Is GRM1 p.Ser667Phe (c.2000C>T) pathogenic?

GRM1 p.Ser667Phe (c.2000C>T) is classified Uncertain significance in GRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.981); Absent from gnomAD v4.1.

How common is GRM1 p.Ser667Phe (c.2000C>T) in the general population?

GRM1 p.Ser667Phe (c.2000C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRM1 p.Ser667Phe (c.2000C>T)?

AlphaMissense predicts likely pathogenic (score 0.981) — an in-silico prediction, not a clinical call.

GRM1 p.Ser667Phe

c.2000C>T · rs374477698 · VCV1807528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.981	likely pathogenic
REVEL	0.93	moderately pathogenic-leaning
SaProt	LLR -13.64	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 240 kb · p 4.8e-14 · regional, not allelic
Overall
CADD	29.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRM1
Protein: p.Ser667Phe
Coding: c.2000C>T
MANE Select: NM_001278064
dbSNP: rs374477698
Type: single nucleotide variant
Location: chr6:146399039 (GRCh38)
Gene constraint: LOEUF 0.417 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 8 PDB
Residue 667: an α-helix

Full GRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRM1 c.2661-7309A>T Uncertain significance ★★ same type
GRM1 c.951-6T>A Uncertain significance ★★ same type
GRM1 p.Ala1005Thr Uncertain significance ★★ ⚠ same type
GRM1 p.Ala11Gly Uncertain significance ★★ ⚠ same type
GRM1 p.Ala883Ser Uncertain significance ★★ ⚠ same type
GRM1 p.Ala91Val Uncertain significance ★★ ⚠ same type
GRM1 p.Arg1185Gln Uncertain significance ★★ ⚠ same type
GRM1 p.Arg358Lys Uncertain significance ★★ ⚠ 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/grm1-p-ser667phe (accessed [today's date]).

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