GCK p.Phe148Ser
c.443T>C · rs2484529584 · VCV2628363
ClinGen expert panel — Monogenic Diabetes VCEP
Uncertain Significance for monogenic diabetes. Applied ACMG criteria (verbatim):
PM2_Supporting PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.443T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 148 (p.(Phe148Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.442T>A (p.(Phe148Ile)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.991, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.443T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.998 | likely pathogenic · top 1% in GCK |
|---|---|---|
| REVEL | 0.991 | strongly pathogenic-leaning |
| SaProt | LLR -15.55 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 1.8, phastCons 1 |
| Regional constraint | o/e 0.71 | unconstrained · MANE · 7,224 bp · p 1.1e-11 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- GCK
- Protein
- p.Phe148Ser
- Coding
- c.443T>C
- MANE Select
- NM_000162
- dbSNP
- rs2484529584
- Type
- single nucleotide variant
- Location
- chr7:44150996 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 93.87 · 35 PDB
- Residue 148
- the hexokinase domain; a β-strand; the 'hexokinase small subdomain' region; a UniProt-annotated variant site (in mody2)
Similar variants
- GCK p.Phe148Ile Uncertain significance ★★★ ⚠ 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
- GCK c.1020-1G>C 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-phe148ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown