# NM_000834.5(GRIN2B):c.2910C>T (p.Phe970=)

https://sugi.bio/variant/grin2b-p-phe970

## Summary

**GRIN2B p.Phe970= (c.2910C>T)** is classified **Likely benign** in GRIN2B (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Very rare (popmax 0.0061%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs201252525 · 4 submitters · 3 linked conditions · very rare (popmax 0.0061%, nfe)

## For patients & families {#patients}

This is a change in the GRIN2B gene that is classified as likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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 | [GRIN2B](https://sugi.bio/atlas/gene/GRIN2B/) |
| Protein change (HGVS p.) | p.Phe970= |
| Coding change (HGVS c.) | c.2910C>T |
| MANE Select transcript | [NM_000834](https://www.ncbi.nlm.nih.gov/nuccore/NM_000834) |
| dbSNP | [rs201252525](https://www.ncbi.nlm.nih.gov/snp/rs201252525/) |
| Variant type | single nucleotide variant |
| Location | chr12:13564328-13564328 (GRCh38) |
| ClinVar | [VCV1300690](https://www.ncbi.nlm.nih.gov/clinvar/variation/1300690/) |

**All HGVS expressions:** `NC_000012.11:g.13717262G>A`, `NC_000012.12:g.13564328G>A`, `NG_031854.2:g.422685C>T`, `NM_000834.5:c.2910C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -4.052, GERP -3.17 — fast-evolving / accelerated position
- CADD: **PHRED 2.163**. 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.*
- 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 GRIN2B (1,520 scored positions, the nearest 312 bases 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 (gnomAD v4.1): grpmax **0.0061%** (nfe) · FAF95 0.00495% · FAF99 0.00455% · 72/1,180,040 in the highest group · 83/1,614,094 alleles overall — very rare (popmax 0.0061%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00937% | 10,674 |
| European (non-Finnish) (grpmax) | 0.0061% | 16,389 |
| East Asian | 0.00223% | 44,884 |
| South Asian | 0.0022% | 45,544 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |
| African / African-American | 0.00133% | 74,930 |

Finnish 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}

**GRIN2B** population constraint: LOEUF 0.102, pLI 1, missense-Z 7.3414; 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}


AlphaFold model confidence (whole protein): pLDDT 60.66, 18% of residues very-high.

**36 experimental structure(s)** (PDB): [10EX](https://www.rcsb.org/structure/10EX), [10EY](https://www.rcsb.org/structure/10EY), [10EZ](https://www.rcsb.org/structure/10EZ), [10FD](https://www.rcsb.org/structure/10FD), [10FE](https://www.rcsb.org/structure/10FE), [10FF](https://www.rcsb.org/structure/10FF).

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

*Describes the biological roles of GRIN2B (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:** GRIN2B's established molecular role includes NMDA glutamate receptor activity.


### Pathways affected {#pathways}

GRIN2B participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Synaptic adhesion-like molecules](https://reactome.org/content/detail/R-HSA-8849932) | curated |
| [Activated NTRK2 signals through FYN](https://reactome.org/content/detail/R-HSA-9032500) | electronic |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | 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 |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | 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, glycine binding, glutamate-gated calcium ion channel activity, ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential.

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

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** unanimous (4/4 Likely benign).

**Submission history:** 4 submissions (2018–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-03-19 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-06-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-12 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [intellectual disability, autosomal dominant 6](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-dominant-6/), [developmental and epileptic encephalopathy, 27](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-27/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Developmental and epileptic encephalopathy, 27, Intellectual disability, autosomal dominant 6, not specified, INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6, WITH OR WITHOUT SEIZURES, GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder, Epileptic encephalopathy, early infantile, 27, GRIN2B-Related Neurodevelopmental Disorder, AllHighlyPenetrant.

## Similar variants {#similar}

Related GRIN2B variant pages (same residue, condition, or type): [GRIN2B c.2172-2A>G](/variant/grin2b-c-2172-minus-2a-g), [GRIN2B p.Ala639Val](/variant/grin2b-p-ala639val), [GRIN2B p.Ala644Asp](/variant/grin2b-p-ala644asp), [GRIN2B p.Ala734Val](/variant/grin2b-p-ala734val), [GRIN2B p.Ala819Thr](/variant/grin2b-p-ala819thr), [GRIN2B p.Arg1111His](/variant/grin2b-p-arg1111his), [GRIN2B p.Arg393Ter](/variant/grin2b-p-arg393ter), [GRIN2B p.Arg519Gln](/variant/grin2b-p-arg519gln).

### 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 1300690). 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.*