Is GRIN2A p.Phe652Val (c.1954T>G) pathogenic?

GRIN2A p.Phe652Val (c.1954T>G) is classified Likely pathogenic in GRIN2A (ClinVar, Single submitter, 2 submitters; last evaluated 2019-01-01). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with Landau-Kleffner syndrome.

What condition is associated with GRIN2A p.Phe652Val (c.1954T>G)?

GRIN2A p.Phe652Val (c.1954T>G) is associated with Landau-Kleffner syndrome (ClinVar).

How common is GRIN2A p.Phe652Val (c.1954T>G) in the general population?

GRIN2A p.Phe652Val (c.1954T>G) 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.Phe652Val (c.1954T>G)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

GRIN2A p.Phe652Val

c.1954T>G · rs397518471 · VCV88733

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Landau-Kleffner syndrome

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 4% in GRIN2A
REVEL	0.751	pathogenic-leaning
SaProt	LLR -14.36	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 79 bp · p 6.2e-08 · regional, not allelic
Overall
CADD	29.8	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.Phe652Val
Coding: c.1954T>G
MANE Select: NM_001134407
dbSNP: rs397518471
Type: single nucleotide variant
Location: chr16:9829476 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 37 PDB
Residue 652: a UniProt-annotated variant site (in fesd; likely pathogenic; results in increased agonist potency and channel activation at lower glutamate and glycine concentrations compared to wild type channels; results in substantial alterations of channel gating properties and affects duration of channel open and closed states); 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

For Landau-Kleffner syndrome (Orphanet):

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

Similar variants

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
GRIN2A c.415-2A>G Likely pathogenic ★★ same condition
GRIN2A p.Ala548Pro 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-phe652val (accessed [today's date]).

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