# NM_000178.4(GSS):c.988C>T (p.Arg330Cys)

https://sugi.bio/variant/gss-p-arg330cys

## Summary

**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.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs148640446 · 6 submitters · 2 linked conditions · AlphaMissense likely benign · rare (popmax 0.235%, amr)

## For patients & families {#patients}

This is a change in the GSS gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to glutathione synthetase deficiency with 5-oxoprolinuria.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GSS is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Glutathione synthetase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the nervous system — Very frequent (99-80%)
- Hemolytic anemia — Very frequent (99-80%)
- Chronic metabolic acidosis — Very frequent (99-80%)
- Glutathione synthetase deficiency — Very frequent (99-80%)
- Abnormality of immune system physiology — Very frequent (99-80%)
- Reduced erythrocyte glutathione concentration — Very frequent (99-80%)
- Increased level of L-pyroglutamic acid in urine — Very frequent (99-80%)
- Jaundice — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017330/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GSS](https://sugi.bio/atlas/gene/GSS/) |
| Protein change (HGVS p.) | p.Arg330Cys |
| Coding change (HGVS c.) | c.988C>T |
| MANE Select transcript | [NM_000178](https://www.ncbi.nlm.nih.gov/nuccore/NM_000178) |
| dbSNP | [rs148640446](https://www.ncbi.nlm.nih.gov/snp/rs148640446/) |
| Variant type | single nucleotide variant |
| Location | chr20:34931980-34931980 (GRCh38) |
| ClinVar | [VCV897215](https://www.ncbi.nlm.nih.gov/clinvar/variation/897215/) |

**All HGVS expressions:** `LRG_1168:g.29048C>T`, `LRG_1168t1:c.988C>T`, `NC_000020.10:g.33519783G>A`, `NC_000020.11:g.34931980G>A`, `NG_008848.2:g.29048C>T`, `NM_000178.3:c.988C>T`, `NM_000178.4:c.988C>T`, `NM_001322494.1:c.988C>T`, `NM_001322495.1:c.988C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2436)
- REVEL 0.842 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -14.332 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 9.662, GERP 1.06, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 31.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (34,928,831–34,951,852), spanning 23,021 bp. Chi-square p 8.1e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.235%** (amr) · FAF95 0.203% · FAF99 0.191% · 141/60,022 in the highest group · 1,594/1,614,144 alleles overall — rare (popmax 0.235%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.423% | 236 |
| Admixed American (grpmax) | 0.235% | 426 |
| European (non-Finnish) | 0.0961% | 1,041 |
| Remaining individuals (not grpmax-eligible) | 0.056% | 1,786 |
| African / African-American | 0.0173% | 5,773 |

Finnish shows a higher raw frequency than the grpmax group. 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.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GSS** population constraint: LOEUF 0.819, pLI 1.795e-06, missense-Z 1.8313. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **inherited glutathione synthetase deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **330** lies in a UniProt-annotated variant site (in cnsha6; uncertain significance); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 95.25, 91% of residues very-high.

**2 experimental structure(s)** (PDB): [2HGS](https://www.rcsb.org/structure/2HGS), [8FBZ](https://www.rcsb.org/structure/8FBZ).

## What this gene does {#gene-function}

*Describes the biological roles of GSS (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GSS's established molecular role includes magnesium ion binding. In Reactome, GSS is annotated in disease pathway(s) including **Defective GSS causes GSS deficiency**.

**Disease mechanism (Reactome):** GSS loss or alteration is curated in [Defective GSS causes GSS deficiency](https://reactome.org/content/detail/R-HSA-5579006).

### Pathways affected {#pathways}

GSS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective GSS causes GSS deficiency](https://reactome.org/content/detail/R-HSA-5579006) | curated |
| [Glutathione synthesis and recycling](https://reactome.org/content/detail/R-HSA-174403) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** magnesium ion binding, ATP binding, identical protein binding, protein homodimerization activity, glutathione binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-28.

**Submitter consensus:** conflicting (5 Likely benign, 1 Uncertain significance).

**Submission history:** 6 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-06 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-01-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-28 |

## Associated conditions {#conditions}

[glutathione synthetase deficiency with 5-oxoprolinuria](https://sugi.bio/atlas/disease/glutathione-synthetase-deficiency-with-5-oxoprolinuria/), [inherited glutathione synthetase deficiency](https://sugi.bio/atlas/disease/inherited-glutathione-synthetase-deficiency/).

**Reported phenotype names (ClinVar):** Glutathione synthetase deficiency with 5-oxoprolinuria, Inherited glutathione synthetase deficiency, not provided, GSS-related disorder, not specified, Gluthathione synthetase deficiency, 5-Oxoprolinuria, Reduced glutathione synthetase level, 5-OXOPROLINURIA DUE TO GLUTATHIONE SYNTHETASE DEFICIENCY, PYROGLUTAMIC ACIDURIA.

## Similar variants {#similar}

Related GSS variant pages (same residue, condition, or type): [GSS p.Arg330His](/variant/gss-p-arg330his), [GSS p.Arg330=](/variant/gss-p-arg330), [GSS c.130-1G>C](/variant/gss-c-130-minus-1g-c), [GSS c.-9+5G>A](/variant/gss-c-minus-9-plus-5g-a), [GSS p.Arg125Cys](/variant/gss-p-arg125cys), [GSS p.Arg164Gln](/variant/gss-p-arg164gln), [GSS p.Arg164Ter](/variant/gss-p-arg164ter), [GSS p.Arg236Ter](/variant/gss-p-arg236ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 897215). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*