Is GRIN2B p.Ala652Pro (c.1954G>C) pathogenic?

GRIN2B p.Ala652Pro (c.1954G>C) is classified Pathogenic in GRIN2B (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-18). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

How common is GRIN2B p.Ala652Pro (c.1954G>C) in the general population?

GRIN2B p.Ala652Pro (c.1954G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRIN2B p.Ala652Pro (c.1954G>C)?

AlphaMissense predicts likely pathogenic (score 0.9996) — an in-silico prediction, not a clinical call.

GRIN2B p.Ala652Pro

c.1954G>C · rs1555110812 · VCV452873

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9996 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9996	likely pathogenic ✓ concordant with ClinVar · top 4% in GRIN2B
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -13.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.09	constrained · MANE · 215 bp · p 1.6e-17 · 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRIN2B
Protein: p.Ala652Pro
Coding: c.1954G>C
MANE Select: NM_000834
dbSNP: rs1555110812
Type: single nucleotide variant
Location: chr12:13608659 (GRCh38)
Gene constraint: LOEUF 0.102 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.66 · 36 PDB
Residue 652: an α-helix; a UniProt-annotated variant site (in mrd6; uncertain significance; changed glutamate-gated calcium ion channel activity; results in decreased agonist potency and mutant channels activated at higher glutamate and glycine concentrations)

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

Similar variants

GRIN2B p.Ala652Gly Likely pathogenic ★ same residue
GRIN2B c.2172-2A>G Pathogenic ★★ same type
GRIN2B p.Ala639Val Pathogenic/Likely pathogenic ★★ same type
GRIN2B p.Ala644Asp Pathogenic ★★ same type
GRIN2B p.Ala734Val Likely pathogenic ★★ same type
GRIN2B p.Ala819Thr Pathogenic/Likely pathogenic ★★ same type
GRIN2B p.Arg1111His Pathogenic/Likely pathogenic ★★ ⚠ same type
GRIN2B p.Arg393Ter Pathogenic/Likely pathogenic ★★ 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/grin2b-p-ala652pro (accessed [today's date]).

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