Is GRM4 p.Trp14Ter (c.41G>A) pathogenic?

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).

How common is GRM4 p.Trp14Ter (c.41G>A) in the general population?

GRM4 p.Trp14Ter (c.41G>A) is very rare (popmax 0.00124%, sas) (gnomAD).

GRM4 p.Trp14Ter

c.41G>A · VCV4891721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00124%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP -1.1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00124% South Asian · 1/80,854 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000198% 3/1,511,722 alleles · very rare exomes 3/1,359,440 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00124%	80,854
European (non-Finnish)	0.000177%	566,421

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: GRM4
Protein: p.Trp14Ter
Coding: c.41G>A
MANE Select: NM_000841 · reported on NM_001256809
Type: single nucleotide variant
Location: chr6:34155350 (GRCh38)
Gene constraint: LOEUF 0.483 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 8 PDB

Full GRM4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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GRM4 p.Ala399Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala422Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala701Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala81Thr Uncertain significance ★ ⚠ same type
GRM4 p.Ala862Val Uncertain significance ★ ⚠ same type
GRM4 p.Ala885Thr Uncertain significance ★ ⚠ 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/grm4-p-trp14ter (accessed [today's date]).

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