Is GRM8 p.Lys681Arg (c.2042A>G) pathogenic?

GRM8 p.Lys681Arg (c.2042A>G) is classified Uncertain significance in GRM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.1371); Very rare (popmax 0.00134%, afr).

How common is GRM8 p.Lys681Arg (c.2042A>G) in the general population?

GRM8 p.Lys681Arg (c.2042A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about GRM8 p.Lys681Arg (c.2042A>G)?

AlphaMissense predicts likely benign (score 0.1371) — an in-silico prediction, not a clinical call.

GRM8 p.Lys681Arg

c.2042A>G · VCV3855960

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1371 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1371	likely benign
REVEL	0.399	indeterminate
SaProt	LLR -10.16	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 804 kb · p 0.00037 · regional, not allelic
Overall
CADD	24.6	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 0.00134% African / African-American · 1/74,888 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,732 alleles · very rare exomes 2/1,461,700 · genomes 1/152,032 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,888
European (non-Finnish)	0.00017%	589,932

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: GRM8
Protein: p.Lys681Arg
Coding: c.2042A>G
MANE Select: NM_000845
Type: single nucleotide variant
Location: chr7:126533340 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.11 · 10 PDB

Full GRM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRM8 c.1495-9T>C Benign ★★ same type
GRM8 p.Arg561= Benign ★★ same type
GRM8 p.Gly231= Benign ★★ same type
GRM8 p.His32Gln Benign ★★ same type
GRM8 p.Ile265Thr Benign ★★ same type
GRM8 p.Ile488= Benign ★★ same type
GRM8 p.Phe119= Benign ★★ same type
GRM8 p.Phe21Cys Benign ★★ 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/grm8-p-lys681arg (accessed [today's date]).

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