Is GRM6 p.Pro575Ser (c.1723C>T) pathogenic?

GRM6 p.Pro575Ser (c.1723C>T) is classified Uncertain significance in GRM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-24). AlphaMissense: likely benign (0.1931); Ultra-rare (popmax 0.0165%, mid).

How common is GRM6 p.Pro575Ser (c.1723C>T) in the general population?

GRM6 p.Pro575Ser (c.1723C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about GRM6 p.Pro575Ser (c.1723C>T)?

AlphaMissense predicts likely benign (score 0.1931) — an in-silico prediction, not a clinical call.

GRM6 p.Pro575Ser

c.1723C>T · rs775137930 · VCV2062463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1931 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1931	likely benign
REVEL	0.751	pathogenic-leaning
SaProt	LLR -10.86	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	26.1	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

Grpmax group 0.0165% Middle Eastern · 1/6,078 alleles

Overall 0.000124% 2/1,608,142 alleles · ultra-rare exomes 1/1,455,920 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
European (non-Finnish)	8.49e-05%	1,178,543

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.Pro575Ser
Coding: c.1723C>T
MANE Select: NM_000843
dbSNP: rs775137930
Type: single nucleotide variant
Location: chr5:178986531 (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 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
GRM6 p.Gln708Ter Pathogenic ★★ same type
GRM6 p.Glu622Ter 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-pro575ser (accessed [today's date]).

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