# NM_001510.4(GRID2):c.2490C>A (p.Ser830Arg)

https://sugi.bio/variant/grid2-p-ser830arg

## Summary

**GRID2 p.Ser830Arg (c.2490C>A)** is classified **Uncertain significance** in GRID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely pathogenic (0.8899); Ultra-rare (popmax 0.0175%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0175%, nfe)

## 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 1 submitter.

*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 | [GRID2](https://sugi.bio/atlas/gene/GRID2/) |
| Protein change (HGVS p.) | p.Ser830Arg |
| Coding change (HGVS c.) | c.2490C>A |
| MANE Select transcript | [NM_001510](https://www.ncbi.nlm.nih.gov/nuccore/NM_001510) |
| Variant type | single nucleotide variant |
| Location | chr4:93769339-93769339 (GRCh38) |
| ClinVar | [VCV3360924](https://www.ncbi.nlm.nih.gov/clinvar/variation/3360924/) |

**All HGVS expressions:** `NC_000004.11:g.94690490C>A`, `NC_000004.12:g.93769339C>A`, `NG_034113.2:g.1470375C>A`, `NM_001286838.1:c.2205C>A`, `NM_001510.4:c.2490C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8899)
- REVEL 0.405 (indeterminate)
- SaProt LLR -10.819 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 1.412, GERP -1.23, phastCons 1 — weakly conserved position
- CADD: **PHRED 23.7**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.69 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0175%** (nfe) · FAF95 0.0155% · FAF99 0.0147% · 206/1,179,988 in the highest group · 237/1,613,972 alleles overall — ultra-rare (popmax 0.0175%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0208% | 4,807 |
| European (non-Finnish) (grpmax) | 0.0175% | 5,728 |
| African / African-American | 0.0147% | 6,810 |
| Admixed American | 0.01% | 9,997 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,036 |

Remaining individuals 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}

**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 2023-07-07.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-07 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related GRID2 variant pages (same residue, condition, or type): [GRID2 p.Ser830Thr](/variant/grid2-p-ser830thr), [GRID2 p.Ala654Thr](/variant/grid2-p-ala654thr), [GRID2 p.Thr649Ala](/variant/grid2-p-thr649ala), [GRID2 p.Ala196Glu](/variant/grid2-p-ala196glu), [GRID2 p.Ala21Val](/variant/grid2-p-ala21val), [GRID2 p.Ala574Ser](/variant/grid2-p-ala574ser), [GRID2 p.Arg229Gln](/variant/grid2-p-arg229gln), [GRID2 p.Arg297Gln](/variant/grid2-p-arg297gln).

### 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 3360924). 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.*