Is GRID2 p.Val490Ile (c.1468G>A) pathogenic?

GRID2 p.Val490Ile (c.1468G>A) is classified Benign in GRID2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0684); Common (popmax 15.9%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about GRID2 p.Val490Ile (c.1468G>A)?

AlphaMissense predicts likely benign (score 0.0684) — an in-silico prediction, not a clinical call.

GRID2 p.Val490Ile

Q: How common is GRID2 p.Val490Ile (c.1468G>A) in the general population?

GRID2 p.Val490Ile (c.1468G>A) is common (popmax 15.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1468G>A · rs10034345 · VCV1267971

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0684 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 15.9%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0684	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP -0.67, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 548 kb · p 0.0047 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.9% African / African-American · 11,900/74,946 alleles

Filtering AF 15.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.5%

Overall 7.16% 115,484/1,612,632 alleles · common exomes 100,835/1,460,524 · genomes 14,649/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	15.9%	6
Finnishnot grpmax-eligible	14.4%	7
South Asian	13.7%	7
Ashkenazi Jewishnot grpmax-eligible	8.47%	12
Remaining individualsnot grpmax-eligible	7.44%	13
Middle Eastern	7.13%	14
European (non-Finnish)	6.04%	17
Admixed American	4.52%	22
Amishnot grpmax-eligible	1.43%	70
East Asian	0.881%	114

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.Val490Ile
Coding: c.1468G>A
MANE Select: NM_001510
dbSNP: rs10034345
Type: single nucleotide variant
Location: chr4:93422891 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.07 · 6 PDB
Residue 490: a UniProt-annotated variant site (in)

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

Similar variants

GRID2 p.Val490Leu Uncertain significance ★ ⚠ same residue
GRID2 p.Ala654Thr Pathogenic/Likely pathogenic ★★ same type
GRID2 p.Thr649Ala Pathogenic/Likely pathogenic ★★ same type
GRID2 p.Ala196Glu Uncertain significance ★★ ⚠ same type
GRID2 p.Ala21Val Uncertain significance ★★ ⚠ same type
GRID2 p.Ala574Ser Uncertain significance ★★ ⚠ same type
GRID2 p.Arg229Gln Uncertain significance ★★ ⚠ same type
GRID2 p.Arg297Gln Uncertain significance ★★ ⚠ same type

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-val490ile (accessed [today's date]).

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