Is GCK p.Phe423Ser (c.1268T>C) pathogenic?

GCK p.Phe423Ser (c.1268T>C) is classified Uncertain significance in GCK (ClinVar, Expert panel, 2 submitters; last evaluated 2024-04-27). AlphaMissense: likely pathogenic (0.9826); Absent from gnomAD v4.1; Associated with monogenic diabetes.

What condition is associated with GCK p.Phe423Ser (c.1268T>C)?

GCK p.Phe423Ser (c.1268T>C) is associated with monogenic diabetes (ClinVar).

How common is GCK p.Phe423Ser (c.1268T>C) in the general population?

GCK p.Phe423Ser (c.1268T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCK p.Phe423Ser (c.1268T>C)?

AlphaMissense predicts likely pathogenic (score 0.9826) — an in-silico prediction, not a clinical call.

GCK p.Phe423Ser

c.1268T>C · rs193922273 · VCV447389

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9826 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

ClinGen expert panel — Monogenic Diabetes VCEP

Uncertain Significance for monogenic diabetes. Applied ACMG criteria (verbatim):

PM2_Supporting PP2 PP3 PM5

Curation rationale (ClinGen, verbatim)

The c.1268T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 423 (p.(Phe423Ser)) of NM_000162.5. 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 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1268T>A, p.Phe423Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe423Ser has a greater Grantham distance (PM5). 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 (PMIDs: 25555642, internal lab contributors). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 25555642, internal lab contributors). In summary, c.1268T>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, PM5.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9826	likely pathogenic
REVEL	0.973	strongly pathogenic-leaning
SaProt	LLR -12.64	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 9.3	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	31.0	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

gnomAD v4.1 · exomes + genomes

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.Phe423Ser
Coding: c.1268T>C
MANE Select: NM_000162
dbSNP: rs193922273
Type: single nucleotide variant
Location: chr7:44145266 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 423: 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)

Full GCK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GCK p.Phe423Tyr 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
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-phe423ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown