Is GRM6 p.Ile245Val (c.733A>G) pathogenic?

GRM6 p.Ile245Val (c.733A>G) is classified Benign in GRM6 (ClinVar, Single submitter, 3 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1408); Low-frequency (popmax 1.99%, sas).

How common is GRM6 p.Ile245Val (c.733A>G) in the general population?

GRM6 p.Ile245Val (c.733A>G) is low-frequency (popmax 1.99%, sas) (gnomAD).

What do computational predictors say about GRM6 p.Ile245Val (c.733A>G)?

AlphaMissense predicts likely benign (score 0.1408) — an in-silico prediction, not a clinical call.

GRM6 p.Ile245Val

c.733A>G · rs62638207 · VCV99659

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1408 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.99%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1408	likely benign
REVEL	0.452	indeterminate
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 13 kb · p 0.88 · regional, not allelic
Overall
CADD	24.0	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 1.99% South Asian · 1,810/91,066 alleles

Filtering AF 1.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.88%

Overall 0.242% 3,912/1,613,710 alleles · low-frequency exomes 3,590/1,461,710 · genomes 322/152,000 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	1.99%	50
Middle Eastern	0.759%	132
Finnishnot grpmax-eligible	0.447%	224
Remaining individualsnot grpmax-eligible	0.266%	377
European (non-Finnish)	0.128%	779
Ashkenazi Jewishnot grpmax-eligible	0.101%	987
Admixed American	0.0583%	1,715
African / African-American	0.0307%	3,258
East Asian	0.00446%	22,413

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.Ile245Val
Coding: c.733A>G
MANE Select: NM_000843
dbSNP: rs62638207
Type: single nucleotide variant
Location: chr5:178991548 (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-ile245val (accessed [today's date]).

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