Is GRM6 p.Pro431Ser (c.1291C>T) pathogenic?

GRM6 p.Pro431Ser (c.1291C>T) is classified Uncertain significance in GRM6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-08). AlphaMissense: likely benign (0.0933); Ultra-rare (popmax 0.0158%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GRM6 p.Pro431Ser (c.1291C>T)?

GRM6 p.Pro431Ser (c.1291C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRM6 p.Pro431Ser (c.1291C>T) in the general population?

GRM6 p.Pro431Ser (c.1291C>T) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

What do computational predictors say about GRM6 p.Pro431Ser (c.1291C>T)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

GRM6 p.Pro431Ser

c.1291C>T · rs768987346 · VCV854629

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -8.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	18.07	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 0.0158% European (non-Finnish) · 187/1,180,002 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0116% 187/1,613,950 alleles · ultra-rare exomes 180/1,461,784 · genomes 7/152,166 · joint denominator

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.Pro431Ser
Coding: c.1291C>T
MANE Select: NM_000843
dbSNP: rs768987346
Type: single nucleotide variant
Location: chr5:178988998 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRM6 p.Pro431Leu Uncertain significance ★★ ⚠ same residue
GRM6 p.Pro431= Likely benign ★★ same residue
GRM6 p.Pro431Thr Uncertain significance ★ ⚠ same residue
GRM6 p.Ala240Pro Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala414Thr Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala421Val Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala432Val Uncertain significance ★★ ⚠ same condition
GRM6 p.Ala466Val Uncertain significance ★★ ⚠ same condition

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-pro431ser (accessed [today's date]).

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