Is GCK p.Ser69= (c.207A>G) pathogenic?

GCK p.Ser69= (c.207A>G) is classified Conflicting classifications of pathogenicity in GCK (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-03-12). Very rare (popmax 0.00167%, amr); Associated with maturity-onset diabetes of the young.

What condition is associated with GCK p.Ser69= (c.207A>G)?

GCK p.Ser69= (c.207A>G) is associated with maturity-onset diabetes of the young, maturity-onset diabetes of the young type 2 (ClinVar).

How common is GCK p.Ser69= (c.207A>G) in the general population?

GCK p.Ser69= (c.207A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

How is MODY inherited?

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

GCK p.Ser69=

c.207A>G · rs779548342 · VCV972808

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.67	loss · gain 0.49 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 2.9	GERP -1.6, phastCons 1
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,030 alleles

Overall 0.000137% 2/1,461,706 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,030
South Asian	0.0011%	91,080

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GCK
Protein: p.Ser69=
Coding: c.207A>G
MANE Select: NM_000162
dbSNP: rs779548342
Type: single nucleotide variant
Location: chr7:44153302 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 69: the hexokinase domain; an α-helix; 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 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: maturity-onset diabetes of the young type 2

For MODY (Orphanet):

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

Similar variants

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
GCK c.1253+1G>C Pathogenic ★★★ same condition
GCK c.46-2A>G Pathogenic ★★★ same condition
GCK c.580-9T>G Likely pathogenic ★★★ same condition
GCK c.679+1G>A Pathogenic ★★★ same condition
GCK c.679+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-ser69 (accessed [today's date]).

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