Is GRID2 p.Val268Glu (c.803T>A) pathogenic?

GRID2 p.Val268Glu (c.803T>A) is classified Uncertain significance in GRID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-25). AlphaMissense: likely benign (0.1582); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

What condition is associated with GRID2 p.Val268Glu (c.803T>A)?

GRID2 p.Val268Glu (c.803T>A) is associated with Inborn genetic diseases (ClinVar).

How common is GRID2 p.Val268Glu (c.803T>A) in the general population?

GRID2 p.Val268Glu (c.803T>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about GRID2 p.Val268Glu (c.803T>A)?

AlphaMissense predicts likely benign (score 0.1582) — an in-silico prediction, not a clinical call.

GRID2 p.Val268Glu

c.803T>A · VCV4032292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1582 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1582	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP 0.14, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 920 kb · p 0.22 · regional, not allelic
Overall
CADD	18.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,040 alleles

Filtering AF 0.00284% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00253%

Overall 0.00298% 48/1,608,342 alleles · ultra-rare exomes 43/1,456,028 · genomes 5/152,314 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,040
European (non-Finnish)	0.00374%	26,706
Remaining individualsnot grpmax-eligible	0.00321%	31,142
Admixed American	0.00167%	59,922

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GRID2
Protein: p.Val268Glu
Coding: c.803T>A
MANE Select: NM_001510
Type: single nucleotide variant
Location: chr4:93216751 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.07 · 6 PDB
Residue 268: the 'interaction with cbln1 homotrimer' region; an α-helix

Full GRID2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRID2 p.Ala654Thr Pathogenic/Likely pathogenic ★★ same condition
GRID2 p.Ala196Glu Uncertain significance ★★ ⚠ same condition
GRID2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
GRID2 p.Ala574Ser Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg229Gln Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg297Gln Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg439Leu Uncertain significance ★★ same condition
GRID2 p.Arg714Gln Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/grid2-p-val268glu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown