Is GRM6 p.Val230Phe (c.688G>T) pathogenic?

GRM6 p.Val230Phe (c.688G>T) is classified Uncertain significance in GRM6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.6222); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with GRM6 p.Val230Phe (c.688G>T)?

GRM6 p.Val230Phe (c.688G>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRM6 p.Val230Phe (c.688G>T) in the general population?

GRM6 p.Val230Phe (c.688G>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about GRM6 p.Val230Phe (c.688G>T)?

AlphaMissense predicts likely pathogenic (score 0.6222) — an in-silico prediction, not a clinical call.

GRM6 p.Val230Phe

c.688G>T · rs371828482 · VCV1399780

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6222 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6222	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -14.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	25.9	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 0.015% Admixed American · 9/60,032 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.00353% 57/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,670
Remaining individualsnot grpmax-eligible	0.0064%	15,627
African / African-American	0.00533%	18,763
European (non-Finnish)	0.00339%	29,500

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.Val230Phe
Coding: c.688G>T
MANE Select: NM_000843
dbSNP: rs371828482
Type: single nucleotide variant
Location: chr5:178991900 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRM6 p.Val230Ile 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
GRM6 p.Ala586Thr 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-val230phe (accessed [today's date]).

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