# NM_000178.4(GSS):c.129+1663A>G

https://sugi.bio/variant/gss-c-129-plus-1663a-g

## Summary

**GSS c.129+1663A>G** is classified **Pathogenic/Likely pathogenic** in GSS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). Absent from gnomAD v4.1; Associated with GSS-related disorders.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GSS gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to GSS-related disorders.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GSS](https://sugi.bio/atlas/gene/GSS/) |
| Coding change (HGVS c.) | c.129+1663A>G |
| MANE Select transcript | [NM_000178](https://www.ncbi.nlm.nih.gov/nuccore/NM_000178) |
| Variant type | single nucleotide variant |
| Location | chr20:34950061-34950061 (GRCh38) |
| ClinVar | [VCV4821899](https://www.ncbi.nlm.nih.gov/clinvar/variation/4821899/) |

**All HGVS expressions:** `LRG_1168:g.10967A>G`, `LRG_1168t1:c.129+1663A>G`, `NC_000020.10:g.33537864T>C`, `NC_000020.11:g.34950061T>C`, `NG_008848.2:g.10967A>G`, `NM_000178.4:c.129+1663A>G`, `NM_001322494.1:c.129+1663A>G`, `NM_001322495.1:c.129+1663A>G`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.77) — consistent with the pathogenic call
- Conservation: phyloP 0.238, GERP -1.33 — weakly conserved position
- CADD: **PHRED 5.51**. 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.*
- Splice region: **deep intronic (+1663 nt into the intron)**.
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.77**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.77**.
- Pangolin: Δ**0.72** (gain), gain 0.72 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-01.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2023–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-01-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-01 |

## Associated conditions {#conditions}

[GSS-related disorders](https://sugi.bio/atlas/disease/gss-related-disorders/).

**Reported phenotype names (ClinVar):** GSS-related disorders, not provided, none provided.

## Similar variants {#similar}

Related GSS variant pages (same residue, condition, or type): [GSS p.Arg236fs](/variant/gss-p-arg236fs), [GSS p.Phe255fs](/variant/gss-p-phe255fs), [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 2026-10-14); 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 4821899). 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.*