Is GRM6 p.Pro689Arg (c.2066C>G) pathogenic?

GRM6 p.Pro689Arg (c.2066C>G) is classified Uncertain significance in GRM6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-19). AlphaMissense: likely pathogenic (0.7509); Very rare (popmax 0.00669%, eas).

How common is GRM6 p.Pro689Arg (c.2066C>G) in the general population?

GRM6 p.Pro689Arg (c.2066C>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about GRM6 p.Pro689Arg (c.2066C>G)?

AlphaMissense predicts likely pathogenic (score 0.7509) — an in-silico prediction, not a clinical call.

GRM6 p.Pro689Arg

c.2066C>G · rs751452976 · VCV2063780

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7509	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -17.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · 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 0.00669% East Asian · 3/44,866 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000558% 9/1,613,994 alleles · very rare exomes 9/1,461,660 · genomes 0/152,334 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,955
Admixed American	0.00333%	30,013
South Asian	0.0011%	90,990
European (non-Finnish)	0.000254%	393,324

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.Pro689Arg
Coding: c.2066C>G
MANE Select: NM_000843
dbSNP: rs751452976
Type: single nucleotide variant
Location: chr5:178986188 (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

Similar variants

GRM6 p.Pro689fs Pathogenic/Likely pathogenic ★★ same residue
GRM6 c.722-2A>C Likely pathogenic ★★ same type
GRM6 p.Arg238Ter Pathogenic ★★ same type
GRM6 p.Arg446Ter Pathogenic ★★ same type
GRM6 p.Arg621Ter Pathogenic ★★ same type
GRM6 p.Gln488Ter Pathogenic ★★ same type
GRM6 p.Gln681Ter Pathogenic/Likely pathogenic ★★ same type
GRM6 p.Gln708Ter Pathogenic ★★ same type

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-pro689arg (accessed [today's date]).

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