Is GRIN2A p.Pro21= (c.63G>C) pathogenic?

GRIN2A p.Pro21= (c.63G>C) is classified Likely benign in GRIN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2017-01-02). Very rare (popmax 0.0011%, sas); Associated with Landau-Kleffner syndrome.

What condition is associated with GRIN2A p.Pro21= (c.63G>C)?

GRIN2A p.Pro21= (c.63G>C) is associated with Landau-Kleffner syndrome (ClinVar).

How common is GRIN2A p.Pro21= (c.63G>C) in the general population?

GRIN2A p.Pro21= (c.63G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Landau-Kleffner syndrome inherited?

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

GRIN2A p.Pro21=

c.63G>C · rs1060504865 · VCV416694

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Landau-Kleffner syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63	GERP -2.2, phastCons 0.011
Overall
CADD	9.041	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,060 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000311% 5/1,608,204 alleles · very rare exomes 4/1,456,028 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	0.000339%	294,965

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.Pro21=
Coding: c.63G>C
MANE Select: NM_001134407
dbSNP: rs1060504865
Type: single nucleotide variant
Location: chr16:10180349 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.70 · 37 PDB

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.Pro21Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
GRIN2A p.Pro21Leu 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
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-pro21 (accessed [today's date]).

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