Is GRM6 p.Pro87= (c.261C>T) pathogenic?

GRM6 p.Pro87= (c.261C>T) is classified Likely benign in GRM6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-03). Ultra-rare (popmax 0.018%, nfe).

How common is GRM6 p.Pro87= (c.261C>T) in the general population?

GRM6 p.Pro87= (c.261C>T) is ultra-rare (popmax 0.018%, nfe) (gnomAD).

GRM6 p.Pro87=

c.261C>T · rs62638199 · VCV99649

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -4.1
Overall
CADD	8.378	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.018% European (non-Finnish) · 201/1,113,850 alleles

Filtering AF 0.016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0175% 257/1,469,934 alleles · ultra-rare exomes 209/1,318,538 · genomes 48/151,396 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0833%	1,200
European (non-Finnish)grpmax	0.018%	5,542
Remaining individualsnot grpmax-eligible	0.0178%	5,622
Admixed American	0.0157%	6,382
Ashkenazi Jewishnot grpmax-eligible	0.0038%	26,304
South Asian	0.00254%	39,347

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro87=
Coding: c.261C>T
MANE Select: NM_000843
dbSNP: rs62638199
Type: single nucleotide variant
Location: chr5:178994684 (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

Similar variants

GRM6 p.Pro87Ser Uncertain significance ★ same residue
GRM6 p.Pro87Thr Uncertain significance ★ same residue
GRM6 c.722-2A>C Likely pathogenic ★★ same type
GRM6 p.Arg238Ter Pathogenic ★★ same type
GRM6 p.Arg446Ter Pathogenic ★★ same type
GRM6 p.Arg621Ter Pathogenic ★★ same type
GRM6 p.Gln488Ter Pathogenic ★★ same type
GRM6 p.Gln681Ter Pathogenic/Likely pathogenic ★★ 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/grm6-p-pro87 (accessed [today's date]).

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