GCK p.Arg447fs
c.1340_1368del · rs1339598338 · VCV1365679
ClinGen expert panel — Monogenic Diabetes VCEP
Pathogenic for monogenic diabetes. Applied ACMG criteria (verbatim):
PVS1 PP1_Strong PM2_Supporting PS4 PP4
Curation rationale (ClinGen, verbatim)
The c.1340_1368del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 2 novel amino acids before encountering a stop codon (p.(Arg447LeufsTer2)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID 19790256) This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 16 unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia with 8 informative meioses in one family with MODY (PP1_Strong; internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4, PM2_Supporting).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | escapes | premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 8 | GERP 0.9, phastCons 1 |
| Region caveats | ||
| Repeat context | tandem | (GGCCAC)n simple repeat · ambiguous alignment · confidence, not pathogenicity |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- GCK
- Protein
- p.Arg447fs
- Coding
- c.1340_1368del
- MANE Select
- NM_000162
- dbSNP
- rs1339598338
- Type
- Deletion
- Location
- chr7:44145166 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 93.87 · 35 PDB
- Residue 447
- the hexokinase domain; a UniProt-annotated variant site (in mody2); an α-helix; a UniProt-annotated variant site (in mody2 and t2d)
Similar variants
- GCK p.Arg447Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
- GCK p.Arg447Gly Pathogenic/Likely pathogenic ★★ ⚠ same residue
- GCK p.Arg447Pro Likely pathogenic ★★ same residue
- GCK c.1254-12_1257del Pathogenic ★★★ same condition
- GCK c.1255_1264delTTCAAGGAGC Likely pathogenic ★★★ same condition
- GCK c.579+4del Pathogenic ★★★ same condition
- GCK p.Ala449fs Pathogenic ★★★ same condition
- GCK p.Ala450fs Likely pathogenic ★★★ same condition
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/gck-p-arg447fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown