Is GRM6 p.Arg352Ser (c.1054C>A) pathogenic?

GRM6 p.Arg352Ser (c.1054C>A) is classified Uncertain significance in GRM6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-15). AlphaMissense: likely pathogenic (0.6443); Very rare (popmax 8.48e-05%, nfe).

How common is GRM6 p.Arg352Ser (c.1054C>A) in the general population?

GRM6 p.Arg352Ser (c.1054C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GRM6 p.Arg352Ser (c.1054C>A)?

AlphaMissense predicts likely pathogenic (score 0.6443) — an in-silico prediction, not a clinical call.

GRM6 p.Arg352Ser

c.1054C>A · rs754475848 · VCV2065005

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6443 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6443	likely pathogenic
REVEL	0.585	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 0.99, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	26.4	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 8.48e-05% European (non-Finnish) · 1/1,179,672 alleles

Overall 6.2e-05% 1/1,613,782 alleles · very rare exomes 1/1,461,478 · genomes 0/152,304 · 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.Arg352Ser
Coding: c.1054C>A
MANE Select: NM_000843
dbSNP: rs754475848
Type: single nucleotide variant
Location: chr5:178989364 (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.Arg352Cys Uncertain significance ★★ ⚠ same residue
GRM6 p.Arg352His Uncertain significance ★ ⚠ same residue
GRM6 p.Arg352Leu Uncertain significance ★ ⚠ 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

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-arg352ser (accessed [today's date]).

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