# NM_001033044.4(GLUL):c.173C>G (p.Pro58Arg)

https://sugi.bio/variant/glul-p-pro58arg

## Summary

**GLUL p.Pro58Arg (c.173C>G)** is classified **Uncertain significance** in GLUL (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.7916); Absent from gnomAD v4.1; Associated with congenital brain dysgenesis due to glutamine synthetase deficiency.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750521238 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GLUL gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to congenital brain dysgenesis due to glutamine synthetase deficiency.

*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) | Infancy, Neonatal |
| Diagnostic panels | GLUL is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009848/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GLUL](https://sugi.bio/atlas/gene/GLUL/) |
| Protein change (HGVS p.) | p.Pro58Arg |
| Coding change (HGVS c.) | c.173C>G |
| MANE Select transcript | [NM_001033044](https://www.ncbi.nlm.nih.gov/nuccore/NM_001033044) |
| dbSNP | [rs750521238](https://www.ncbi.nlm.nih.gov/snp/rs750521238/) |
| Variant type | single nucleotide variant |
| Location | chr1:182387286-182387286 (GRCh38) |
| ClinVar | [VCV2580915](https://www.ncbi.nlm.nih.gov/clinvar/variation/2580915/) |

**All HGVS expressions:** `NC_000001.10:g.182356421G>C`, `NC_000001.11:g.182387286G>C`, `NG_013347.2:g.9921C>G`, `NM_001033044.4:c.173C>G`, `NM_001033056.4:c.173C>G`, `NM_002065.7:c.173C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.7916)
- REVEL 0.594 (indeterminate)
- SaProt LLR -11.891 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 11.775, GERP 1.08, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 30.0**. 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 0.65** across the covering region of the MANE Select transcript (182,384,630–182,388,737), spanning 4,107 bp. Chi-square p 1.9e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for GLUL (306 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

**GLUL** population constraint: LOEUF 0.377, pLI 0.99971, missense-Z 3.2304; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **congenital brain dysgenesis due to glutamine synthetase deficiency** — Moderate (AR)
- **genetic developmental and epileptic encephalopathy** — Moderate (AD)

## Protein context {#protein}

Residue **58** lies in the gs beta-grasp domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 97.58, 97% of residues very-high.

**12 experimental structure(s)** (PDB): [2OJW](https://www.rcsb.org/structure/2OJW), [2QC8](https://www.rcsb.org/structure/2QC8), [7EVT](https://www.rcsb.org/structure/7EVT), [8DNU](https://www.rcsb.org/structure/8DNU), [9NLR](https://www.rcsb.org/structure/9NLR), [9NM5](https://www.rcsb.org/structure/9NM5).

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

*Describes the biological roles of GLUL (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:** GLUL's established molecular role includes glutamine synthetase activity. p.Pro58Arg falls in the gs beta-grasp domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Astrocytic Glutamate-Glutamine Uptake And Metabolism](https://reactome.org/content/detail/R-HSA-210455) | curated |
| [Glutamate and glutamine metabolism](https://reactome.org/content/detail/R-HSA-8964539) | curated |

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

**Molecular function:** glutamine synthetase activity, protein-cysteine S-palmitoyltransferase activity, identical protein binding.

**Biological process:** cell population proliferation, regulation of endothelial cell migration, protein palmitoylation, ribosome biogenesis, regulation of sprouting angiogenesis, regulation of protein localization to nucleolus.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Uncertain significance | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[congenital brain dysgenesis due to glutamine synthetase deficiency](https://sugi.bio/atlas/disease/congenital-brain-dysgenesis-due-to-glutamine-synthetase-deficiency/).

**Reported phenotype names (ClinVar):** Congenital brain dysgenesis due to glutamine synthetase deficiency, GLUTAMINE SYNTHASE DEFICIENCY, CONGENITAL SYSTEMIC.

## Similar variants {#similar}

Related GLUL variant pages (same residue, condition, or type): [GLUL c.*129G>T](/variant/glul-c-star-129g-t), [GLUL c.*272C>G](/variant/glul-c-star-272c-g), [GLUL c.*849C>T](/variant/glul-c-star-849c-t), [GLUL p.Arg181Gln](/variant/glul-p-arg181gln), [GLUL p.Arg286His](/variant/glul-p-arg286his), [GLUL p.Arg357Cys](/variant/glul-p-arg357cys), [GLUL p.Arg90Cys](/variant/glul-p-arg90cys), [GLUL p.Asn362Ser](/variant/glul-p-asn362ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2580915). 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.*