Is GRID2 p.Asp41Tyr (c.121G>T) pathogenic?

GRID2 p.Asp41Tyr (c.121G>T) is classified Uncertain significance in GRID2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-18). AlphaMissense: ambiguous (0.4585); Very rare (popmax 8.49e-05%, nfe); Associated with autosomal recessive spinocerebellar ataxia 18.

What condition is associated with GRID2 p.Asp41Tyr (c.121G>T)?

GRID2 p.Asp41Tyr (c.121G>T) is associated with autosomal recessive spinocerebellar ataxia 18 (ClinVar).

How common is GRID2 p.Asp41Tyr (c.121G>T) in the general population?

GRID2 p.Asp41Tyr (c.121G>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about GRID2 p.Asp41Tyr (c.121G>T)?

AlphaMissense predicts ambiguous (score 0.4585) — an in-silico prediction, not a clinical call.

GRID2 p.Asp41Tyr

Q: How is Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome inherited?

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

c.121G>T · rs1728640535 · VCV1031990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Conditions

autosomal recessive spinocerebellar ataxia 18

Computational evidence

Protein change
AlphaMissense	0.4585	ambiguous
REVEL	0.57	indeterminate
SaProt	LLR -2.59	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 920 kb · p 0.22 · regional, not allelic
Overall
CADD	28.9	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 8.49e-05% European (non-Finnish) · 1/1,178,496 alleles

Overall 6.2e-05% 1/1,612,296 alleles · very rare exomes 1/1,460,010 · genomes 0/152,286 · 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: GRID2
Protein: p.Asp41Tyr
Coding: c.121G>T
MANE Select: NM_001510
dbSNP: rs1728640535
Type: single nucleotide variant
Location: chr4:92590163 (GRCh38)
Gene constraint: LOEUF 0.332 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.07 · 6 PDB
Residue 41: the 'interaction with cbln1 homotrimer' region; an α-helix

Full GRID2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive spinocerebellar ataxia 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive cerebellar ataxia-pyramidal signs-nystagmus-oculomotor apraxia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

GRID2 p.Thr649Ala Pathogenic/Likely pathogenic ★★ same condition
GRID2 p.Arg300His Uncertain significance ★★ ⚠ same condition
GRID2 p.Arg367His Uncertain significance ★★ ⚠ same condition
GRID2 p.Asp473Glu Uncertain significance ★★ ⚠ same condition
GRID2 p.Gly391Arg Uncertain significance ★★ ⚠ same condition
GRID2 c.735+21G>C Benign ★★ same condition
GRID2 p.Gly417= Benign ★★ same condition
GRID2 p.Arg224Gln 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/grid2-p-asp41tyr (accessed [today's date]).

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