# NM_000843.4(GRM6):c.1455C>T (p.Gly485=)

https://sugi.bio/variant/grm6-p-gly485

## Summary

**GRM6 p.Gly485= (c.1455C>T)** is classified **Conflicting classifications of pathogenicity** in GRM6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-01). Rare (popmax 0.122%, sas).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs149519053 · 4 submitters · rare (popmax 0.122%, sas)

## For patients & families {#patients}

This is a change in the GRM6 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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.Gly485= |
| Coding change (HGVS c.) | c.1455C>T |
| MANE Select transcript | [NM_000843](https://www.ncbi.nlm.nih.gov/nuccore/NM_000843) |
| dbSNP | [rs149519053](https://www.ncbi.nlm.nih.gov/snp/rs149519053/) |
| Variant type | single nucleotide variant |
| Location | chr5:178986883-178986883 (GRCh38) |
| ClinVar | [VCV498251](https://www.ncbi.nlm.nih.gov/clinvar/variation/498251/) |

**All HGVS expressions:** `LRG_1236:g.13241C>T`, `LRG_1236t1:c.1455C>T`, `NC_000005.10:g.178986883G>A`, `NC_000005.9:g.178413884G>A`, `NG_008105.1:g.13241C>T`, `NM_000843.4:c.1455C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.85) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.991, GERP -3.54 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 21.9**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.49**, acceptor gain **0.00**, donor gain **0.85**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.85**.
- Pangolin: Δ**0.69** (gain), gain 0.69 / loss 0.38. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.122%** (sas) · FAF95 0.103% · FAF99 0.0965% · 111/91,080 in the highest group · 593/1,614,110 alleles overall — rare (popmax 0.122%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.122% | 821 |
| Admixed American | 0.05% | 2,001 |
| Remaining individuals (not grpmax-eligible) | 0.0416% | 2,404 |
| European (non-Finnish) | 0.0343% | 2,914 |
| Middle Eastern | 0.033% | 3,031 |
| African / African-American | 0.0147% | 6,825 |
| East Asian | 0.0111% | 8,974 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,319 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-01.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-11-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

**Reported phenotype names (ClinVar):** not provided, Ovarian serous cystadenocarcinoma, not specified, AllHighlyPenetrant, 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 2026-10-14); 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 498251). 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.*