Is GRIN2B p.Ser63Phe (c.188C>T) pathogenic?

GRIN2B p.Ser63Phe (c.188C>T) is classified Benign in GRIN2B (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: ambiguous (0.4761); Very rare (popmax 0.000254%, nfe); Associated with intellectual disability, autosomal dominant 6.

What condition is associated with GRIN2B p.Ser63Phe (c.188C>T)?

GRIN2B p.Ser63Phe (c.188C>T) is associated with intellectual disability, autosomal dominant 6, developmental and epileptic encephalopathy, 27 (ClinVar).

How common is GRIN2B p.Ser63Phe (c.188C>T) in the general population?

GRIN2B p.Ser63Phe (c.188C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about GRIN2B p.Ser63Phe (c.188C>T)?

AlphaMissense predicts ambiguous (score 0.4761) — an in-silico prediction, not a clinical call.

GRIN2B p.Ser63Phe

Q: How is GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder inherited?

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

c.188C>T · rs1865821627 · VCV1473866

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4761 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

intellectual disability, autosomal dominant 6

Computational evidence

Protein change
AlphaMissense	0.4761	ambiguous
REVEL	0.347	indeterminate
SaProt	LLR -10.21	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 249 kb · p 1.8e-30 · regional, not allelic
Overall
CADD	26.9	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 0.000254% European (non-Finnish) · 3/1,179,956 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,066 alleles · very rare exomes 3/1,461,798 · genomes 0/152,268 · 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: GRIN2B
Protein: p.Ser63Phe
Coding: c.188C>T
MANE Select: NM_000834
dbSNP: rs1865821627
Type: single nucleotide variant
Location: chr12:13866021 (GRCh38)
Gene constraint: LOEUF 0.102 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.66 · 36 PDB
Residue 63: a β-strand

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

Disease context

intellectual disability, autosomal dominant 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: developmental and epileptic encephalopathy, 27

For GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal

Similar variants

GRIN2B p.Ser63= Likely benign ★★ same residue
GRIN2B p.Ser63Pro Uncertain significance ★ ⚠ same residue
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

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-ser63phe (accessed [today's date]).

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