# NM_001134407.3(GRIN2A):c.2346T>G (p.Phe782Leu)

https://sugi.bio/variant/grin2a-p-phe782leu

## Summary

**GRIN2A p.Phe782Leu (c.2346T>G)** is classified **Uncertain significance** in GRIN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-18). AlphaMissense: likely pathogenic (0.9179); Absent from gnomAD v4.1; Associated with Landau-Kleffner syndrome.

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

## For patients & families {#patients}

This is a change in the GRIN2A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Landau-Kleffner syndrome.

*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 dominant, Unknown |
| Age of onset (of this condition) | Childhood |
| Prevalence | 1-9 / 1 000 000 (Japan) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GRIN2A is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Landau-Kleffner syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Seizure — Very frequent (99-80%)
- Loss of speech — Very frequent (99-80%)
- Aphasia — Very frequent (99-80%)
- Language impairment — Very frequent (99-80%)
- Speech apraxia — Very frequent (99-80%)
- Interictal EEG abnormality — Very frequent (99-80%)
- Spoken Word Recognition Deficit — Very frequent (99-80%)
- Continuous spike and waves during slow sleep — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006855/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GRIN2A](https://sugi.bio/atlas/gene/GRIN2A/) |
| Protein change (HGVS p.) | p.Phe782Leu |
| Coding change (HGVS c.) | c.2346T>G |
| MANE Select transcript | [NM_001134407](https://www.ncbi.nlm.nih.gov/nuccore/NM_001134407) |
| Variant type | single nucleotide variant |
| Location | chr16:9798287-9798287 (GRCh38) |
| ClinVar | [VCV3662746](https://www.ncbi.nlm.nih.gov/clinvar/variation/3662746/) |

**All HGVS expressions:** `NC_000016.10:g.9798287A>C`, `NC_000016.9:g.9892144A>C`, `NG_011812.2:g.389468T>G`, `NM_000833.5:c.2346T>G`, `NM_001134407.3:c.2346T>G`, `NM_001134408.2:c.2346T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9179)
- REVEL 0.076 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -6.676 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; REVEL and SaProt do not
- SpliceAI predicts **donor gain** (Δ 0.71) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.597, GERP -1.83, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.3**. 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 0.42** across the covering region of the MANE Select transcript (9,768,911–9,829,458), spanning 60,547 bp. Chi-square p 2.4e-19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.71**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.71**.
- Pangolin: Δ**0.28** (gain), gain 0.28 / loss 0.04. 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}

**GRIN2A** population constraint: LOEUF 0.268, pLI 1, missense-Z 3.7232; ClinGen dosage — haploinsufficiency 3/3, 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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **782** lies in a UniProt-annotated variant site (found in schizophrenia; uncertain significance; loss of function in ion transmembrane transport; the channel is not activated by glutamate); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 60.70, 18% of residues very-high.

**37 experimental structure(s)** (PDB): [3NFL](https://www.rcsb.org/structure/3NFL), [5H8F](https://www.rcsb.org/structure/5H8F), [5H8H](https://www.rcsb.org/structure/5H8H), [5H8N](https://www.rcsb.org/structure/5H8N), [5H8Q](https://www.rcsb.org/structure/5H8Q), [5I2K](https://www.rcsb.org/structure/5I2K).

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

*Describes the biological roles of GRIN2A (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:** GRIN2A's established molecular role includes NMDA glutamate receptor activity.


### Pathways affected {#pathways}

GRIN2A participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synaptic adhesion-like molecules](https://reactome.org/content/detail/R-HSA-8849932) | curated |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | electronic |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | electronic |

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

**Molecular function:** NMDA glutamate receptor activity, glutamate-gated calcium ion channel activity.

**Biological process:** sodium ion transmembrane transport, response to ethanol, calcium ion transmembrane transport, calcium ion transmembrane import into cytosol, monoatomic cation transmembrane transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-08-18.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-18 |

## Associated conditions {#conditions}

[Landau-Kleffner syndrome](https://sugi.bio/atlas/disease/landau-kleffner-syndrome/).

**Reported phenotype names (ClinVar):** Landau-Kleffner syndrome, EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT MENTAL RETARDATION, APHASIA, ACQUIRED, WITH EPILEPSY, EPILEPSY, FOCAL, WITH SPEECH DISORDER AND WITH OR WITHOUT IMPAIRED INTELLECTUAL DEVELOPMENT.

## Similar variants {#similar}

Related GRIN2A variant pages (same residue, condition, or type): [GRIN2A c.1007+1G>A](/variant/grin2a-c-1007-plus-1g-a), [GRIN2A c.1007+1G>T](/variant/grin2a-c-1007-plus-1g-t), [GRIN2A c.1123-2A>G](/variant/grin2a-c-1123-minus-2a-g), [GRIN2A c.1497+1G>T](/variant/grin2a-c-1497-plus-1g-t), [GRIN2A c.2007+1G>T](/variant/grin2a-c-2007-plus-1g-t), [GRIN2A c.2168+1G>C](/variant/grin2a-c-2168-plus-1g-c), [GRIN2A c.415-2A>G](/variant/grin2a-c-415-minus-2a-g), [GRIN2A p.Ala548Pro](/variant/grin2a-p-ala548pro).

### 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 3662746). 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.*