Is GRID2 p.Ser667Phe (c.2000C>T) pathogenic?

GRID2 p.Ser667Phe (c.2000C>T) is classified Uncertain significance in GRID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.9271); Very rare (popmax 0.00423%, afr); Associated with Inborn genetic diseases.

What condition is associated with GRID2 p.Ser667Phe (c.2000C>T)?

GRID2 p.Ser667Phe (c.2000C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRID2 p.Ser667Phe (c.2000C>T) in the general population?

GRID2 p.Ser667Phe (c.2000C>T) is very rare (popmax 0.00423%, afr) (gnomAD).

What do computational predictors say about GRID2 p.Ser667Phe (c.2000C>T)?

AlphaMissense predicts likely pathogenic (score 0.9271) — an in-silico prediction, not a clinical call.

GRID2 p.Ser667Phe

c.2000C>T · VCV4266880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00423%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9271	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -13.29	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 548 kb · p 0.0047 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00423% African / African-American · 3/70,902 alleles

Filtering AF 0.00112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000896%

Overall 0.00149% 22/1,479,192 alleles · very rare exomes 18/1,327,180 · genomes 4/152,012 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00423%	23,634
European (non-Finnish)	0.00174%	57,523

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: GRID2
Protein: p.Ser667Phe
Coding: c.2000C>T
MANE Select: NM_001510
Type: single nucleotide variant
Location: chr4:93515218 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.07 · 6 PDB

Full GRID2 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

Similar variants

GRID2 p.Ala654Thr Pathogenic/Likely pathogenic ★★ same condition
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GRID2 p.Ala21Val Uncertain significance ★★ ⚠ same condition
GRID2 p.Ala574Ser Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg229Gln Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg297Gln Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg439Leu Uncertain significance ★★ same condition
GRID2 p.Arg714Gln 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/grid2-p-ser667phe (accessed [today's date]).

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