GCK p.Ser375Phe
c.1124C>T · rs193922263 · VCV36175
ClinGen expert panel — Monogenic Diabetes VCEP
Likely Pathogenic for monogenic diabetes. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PS4_Moderate PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.1124C>T variant in the glucokinase gene, GCK, causes an amino acid change of serine to phenylalanine at codon 375 (p.(Ser375Phe)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4; ClinVar 36175, internal lab contributors). The variant was identified in an individual with a clinical history highly specific for GCK-MODY (fasting glucose 5.5-8 mol/L and HbA1c 5.6-7.6% and three-generation, dominant family history of hyperglycemia. (PP4_Moderate; internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS4_Moderate.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9867 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.969 | strongly pathogenic-leaning |
| SaProt | LLR -15.68 | 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 12 | GERP 1.7, phastCons 1 |
| Regional constraint | o/e 0.71 | unconstrained · MANE · 7,224 bp · p 1.1e-11 · regional, not allelic |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
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.Ser375Phe
- Coding
- c.1124C>T
- MANE Select
- NM_000162
- dbSNP
- rs193922263
- Type
- single nucleotide variant
- Location
- chr7:44145626 (GRCh38)
- Gene constraint
- LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 93.87 · 35 PDB
- Residue 375
- 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.Ser375Pro Uncertain significance ★★ ⚠ same residue
- GCK p.Ser375Tyr Conflicting classifications of pathogenicity ★ ⚠ 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-ser375phe (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown