Is GRM4 p.Pro577Leu (c.1730C>T) pathogenic?

GRM4 p.Pro577Leu (c.1730C>T) is classified Uncertain significance in GRM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). AlphaMissense: ambiguous (0.4653); Absent from gnomAD v4.1.

How common is GRM4 p.Pro577Leu (c.1730C>T) in the general population?

GRM4 p.Pro577Leu (c.1730C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRM4 p.Pro577Leu (c.1730C>T)?

AlphaMissense predicts ambiguous (score 0.4653) — an in-silico prediction, not a clinical call.

GRM4 p.Pro577Leu

c.1730C>T · VCV3855934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4653 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4653	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -10.85	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 111 kb · p 1.7e-21 · regional, not allelic
Overall
CADD	31.0	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

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: GRM4
Protein: p.Pro577Leu
Coding: c.1730C>T
MANE Select: NM_000841
Type: single nucleotide variant
Location: chr6:34036380 (GRCh38)
Gene constraint: LOEUF 0.483 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 8 PDB

Full GRM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GRM4 p.Ala251Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala278Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala399Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala422Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala701Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala81Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala862Val Uncertain significance ★ ⚠ same type
GRM4 p.Ala885Thr 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/grm4-p-pro577leu (accessed [today's date]).

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