# NM_001256809.3(GRM4):c.41G>A (p.Trp14Ter)

https://sugi.bio/variant/grm4-p-trp14ter

## Summary

**GRM4 p.Trp14Ter (c.41G>A)** is classified **Uncertain significance** in GRM4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-05). Very rare (popmax 0.00124%, sas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.00124%, sas)

## For patients & families {#patients}

This is a change in the GRM4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [GRM4](https://sugi.bio/atlas/gene/GRM4/) |
| Protein change (HGVS p.) | p.Trp14Ter |
| Coding change (HGVS c.) | c.41G>A |
| MANE Select transcript | [NM_000841](https://www.ncbi.nlm.nih.gov/nuccore/NM_000841) (variant reported on NM_001256809) |
| Variant type | single nucleotide variant |
| Location | chr6:34155350-34155350 (GRCh38) |
| ClinVar | [VCV4891721](https://www.ncbi.nlm.nih.gov/clinvar/variation/4891721/) |

**All HGVS expressions:** `NC_000006.11:g.34123127C>T`, `NC_000006.12:g.34155350C>T`, `NG_029677.3:g.5273G>A`, `NM_001256809.3:c.41G>A`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -0.43, GERP -1.08 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.483, pLI 0.99038), supporting a loss-of-function disease mechanism. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 33.0**. 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.*
- SpliceAI: **not assessed** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00124%** (sas) · FAF95 2.9e-05% · FAF99 1.1e-05% · 1/80,854 in the highest group · 3/1,511,722 alleles overall — very rare (popmax 0.00124%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00124% | 80,854 |
| European (non-Finnish) | 0.000177% | 566,421 |

*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}

**GRM4** population constraint: LOEUF 0.483, pLI 0.99038, missense-Z 3.8744. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 83.76, 54% of residues very-high.

**8 experimental structure(s)** (PDB): [7E9H](https://www.rcsb.org/structure/7E9H), [8JD4](https://www.rcsb.org/structure/8JD4), [8JD5](https://www.rcsb.org/structure/8JD5), [8JD6](https://www.rcsb.org/structure/8JD6), [8WG9](https://www.rcsb.org/structure/8WG9), [8WGB](https://www.rcsb.org/structure/8WGB).

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

*Describes the biological roles of GRM4 (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:** GRM4's established molecular role includes G protein-coupled receptor activity.


### Pathways affected {#pathways}

GRM4 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class C/3 (Metabotropic glutamate/pheromone receptors)](https://reactome.org/content/detail/R-HSA-420499) | other |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | other |
| [Sensory perception of sweet, bitter, and umami (glutamate) taste](https://reactome.org/content/detail/R-HSA-9717207) | other |

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

**Molecular function:** G protein-coupled receptor activity, glutamate receptor activity.

**Biological process:** adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway, G protein-coupled glutamate receptor signaling pathway, positive regulation of MAPK cascade.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-11-05.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-05 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related GRM4 variant pages (same residue, condition, or type): [GRM4 p.Ala251Thr](/variant/grm4-p-ala251thr), [GRM4 p.Ala278Thr](/variant/grm4-p-ala278thr), [GRM4 p.Ala399Thr](/variant/grm4-p-ala399thr), [GRM4 p.Ala422Thr](/variant/grm4-p-ala422thr), [GRM4 p.Ala701Thr](/variant/grm4-p-ala701thr), [GRM4 p.Ala81Thr](/variant/grm4-p-ala81thr), [GRM4 p.Ala862Val](/variant/grm4-p-ala862val), [GRM4 p.Ala885Thr](/variant/grm4-p-ala885thr).

### 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 4891721). 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.*