Is GRM1 p.Pro149Arg (c.446C>G) pathogenic?

GRM1 p.Pro149Arg (c.446C>G) is classified Uncertain significance in GRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-28). AlphaMissense: likely benign (0.0819); Very rare (popmax 0.005%, amr).

How common is GRM1 p.Pro149Arg (c.446C>G) in the general population?

GRM1 p.Pro149Arg (c.446C>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about GRM1 p.Pro149Arg (c.446C>G)?

AlphaMissense predicts likely benign (score 0.0819) — an in-silico prediction, not a clinical call.

GRM1 p.Pro149Arg

c.446C>G · rs199749018 · VCV3001151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0819	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP 0.24, phastCons 0.001
Regional constraint	o/e 0.95	unconstrained · MANE · 223 bp · p 0.64 · regional, not allelic
Overall
CADD	19.03	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000805% 13/1,614,008 alleles · very rare exomes 9/1,461,828 · genomes 4/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
South Asian	0.0022%	45,545
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,916
European (non-Finnish)	0.000508%	196,665

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: GRM1
Protein: p.Pro149Arg
Coding: c.446C>G
MANE Select: NM_001278064
dbSNP: rs199749018
Type: single nucleotide variant
Location: chr6:146029963 (GRCh38)
Gene constraint: LOEUF 0.417 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.38 · 8 PDB

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

Similar variants

GRM1 p.Pro149Ala Uncertain significance ★ ⚠ same residue
GRM1 p.Pro149Gln Uncertain significance ★ ⚠ same residue
GRM1 p.Pro149Leu Uncertain significance ★ ⚠ same residue
GRM1 p.Pro149Thr Uncertain significance ★ ⚠ same residue
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

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-pro149arg (accessed [today's date]).

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