Is GCK p.Ser64fs (c.190dup) pathogenic?

GCK p.Ser64fs (c.190dup) is classified Likely pathogenic in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). Associated with maturity-onset diabetes of the young type 2.

What condition is associated with GCK p.Ser64fs (c.190dup)?

GCK p.Ser64fs (c.190dup) is associated with maturity-onset diabetes of the young type 2 (ClinVar).

How is MODY inherited?

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

GCK p.Ser64fs

c.190dup · VCV4277269

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

maturity-onset diabetes of the young type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 0.66, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: GCK
Protein: p.Ser64fs
Coding: c.190dup
MANE Select: NM_000162
Type: Duplication
Location: chr7:44153318 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 64: the hexokinase domain; a β-strand; 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.Lys346fs Pathogenic/Likely pathogenic ★★ same condition
GCK p.Tyr214Ter Pathogenic/Likely pathogenic ★★ same condition
GCK c.364-41dup Uncertain significance ★★ same condition
GCK c.364-49dup Uncertain significance ★★ same condition
GCK p.Asp262fs Likely pathogenic ★ same condition
GCK p.Asp267fs Pathogenic ★ same condition
GCK p.Glu435fs Pathogenic ★ same condition
GCK p.Glu51Ter Likely 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-ser64fs (accessed [today's date]).

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