro33= (c.99C>T) pathogenic?

GSR p.Pro33= (c.99C>T) is classified Likely benign in GSR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-06). Very rare (popmax 0.0086%, nfe); Associated with hemolytic anemia due to glutathione reductase deficiency.

What condition is associated with GSR p.Pro33= (c.99C>T)?

GSR p.Pro33= (c.99C>T) is associated with hemolytic anemia due to glutathione reductase deficiency (ClinVar).

How common is GSR p.Pro33= (c.99C>T) in the general population?

GSR p.Pro33= (c.99C>T) is very rare (popmax 0.0086%, nfe) (gnomAD).

GSR p.Pro33=

Q: How is Hemolytic anemia due to glutathione reductase deficiency inherited?

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

c.99C>T · rs905034418 · VCV1907053

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0086%, nfe)

Conditions

hemolytic anemia due to glutathione reductase 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 0.66	GERP -1.2
Overall
CADD	6.373	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0086% European (non-Finnish) · 93/1,081,454 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00664%

Overall 0.00663% 93/1,401,970 alleles · very rare exomes 87/1,250,406 · genomes 6/151,564 · joint denominator

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: GSR
Protein: p.Pro33=
Coding: c.99C>T
MANE Select: NM_000637
dbSNP: rs905034418
Type: single nucleotide variant
Location: chr8:30727737 (GRCh38)
Gene constraint: LOEUF 1.182 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.77 · 27 PDB

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

Disease context

hemolytic anemia due to glutathione reductase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hemolytic anemia due to glutathione reductase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: No data available

Similar variants

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GSR p.Arg171Leu Uncertain significance ★★ ⚠ same condition
GSR p.Arg233Cys Uncertain significance ★★ ⚠ same condition
GSR p.Arg233His Uncertain significance ★★ ⚠ same condition
GSR p.Arg522His Uncertain significance ★★ ⚠ same condition
GSR p.Cys102Trp Uncertain significance ★★ ⚠ 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/gsr-p-pro33 (accessed [today's date]).

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