Is GRIN2D p.Ala899= (c.2697T>C) pathogenic?

GRIN2D p.Ala899= (c.2697T>C) is classified Benign in GRIN2D (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 90.9%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with developmental and epileptic encephalopathy, 46.

What condition is associated with GRIN2D p.Ala899= (c.2697T>C)?

GRIN2D p.Ala899= (c.2697T>C) is associated with developmental and epileptic encephalopathy, 46 (ClinVar).

GRIN2D p.Ala899=

Q: How common is GRIN2D p.Ala899= (c.2697T>C) in the general population?

GRIN2D p.Ala899= (c.2697T>C) is common (popmax 90.9%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

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

c.2697T>C · rs62130268 · VCV1236432

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 90.9%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

developmental and epileptic encephalopathy, 46

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 -9.7	GERP -2.8
Overall
CADD	1.877	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 90.9% European (non-Finnish) · 1,025,944/1,128,500 alleles

Filtering AF 90.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 90.7%

Overall 87.8% 1,318,193/1,501,470 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	95%	1
Ashkenazi Jewishnot grpmax-eligible	93.6%	1
European (non-Finnish)grpmax	90.9%	1
Finnishnot grpmax-eligible	87.7%	1
Middle Eastern	86.4%	1
Admixed American	86.2%	1
Remaining individualsnot grpmax-eligible	85.9%	1
South Asian	78.9%	1
African / African-American	64%	2
East Asian	61.2%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GRIN2D
Protein: p.Ala899=
Coding: c.2697T>C
MANE Select: NM_000836
dbSNP: rs62130268
Type: single nucleotide variant
Location: chr19:48442623 (GRCh38)
Gene constraint: LOEUF 0.642 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.00 · 13 PDB

Full GRIN2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 46 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

GRIN2D p.Ala899Thr Uncertain significance ★ same residue
GRIN2D p.Met681Val Pathogenic/Likely pathogenic ★★ same condition
GRIN2D p.Val667Ile Pathogenic/Likely pathogenic ★★ same condition
GRIN2D p.Ala1085Thr Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala1310Val Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala149Gly Uncertain significance ★★ ⚠ same condition
GRIN2D p.Ala280Thr Uncertain significance ★★ ⚠ same condition
GRIN2D p.Arg1181Pro Uncertain significance ★★ ⚠ 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/grin2d-p-ala899 (accessed [today's date]).

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