Is GRIN2A p.Pro699Ser (c.2095C>T) pathogenic?

GRIN2A p.Pro699Ser (c.2095C>T) is classified Likely pathogenic in GRIN2A (ClinVar, Single submitter, 2 submitters; last evaluated 2019-01-01). AlphaMissense: ambiguous (0.4403); Absent from gnomAD v4.1; Associated with Landau-Kleffner syndrome.

What condition is associated with GRIN2A p.Pro699Ser (c.2095C>T)?

GRIN2A p.Pro699Ser (c.2095C>T) is associated with Landau-Kleffner syndrome, self-limited epilepsy with centrotemporal spikes (ClinVar).

How common is GRIN2A p.Pro699Ser (c.2095C>T) in the general population?

GRIN2A p.Pro699Ser (c.2095C>T) 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.Pro699Ser (c.2095C>T)?

AlphaMissense predicts ambiguous (score 0.4403) — an in-silico prediction, not a clinical call.

GRIN2A p.Pro699Ser

c.2095C>T · rs1555491648 · VCV433125

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4403 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Landau-Kleffner syndrome

Computational evidence

Protein change
AlphaMissense	0.4403	ambiguous
REVEL	0.334	indeterminate
SaProt	LLR -10.85	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.92, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 61 kb · p 2.4e-19 · regional, not allelic
Overall
CADD	27.4	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.Pro699Ser
Coding: c.2095C>T
MANE Select: NM_001134407
dbSNP: rs1555491648
Type: single nucleotide variant
Location: chr16:9822337 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 37 PDB
Residue 699: a UniProt-annotated variant site (in fesd; no effect on localization to the cell membrane; changed glutamate-gated calcium ion channel activity characterized by increased glutamate potency and decreased open probability); an α-helix; 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

Also linked: self-limited epilepsy with centrotemporal spikes

For Landau-Kleffner syndrome (Orphanet):

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

Similar variants

GRIN2A p.Pro699Ala Uncertain significance ★ ⚠ same residue
GRIN2A p.Pro699Thr Uncertain significance ★ 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
GRIN2A c.1497+1G>T Pathogenic/Likely pathogenic ★★ same condition
GRIN2A c.2007+1G>T Likely pathogenic ★★ same condition
GRIN2A c.2168+1G>C 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-pro699ser (accessed [today's date]).

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