GCK p.Arg429=
c.1285A>C · rs140672134 · VCV36192
ClinGen expert panel — Monogenic Diabetes VCEP
Likely Benign for monogenic diabetes. Applied ACMG criteria (verbatim):
BP7 BP4 BP2
Curation rationale (ClinGen, verbatim)
The c.1285A>C variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 429 (p.(Arg429=)) of NM_000162.5. The Popmax filtering frequency of the c.1285A>C variant in gnomAD v2.1.1 is 0.000007310, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant is not predicted by SpliceAI to impact splicing (SpliceAI score less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -0.068, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant has been observed in unknown phase with the variant c.106C>T p.Arg36Trp, which is classified as likely pathogenic by the ClinGen MDEP (BP2). In summary, c.1285A>C meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): BP2, BP4, BP7.
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. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.077 | GERP -3.7, phastCons 0.98 |
| Overall | ||
| CADD | 8.38 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
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
- GCK
- Protein
- p.Arg429=
- Coding
- c.1285A>C
- MANE Select
- NM_000162
- dbSNP
- rs140672134
- Type
- single nucleotide variant
- Location
- chr7:44145249 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 93.87 · 35 PDB
- Residue 429
- the hexokinase domain; a UniProt-annotated variant site (in mody2); an α-helix; the 'hexokinase large subdomain' region; a UniProt-annotated variant site (in mody2 and t2d)
Similar variants
- GCK p.Arg429Lys Likely benign ★★★ same residue
- GCK p.Arg429fs Likely pathogenic ★ same residue
- GCK c.1019+1G>A Pathogenic ★★★ same condition
- GCK c.1019+1G>T Pathogenic ★★★ same condition
- GCK c.1019+2T>G Pathogenic ★★★ same condition
- GCK c.1019+5G>A Likely pathogenic ★★★ same condition
- GCK c.1020-10C>A Likely pathogenic ★★★ same condition
- GCK c.1020-1G>A 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-arg429 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown