Is GRM6 p.Pro435Ser (c.1303C>T) pathogenic?

GRM6 p.Pro435Ser (c.1303C>T) is classified Uncertain significance in GRM6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-09). AlphaMissense: likely benign (0.1163); Very rare (popmax 0.00212%, nfe).

How common is GRM6 p.Pro435Ser (c.1303C>T) in the general population?

GRM6 p.Pro435Ser (c.1303C>T) is very rare (popmax 0.00212%, nfe) (gnomAD).

What do computational predictors say about GRM6 p.Pro435Ser (c.1303C>T)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

GRM6 p.Pro435Ser

c.1303C>T · rs200167284 · VCV1419110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.008, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	20.1	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 0.00212% European (non-Finnish) · 25/1,179,990 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00254% 41/1,614,048 alleles · very rare exomes 31/1,461,756 · genomes 10/152,292 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0187%	5,334
Remaining individualsnot grpmax-eligible	0.0064%	15,626
European (non-Finnish)grpmax	0.00212%	47,200

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.Pro435Ser
Coding: c.1303C>T
MANE Select: NM_000843
dbSNP: rs200167284
Type: single nucleotide variant
Location: chr5:178988986 (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.Pro435Leu 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
GRM6 p.Gln708Ter 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-pro435ser (accessed [today's date]).

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