Is GRM2 p.Phe643Ser (c.1928T>C) pathogenic?

GRM2 p.Phe643Ser (c.1928T>C) is classified Uncertain significance in GRM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely pathogenic (0.9706); Absent from gnomAD v4.1.

How common is GRM2 p.Phe643Ser (c.1928T>C) in the general population?

GRM2 p.Phe643Ser (c.1928T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRM2 p.Phe643Ser (c.1928T>C)?

AlphaMissense predicts likely pathogenic (score 0.9706) — an in-silico prediction, not a clinical call.

GRM2 p.Phe643Ser

c.1928T>C · VCV3522857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9706 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9706	likely pathogenic
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -10.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 9,125 bp · p 2.3e-15 · regional, not allelic
Overall
CADD	28.7	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: GRM2
Protein: p.Phe643Ser
Coding: c.1928T>C
MANE Select: NM_000839
Type: single nucleotide variant
Location: chr3:51715701 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.17 · 31 PDB
Residue 643: an α-helix

Full GRM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRM2 p.Asn824= Benign ★★ same type
GRM2 p.Ala127Glu Uncertain significance ★ ⚠ same type
GRM2 p.Ala275Val Uncertain significance ★ same type
GRM2 p.Ala281Val Uncertain significance ★ ⚠ same type
GRM2 p.Ala287Val Uncertain significance ★ ⚠ same type
GRM2 p.Ala363Thr Uncertain significance ★ ⚠ same type
GRM2 p.Ala430Val Uncertain significance ★ same type
GRM2 p.Ala47Val 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/grm2-p-phe643ser (accessed [today's date]).

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