GRIN2C

Chr 17

glutamate ionotropic receptor NMDA type subunit 2C

Also known as: GluN2C, NMDAR2C, NR2C

NCBI Gene: 2905ENSG00000161509UniProt: Q14957OMIM: 138254

The encoded protein is the GluN2C subunit of NMDA receptors, which form calcium-permeable ion channels essential for synaptic plasticity, learning, and memory in the central nervous system. Mutations cause autosomal dominant intellectual disability with early-onset seizures and developmental delay. This gene shows very high constraint against loss-of-function variants (pLI near 0, LOEUF 0.715), indicating that heterozygous mutations are likely pathogenic.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.71
Clinical Summary— GRIN2C
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 unique Pathogenic / Likely Pathogenic· 154 VUS of 207 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.71LOEUF
pLI 0.000
Z-score 2.89
OE 0.48 (0.33–0.71)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.61Z-score
OE missense 0.82 (0.76–0.88)
519 obs / 633.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.48 (0.33–0.71)
0≤0.351.4
Missense OE0.82 (0.76–0.88)
0≤0.61.4
Synonymous OE0.95
0≤1.21.6
LoF obs/exp: 17 / 35.6Missense obs/exp: 519 / 633.0Syn Z: 0.69
DN
0.74top 25%
GOF
0.75top 25%
LOF
0.3453th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

207 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic1
VUS154
Likely Benign20
Benign6
Conflicting1
12
Pathogenic
1
Likely Pathogenic
154
VUS
20
Likely Benign
6
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
12
0
12
Likely Pathogenic
0
0
1
0
1
VUS
1
153
0
0
154
Likely Benign
0
11
1
8
20
Benign
0
2
2
2
6
Conflicting
—1
Total11661610194

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GRIN2C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients