GRID2IP

Chr 7

Grid2 interacting protein

Also known as: DELPHILIN

NCBI Gene: 392862 ENSG00000215045 UniProt: A4D2P6

GRID2IP encodes a postsynaptic scaffolding protein that links the glutamate receptor GRID2 with the actin cytoskeleton and signaling molecules at parallel fiber-Purkinje cell synapses in the cerebellum. Mutations cause autosomal recessive spinocerebellar ataxia-18, characterized by cerebellar ataxia and intellectual disability. The gene shows significant constraint against loss-of-function variants (LOEUF 0.42), indicating that complete loss of function is likely pathogenic.

ResearchSummary from RefSeq, UniProt

Glutamate receptor delta-2 (GRID2; MIM 602368) is predominantly expressed at parallel fiber-Purkinje cell postsynapses and plays crucial roles in synaptogenesis and synaptic plasticity. GRID2IP1 interacts with GRID2 and may control GRID2 signaling in Purkinje cells (Matsuda et al., 2006 [PubMed 16835239]).[supplied by OMIM, Mar 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.42

Clinical Summary— GRID2IP

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

246 VUS of 278 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.125

Z-score 4.43

OE 0.25 (0.15–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.07Z-score

OE missense 0.88 (0.81–0.94)

513 obs / 585.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.15–0.42)

0≤0.351.4

Missense OE?0.88 (0.81–0.94)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 10 / 40.4Missense obs/exp: 513 / 585.6Syn Z: -0.88

This gene — mechanism propensity

0.6550th %ile

GOF

0.6638th %ile

LOF

0.3744th %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

278 submitted variants in ClinVar

ClinVar

Classification Summary

VUS246

Likely Benign15

Benign2

246

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	245	0	246
Likely Benign	0	4	11	15
Benign	0	2	0	2
Total	1	251	11	263

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 52) ClinVar copy-number / structural variants overlap GRID2IP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →