GCK p.Val222=
c.666C>A · rs193922318 · VCV2684210
Uncertain significance
Multiple submitters
Classification
Uncertain significance
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.0022%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.83 | donor loss · deltas |
|---|---|---|
| Pangolin | Δ0.82 | loss · gain 0.79 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -0.096 | GERP -3.3, phastCons 0.03 |
| Overall | ||
| CADD | 12.6 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0022%
South Asian · 2/91,022 alleles
Filtering AF
0.000365%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000137%
Overall
0.000137%
2/1,461,688 alleles · very rare
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.Val222=
- Coding
- c.666C>A
- MANE Select
- NM_000162
- dbSNP
- rs193922318
- Type
- single nucleotide variant
- Location
- chr7:44149773 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 93.87 · 35 PDB
- Residue 222
- the hexokinase domain; a β-strand; the 'hexokinase large subdomain' region; a UniProt-annotated variant site (in mody2); a UniProt-annotated variant site (in mody2 and t2d)
Similar variants
- GCK c.1019+1G>A Pathogenic ★★★ same type
- GCK c.1019+1G>T Pathogenic ★★★ same type
- GCK c.1019+2T>G Pathogenic ★★★ same type
- GCK c.1019+5G>A Likely pathogenic ★★★ same type
- GCK c.1020-10C>A Likely pathogenic ★★★ same type
- GCK c.1020-1G>A Pathogenic ★★★ same type
- GCK c.1020-1G>C Pathogenic ★★★ same type
- GCK c.1253+1G>A Pathogenic ★★★ 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/gck-p-val222 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown