Is GCK p.Ser445fs (c.1331dup) pathogenic?

GCK p.Ser445fs (c.1331dup) is classified Likely pathogenic in GCK (ClinVar, Expert panel, 1 submitter; last evaluated 2023-07-30). Absent from gnomAD; Associated with monogenic diabetes.

What condition is associated with GCK p.Ser445fs (c.1331dup)?

GCK p.Ser445fs (c.1331dup) is associated with monogenic diabetes (ClinVar).

How common is GCK p.Ser445fs (c.1331dup) in the general population?

GCK p.Ser445fs (c.1331dup) is absent from gnomAD (gnomAD).

GCK p.Ser445fs

c.1331dup · rs2484492358 · VCV2574161

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

monogenic diabetes

ClinGen expert panel — Monogenic Diabetes VCEP

Likely Pathogenic for monogenic diabetes. Applied ACMG criteria (verbatim):

PVS1 PM2_Supporting

Curation rationale (ClinGen, verbatim)

The c.1331dup variant in the GCK gene causes a frameshift in the protein at codon 445 (NM_000162.5), adding 14 novel amino acids before encountering a stop codon (p.(Ser445GlnfsTer14)). While this variant, located in exon 10/10, is predicted to result in a premature stop codon that is predicted to escape nonsense mediated decay, it is a functionally important region in a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a clinical picture consistent with monogenic diabetes; however PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributor). 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). This variant segregated with disease with one informative meiosis in a family with MODY; however, this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, c.1331dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PVS1, PM2_Supporting.

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

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	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.5	GERP 0.73, phastCons 1
Region caveats
Repeat context	tandem	(GGCCAC)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GCK
Protein: p.Ser445fs
Coding: c.1331dup
MANE Select: NM_000162
dbSNP: rs2484492358
Type: Duplication
Location: chr7:44145202 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 445: the hexokinase domain; a UniProt-annotated variant site (in mody2); an α-helix; 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.Glu442fs Pathogenic ★★★ same condition
GCK p.Ile225delinsArgSerAlaTer Likely pathogenic ★★★ same condition
GCK p.Lys172_Ala173insGlyPheLys Likely pathogenic ★★★ same condition
GCK p.Val455fs Likely pathogenic ★★★ same condition
GCK p.Glu48fs Pathogenic ★★ same condition
GCK p.Lys190fs Pathogenic ★★ same condition
GCK p.Thr362fs Pathogenic ★★ same condition
GCK p.Thr206fs 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-ser445fs (accessed [today's date]).

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