Is GRIN2A p.Arg856Pro (c.2567G>C) pathogenic?

GRIN2A p.Arg856Pro (c.2567G>C) is classified Uncertain significance in GRIN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-27). AlphaMissense: likely pathogenic (0.7276); Absent from gnomAD v4.1; Associated with Landau-Kleffner syndrome.

What condition is associated with GRIN2A p.Arg856Pro (c.2567G>C)?

GRIN2A p.Arg856Pro (c.2567G>C) is associated with Landau-Kleffner syndrome (ClinVar).

How common is GRIN2A p.Arg856Pro (c.2567G>C) in the general population?

GRIN2A p.Arg856Pro (c.2567G>C) is absent from gnomAD v4.1 (gnomAD).

How is Landau-Kleffner syndrome inherited?

Typically Autosomal dominant, Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GRIN2A p.Arg856Pro (c.2567G>C)?

AlphaMissense predicts likely pathogenic (score 0.7276) — an in-silico prediction, not a clinical call.

GRIN2A p.Arg856Pro

c.2567G>C · VCV3651325

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7276 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Landau-Kleffner syndrome

Computational evidence

Protein change
AlphaMissense	0.7276	likely pathogenic
REVEL	0.109	moderately benign-leaning
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP -0.62, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 5,758 bp · p 0.13 · regional, not allelic
Overall
CADD	24.8	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: GRIN2A
Protein: p.Arg856Pro
Coding: c.2567G>C
MANE Select: NM_001134407
Type: single nucleotide variant
Location: chr16:9768879 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 37 PDB
Residue 856: a UniProt-annotated variant site (found in schizophrenia; uncertain significance; loss of function in ion transmembrane transport; the channel is not activated by glutamate)

Full GRIN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Landau-Kleffner syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Landau-Kleffner syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Japan)

Similar variants

GRIN2A p.Arg856Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
GRIN2A p.Arg856Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
GRIN2A p.Arg856Leu Uncertain significance ★ ⚠ same residue
GRIN2A p.Arg856= Likely benign ★ same residue
GRIN2A p.Arg856Trp Likely benign ★ ⚠ same residue
GRIN2A c.1007+1G>A Pathogenic/Likely pathogenic ★★ same condition
GRIN2A c.1007+1G>T Pathogenic ★★ same condition
GRIN2A c.1123-2A>G 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/grin2a-p-arg856pro (accessed [today's date]).

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