Is GRIN2B p.Arg375= (c.1125G>A) pathogenic?

GRIN2B p.Arg375= (c.1125G>A) is classified Conflicting classifications of pathogenicity in GRIN2B (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-09). Very rare (popmax 0.0027%, afr); Associated with GRIN2B-related disorder.

What condition is associated with GRIN2B p.Arg375= (c.1125G>A)?

GRIN2B p.Arg375= (c.1125G>A) is associated with GRIN2B-related disorder, intellectual disability, autosomal dominant 6, developmental and epileptic encephalopathy, 27 (ClinVar).

How common is GRIN2B p.Arg375= (c.1125G>A) in the general population?

GRIN2B p.Arg375= (c.1125G>A) is very rare (popmax 0.0027%, afr) (gnomAD).

GRIN2B p.Arg375=

c.1125G>A · rs200126922 · VCV245615

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0027%, afr)

Conditions

GRIN2B-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0027% African / African-American · 2/73,970 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000858%

Overall 0.00134% 21/1,570,790 alleles · very rare exomes 16/1,418,664 · genomes 5/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0027%	36,985
European (non-Finnish)	0.00167%	60,041

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: GRIN2B
Protein: p.Arg375=
Coding: c.1125G>A
MANE Select: NM_000834
dbSNP: rs200126922
Type: single nucleotide variant
Location: chr12:13675745 (GRCh38)
Gene constraint: LOEUF 0.102 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.66 · 36 PDB
Residue 375: a β-strand

Full GRIN2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GRIN2B-related disorder

Also linked: intellectual disability, autosomal dominant 6 developmental and epileptic encephalopathy, 27

Similar variants

GRIN2B p.Arg375Lys Uncertain significance ★ ⚠ same residue
GRIN2B c.2172-2A>G Pathogenic ★★ same condition
GRIN2B p.Ala639Val Pathogenic/Likely pathogenic ★★ same condition
GRIN2B p.Ala644Asp Pathogenic ★★ same condition
GRIN2B p.Ala734Val Likely pathogenic ★★ same condition
GRIN2B p.Ala819Thr Pathogenic/Likely pathogenic ★★ same condition
GRIN2B p.Arg1111His Pathogenic/Likely pathogenic ★★ ⚠ same condition
GRIN2B p.Arg393Ter Pathogenic/Likely pathogenic ★★ 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/grin2b-p-arg375 (accessed [today's date]).

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