# NM_001510.4(GRID2):c.2128C>T (p.Arg710Trp)

https://sugi.bio/variant/grid2-p-arg710trp

## Summary

**GRID2 p.Arg710Trp (c.2128C>T)** is classified **Uncertain significance** in GRID2 (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-15). AlphaMissense: ambiguous (0.5337); Very rare (popmax 0.00892%, eas); Associated with autosomal recessive spinocerebellar ataxia 18.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs750331613 · 2 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00892%, eas)

## For patients & families {#patients}

This is a change in the GRID2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to autosomal recessive spinocerebellar ataxia 18.

*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 | GRID2 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Nystagmus — Very frequent (99-80%)
- Oculomotor apraxia — Very frequent (99-80%)
- Progressive cerebellar ataxia — Very frequent (99-80%)
- Abnormal pyramidal sign — Very frequent (99-80%)
- Ptosis — Frequent (79-30%)
- Optic disc pallor — Frequent (79-30%)
- Esotropia — Frequent (79-30%)
- Hypometric saccades — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017557/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GRID2](https://sugi.bio/atlas/gene/GRID2/) |
| Protein change (HGVS p.) | p.Arg710Trp |
| Coding change (HGVS c.) | c.2128C>T |
| MANE Select transcript | [NM_001510](https://www.ncbi.nlm.nih.gov/nuccore/NM_001510) |
| dbSNP | [rs750331613](https://www.ncbi.nlm.nih.gov/snp/rs750331613/) |
| Variant type | single nucleotide variant |
| Location | chr4:93515346-93515346 (GRCh38) |
| ClinVar | [VCV427806](https://www.ncbi.nlm.nih.gov/clinvar/variation/427806/) |

**All HGVS expressions:** `NC_000004.11:g.94436497C>T`, `NC_000004.12:g.93515346C>T`, `NG_034113.1:g.1215948C>T`, `NM_001286838.1:c.1843C>T`, `NM_001510.4:c.2128C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5337) — no call either way
- REVEL 0.263 (benign-leaning)
- SaProt LLR -9.486 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate
- Conservation: phyloP 0.405, GERP -2.37, phastCons 0.991 — weakly conserved position
- CADD: **PHRED 23.8**. 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 0.90** across the covering region of the MANE Select transcript (93,224,748–93,772,495), spanning 547,747 bp. Chi-square p 0.0047. 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 **0.00892%** (eas) · FAF95 0.00298% · FAF99 0.0018% · 4/44,818 in the highest group · 23/1,612,558 alleles overall — very rare (popmax 0.00892%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00892% | 11,204 |
| Admixed American | 0.00334% | 29,960 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,009 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,434 |
| African / African-American | 0.00134% | 74,840 |
| South Asian | 0.0011% | 91,048 |
| European (non-Finnish) | 0.00102% | 98,243 |

*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}

**GRID2** population constraint: LOEUF 0.332, pLI 0.99997, missense-Z 1.1151. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.07, 32% of residues very-high.

**6 experimental structure(s)** (PDB): [5KC8](https://www.rcsb.org/structure/5KC8), [5KCA](https://www.rcsb.org/structure/5KCA), [9NWO](https://www.rcsb.org/structure/9NWO), [9NWP](https://www.rcsb.org/structure/9NWP), [9NWQ](https://www.rcsb.org/structure/9NWQ), [9OOO](https://www.rcsb.org/structure/9OOO).

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

*Describes the biological roles of GRID2 (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:** GRID2's established molecular role includes transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential.


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

**Molecular function:** transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential.

**Biological process:** positive regulation of synapse assembly, synaptic signaling via neuropeptide, trans-synaptic signaling by trans-synaptic complex, modulating synaptic transmission, positive regulation of long-term synaptic depression, excitatory synapse assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-15.

**Submitter consensus:** conflicting (1 Pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Research Group Niklas Dahl, Uppsala University | Pathogenic | no assertion criteria provided | phenotyping only | 2017-02-21 |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-15 |

## Associated conditions {#conditions}

[autosomal recessive spinocerebellar ataxia 18](https://sugi.bio/atlas/disease/autosomal-recessive-spinocerebellar-ataxia-18/).

**Reported phenotype names (ClinVar):** Autosomal recessive spinocerebellar ataxia 18.

## Similar variants {#similar}

Related GRID2 variant pages (same residue, condition, or type): [GRID2 p.Thr649Ala](/variant/grid2-p-thr649ala), [GRID2 p.Arg300His](/variant/grid2-p-arg300his), [GRID2 p.Arg367His](/variant/grid2-p-arg367his), [GRID2 p.Asp473Glu](/variant/grid2-p-asp473glu), [GRID2 p.Gly391Arg](/variant/grid2-p-gly391arg), [GRID2 c.735+21G>C](/variant/grid2-c-735-plus-21g-c), [GRID2 p.Gly417=](/variant/grid2-p-gly417), [GRID2 p.Arg224Gln](/variant/grid2-p-arg224gln).

### 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 427806). 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.*