Is GRIN2A p.Phe147Ser (c.440T>C) pathogenic?

GRIN2A p.Phe147Ser (c.440T>C) is classified Likely benign in GRIN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely pathogenic (0.985); Very rare (popmax 0.00167%, amr); Associated with Landau-Kleffner syndrome.

What condition is associated with GRIN2A p.Phe147Ser (c.440T>C)?

GRIN2A p.Phe147Ser (c.440T>C) is associated with Landau-Kleffner syndrome (ClinVar).

How common is GRIN2A p.Phe147Ser (c.440T>C) in the general population?

GRIN2A p.Phe147Ser (c.440T>C) is very rare (popmax 0.00167%, amr) (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.Phe147Ser (c.440T>C)?

AlphaMissense predicts likely pathogenic (score 0.985) — an in-silico prediction, not a clinical call.

GRIN2A p.Phe147Ser

c.440T>C · rs1227332120 · VCV2099067

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Landau-Kleffner syndrome

Computational evidence

Protein change
AlphaMissense	0.985	likely pathogenic
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -7.93	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 339 kb · p 0.00058 · regional, not allelic
Overall
CADD	28.1	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

Grpmax group 0.00167% Admixed American · 1/60,022 alleles

Overall 6.22e-05% 1/1,607,372 alleles · very rare exomes 1/1,455,060 · genomes 0/152,312 · joint denominator

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: GRIN2A
Protein: p.Phe147Ser
Coding: c.440T>C
MANE Select: NM_001134407
dbSNP: rs1227332120
Type: single nucleotide variant
Location: chr16:9938526 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 37 PDB
Residue 147: a β-strand; 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-phe147ser (accessed [today's date]).

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