# NM_000843.4(GRM6):c.733A>G (p.Ile245Val)

https://sugi.bio/variant/grm6-p-ile245val

## Summary

**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).

**At a glance:** Benign · review: Single submitter · rsID rs62638207 · 3 submitters · AlphaMissense likely benign · low-frequency (popmax 1.99%, sas)

## For patients & families {#patients}

This is a change in the GRM6 gene that is classified as benign — not considered disease-causing, submitted by 3 submitters.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GRM6](https://sugi.bio/atlas/gene/GRM6/) |
| Protein change (HGVS p.) | p.Ile245Val |
| Coding change (HGVS c.) | c.733A>G |
| MANE Select transcript | [NM_000843](https://www.ncbi.nlm.nih.gov/nuccore/NM_000843) |
| dbSNP | [rs62638207](https://www.ncbi.nlm.nih.gov/snp/rs62638207/) |
| Variant type | single nucleotide variant |
| Location | chr5:178991548-178991548 (GRCh38) |
| ClinVar | [VCV99659](https://www.ncbi.nlm.nih.gov/clinvar/variation/99659/) |

**All HGVS expressions:** `LRG_1236:g.8576A>G`, `LRG_1236t1:c.733A>G`, `NC_000005.10:g.178991548T>C`, `NC_000005.9:g.178418549T>C`, `NG_008105.1:g.8576A>G`, `NM_000843.4:c.733A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1408)
- REVEL 0.452 (indeterminate)
- SaProt LLR -6.159 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.946, GERP 2.1, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (178,981,660–178,994,944), spanning 13,284 bp. Chi-square p 0.88. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.25 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.99%** (sas) · FAF95 1.91% · FAF99 1.88% · 1,810/91,066 in the highest group · 3,912/1,613,710 alleles overall — low-frequency (popmax 1.99%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 1.99% | 50 |
| Middle Eastern | 0.759% | 132 |
| Finnish (not grpmax-eligible) | 0.447% | 224 |
| Remaining individuals (not grpmax-eligible) | 0.266% | 377 |
| European (non-Finnish) | 0.128% | 779 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.101% | 987 |
| Admixed American | 0.0583% | 1,715 |
| African / African-American | 0.0307% | 3,258 |
| East Asian | 0.00446% | 22,413 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GRM6** population constraint: LOEUF 1.229, pLI 3.523e-25, missense-Z -1.0445; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **GRM6-related retinopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.90, 57% of residues very-high.

**5 experimental structure(s)** (PDB): [9LLZ](https://www.rcsb.org/structure/9LLZ), [9LM0](https://www.rcsb.org/structure/9LM0), [9UYO](https://www.rcsb.org/structure/9UYO), [9UYP](https://www.rcsb.org/structure/9UYP), [9UYQ](https://www.rcsb.org/structure/9UYQ).

## What this gene does {#gene-function}

*Describes the biological roles of GRM6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GRM6's established molecular role includes glutamate receptor activity.


### Pathways affected {#pathways}

GRM6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class C/3 (Metabotropic glutamate/pheromone receptors)](https://reactome.org/content/detail/R-HSA-420499) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** glutamate receptor activity, protein homodimerization activity.

**Biological process:** G protein-coupled glutamate receptor signaling pathway, detection of light stimulus involved in visual perception, positive regulation of calcium ion import across plasma membrane.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-01-27.

**Submitter consensus:** conflicting (2 Benign, 1 not provided).

**Submission history:** 3 submissions (2019–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Retina International | not provided | no classification provided | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-27 |

**Reported phenotype names (ClinVar):** not provided, GRM6-related disorder, GRM6-related condition, none provided.

## Similar variants {#similar}

Related GRM6 variant pages (same residue, condition, or type): [GRM6 c.722-2A>C](/variant/grm6-c-722-minus-2a-c), [GRM6 p.Arg238Ter](/variant/grm6-p-arg238ter), [GRM6 p.Arg446Ter](/variant/grm6-p-arg446ter), [GRM6 p.Arg621Ter](/variant/grm6-p-arg621ter), [GRM6 p.Gln488Ter](/variant/grm6-p-gln488ter), [GRM6 p.Gln681Ter](/variant/grm6-p-gln681ter), [GRM6 p.Gln708Ter](/variant/grm6-p-gln708ter), [GRM6 p.Glu622Ter](/variant/grm6-p-glu622ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 99659). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*