Is GCK p.Pro153= (c.459T>G) pathogenic?

GCK p.Pro153= (c.459T>G) is classified Likely pathogenic in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). Absent from gnomAD v4.1; Associated with maturity-onset diabetes of the young type 2.

What condition is associated with GCK p.Pro153= (c.459T>G)?

GCK p.Pro153= (c.459T>G) is associated with maturity-onset diabetes of the young type 2 (ClinVar).

How common is GCK p.Pro153= (c.459T>G) in the general population?

GCK p.Pro153= (c.459T>G) is absent from gnomAD v4.1 (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

GCK p.Pro153=

c.459T>G · VCV4813357

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

maturity-onset diabetes of the young type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.90	donor gain · deltas
Pangolin	Δ0.70	gain · loss 0.12 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -6.9	GERP -3.7
Overall
CADD	18.47	PHRED · no single calibrated threshold — expert panels disagree

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.Pro153=
Coding: c.459T>G
MANE Select: NM_000162
Type: single nucleotide variant
Location: chr7:44150980 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 153: the hexokinase domain; the 'hexokinase small subdomain' region; a UniProt-annotated variant site (in mody2)

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

Disease context

maturity-onset diabetes of the young type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

GCK p.Pro153Ser Pathogenic ★★★ same residue
GCK p.Pro153His Pathogenic ★★★ same residue
GCK c.1020-10C>A Likely pathogenic ★★★ same condition
GCK c.1020-1G>C Pathogenic ★★★ same condition
GCK c.679+1G>C Pathogenic ★★★ same condition
GCK c.680-2A>G Pathogenic ★★★ same condition
GCK c.863+1G>A Pathogenic ★★★ same condition
GCK c.864-1G>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-pro153 (accessed [today's date]).

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