Is GRID2 p.Arg444His (c.1331G>A) pathogenic?

GRID2 p.Arg444His (c.1331G>A) is classified Uncertain significance in GRID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-21). AlphaMissense: likely benign (0.2277); Ultra-rare (popmax 0.0203%, eas).

How common is GRID2 p.Arg444His (c.1331G>A) in the general population?

GRID2 p.Arg444His (c.1331G>A) is ultra-rare (popmax 0.0203%, eas) (gnomAD).

What do computational predictors say about GRID2 p.Arg444His (c.1331G>A)?

AlphaMissense predicts likely benign (score 0.2277) — an in-silico prediction, not a clinical call.

GRID2 p.Arg444His

c.1331G>A · rs778480880 · VCV1897094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2277 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2277	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 548 kb · p 0.0047 · regional, not allelic
Overall
CADD	34.0	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 0.0203% East Asian · 9/44,290 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00788%

Overall 0.00213% 32/1,503,544 alleles · ultra-rare exomes 29/1,351,580 · genomes 3/151,964 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0203%	4,921
Admixed American	0.00503%	19,875
African / African-American	0.00276%	36,237
European (non-Finnish)	0.00157%	63,541
South Asian	0.00113%	88,666

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.Arg444His
Coding: c.1331G>A
MANE Select: NM_001510
dbSNP: rs778480880
Type: single nucleotide variant
Location: chr4:93395692 (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.Arg444Cys 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-arg444his (accessed [today's date]).

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