Is GRM6 p.Arg293Cys (c.877C>T) pathogenic?

GRM6 p.Arg293Cys (c.877C>T) is classified Uncertain significance in GRM6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-26). AlphaMissense: likely benign (0.3135); Very rare (popmax 0.00469%, eas); Associated with Inborn genetic diseases.

What condition is associated with GRM6 p.Arg293Cys (c.877C>T)?

GRM6 p.Arg293Cys (c.877C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRM6 p.Arg293Cys (c.877C>T) in the general population?

GRM6 p.Arg293Cys (c.877C>T) is very rare (popmax 0.00469%, eas) (gnomAD).

What do computational predictors say about GRM6 p.Arg293Cys (c.877C>T)?

AlphaMissense predicts likely benign (score 0.3135) — an in-silico prediction, not a clinical call.

GRM6 p.Arg293Cys

c.877C>T · rs1185965317 · VCV1918726

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00469%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3135	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -13.20	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.93, 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 0.00469% East Asian · 2/42,644 alleles

Filtering AF 0.000777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000291%

Overall 0.000843% 12/1,423,056 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00469%	21,322
Admixed American	0.00183%	54,708
Remaining individualsnot grpmax-eligible	0.00164%	61,000
African / African-American	0.00135%	74,206
South Asian	0.00116%	86,016
European (non-Finnish)	0.000517%	193,597

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.Arg293Cys
Coding: c.877C>T
MANE Select: NM_000843
dbSNP: rs1185965317
Type: single nucleotide variant
Location: chr5:178990727 (GRCh38)
Gene constraint: LOEUF 1.229 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 5 PDB
Residue 293: a disulfide bond

Full GRM6 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

GRM6 p.Arg293His Uncertain significance ★ ⚠ same residue
GRM6 p.Arg293Leu Uncertain significance ★ ⚠ same residue
GRM6 p.Ala240Pro Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala414Thr Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala421Val Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala432Val Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala466Val Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala482Thr 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/grm6-p-arg293cys (accessed [today's date]).

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