Is GRM6 p.Leu668Pro (c.2003T>C) pathogenic?

GRM6 p.Leu668Pro (c.2003T>C) is classified Pathogenic in GRM6 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-05-11). AlphaMissense: likely pathogenic (0.9825); Very rare (popmax 0.000339%, nfe); Associated with congenital stationary night blindness.

What condition is associated with GRM6 p.Leu668Pro (c.2003T>C)?

GRM6 p.Leu668Pro (c.2003T>C) is associated with congenital stationary night blindness (ClinVar).

How common is GRM6 p.Leu668Pro (c.2003T>C) in the general population?

GRM6 p.Leu668Pro (c.2003T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about GRM6 p.Leu668Pro (c.2003T>C)?

AlphaMissense predicts likely pathogenic (score 0.9825) — an in-silico prediction, not a clinical call.

GRM6 p.Leu668Pro

c.2003T>C · rs777168556 · VCV636219

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital stationary night blindness

Computational evidence

Protein change
AlphaMissense	0.9825	likely pathogenic ✓ concordant with ClinVar · top 10% in GRM6
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -16.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	32.0	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 0.000339% European (non-Finnish) · 4/1,180,008 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,148 alleles · very rare exomes 4/1,461,846 · genomes 0/152,302 · 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: GRM6
Protein: p.Leu668Pro
Coding: c.2003T>C
MANE Select: NM_000843
dbSNP: rs777168556
Type: single nucleotide variant
Location: chr5:178986251 (GRCh38)
Gene constraint: LOEUF 1.229 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 5 PDB

Full GRM6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital stationary night blindness — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRM6 p.Leu668Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
GRM6 p.Leu668= Likely benign ★ same residue
GRM6 p.Gln681Ter Pathogenic/Likely pathogenic ★★ same condition
GRM6 p.Pro46Leu Likely pathogenic ★★ same condition
GRM6 p.Ser176Phe Uncertain significance ★★ ⚠ same condition
GRM6 p.Phe639Leu Uncertain significance ★ ⚠ same condition
GRM6 p.Val193fs Pathogenic ★ same condition
GRM6 p.Ala738fs Conflicting classifications of pathogenicity ★ 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/grm6-p-leu668pro (accessed [today's date]).

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