Is GRIN2B p.Pro33= (c.99C>A) pathogenic?

GRIN2B p.Pro33= (c.99C>A) is classified Likely benign in GRIN2B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-09). Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with GRIN2B p.Pro33= (c.99C>A)?

GRIN2B p.Pro33= (c.99C>A) is associated with Inborn genetic diseases, intellectual disability, autosomal dominant 6, developmental and epileptic encephalopathy, 27 (ClinVar).

How common is GRIN2B p.Pro33= (c.99C>A) in the general population?

GRIN2B p.Pro33= (c.99C>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

GRIN2B p.Pro33=

c.99C>A · rs77738206 · VCV245610

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Inborn genetic diseases

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 2.4	GERP -1.2, phastCons 1
Overall
CADD	8.836	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00428% 69/1,613,570 alleles · ultra-rare exomes 57/1,461,384 · genomes 12/152,186 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0096%	10,416
Admixed American	0.00666%	15,006
European (non-Finnish)	0.00458%	21,848
South Asian	0.00329%	30,356
African / African-American	0.00133%	74,992

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: GRIN2B
Protein: p.Pro33=
Coding: c.99C>A
MANE Select: NM_000834
dbSNP: rs77738206
Type: single nucleotide variant
Location: chr12:13866110 (GRCh38)
Gene constraint: LOEUF 0.102 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.66 · 36 PDB

Full GRIN2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability, autosomal dominant 6 developmental and epileptic encephalopathy, 27

Similar variants

GRIN2B c.2172-2A>G Pathogenic ★★ same condition
GRIN2B p.Ala639Val Pathogenic/Likely pathogenic ★★ same condition
GRIN2B p.Ala644Asp Pathogenic ★★ same condition
GRIN2B p.Ala734Val Likely pathogenic ★★ same condition
GRIN2B p.Ala819Thr Pathogenic/Likely pathogenic ★★ same condition
GRIN2B p.Arg1111His Pathogenic/Likely pathogenic ★★ ⚠ same condition
GRIN2B p.Arg393Ter Pathogenic/Likely pathogenic ★★ same condition
GRIN2B p.Arg519Gln 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/grin2b-p-pro33 (accessed [today's date]).

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