Is GRID2 p.Ile661Phe (c.1981A>T) pathogenic?

GRID2 p.Ile661Phe (c.1981A>T) is classified Likely benign in GRID2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-07). AlphaMissense: ambiguous (0.4417); Rare (popmax 0.421%, eas).

How common is GRID2 p.Ile661Phe (c.1981A>T) in the general population?

GRID2 p.Ile661Phe (c.1981A>T) is rare (popmax 0.421%, eas) (gnomAD).

What do computational predictors say about GRID2 p.Ile661Phe (c.1981A>T)?

AlphaMissense predicts ambiguous (score 0.4417) — an in-silico prediction, not a clinical call.

GRID2 p.Ile661Phe

c.1981A>T · rs182933054 · VCV751483

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4417 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.421%, eas)

Computational evidence

Protein change
AlphaMissense	0.4417	ambiguous
REVEL	0.293	indeterminate
SaProt	LLR -8.78	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 548 kb · p 0.0047 · regional, not allelic
Overall
CADD	26.7	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 0.421% East Asian · 188/44,684 alleles

Filtering AF 0.372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.353%

Overall 0.0131% 210/1,607,174 alleles · rare exomes 184/1,455,134 · genomes 26/152,040 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.421%	238
Remaining individualsnot grpmax-eligible	0.0306%	3,272
Admixed American	0.00169%	59,328
South Asian	0.00111%	90,246
European (non-Finnish)	8.51e-05%	1,175,718

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.Ile661Phe
Coding: c.1981A>T
MANE Select: NM_001510
dbSNP: rs182933054
Type: single nucleotide variant
Location: chr4:93490761 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.07 · 6 PDB

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

Similar variants

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
GRID2 p.Arg300His 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-ile661phe (accessed [today's date]).

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