Is GCK p.Ser453= (c.1359G>T) pathogenic?

GCK p.Ser453= (c.1359G>T) is classified Likely benign in GCK (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-21). Ultra-rare (popmax 0.0132%, sas); Associated with maturity-onset diabetes of the young.

What condition is associated with GCK p.Ser453= (c.1359G>T)?

GCK p.Ser453= (c.1359G>T) is associated with maturity-onset diabetes of the young (ClinVar).

How common is GCK p.Ser453= (c.1359G>T) in the general population?

GCK p.Ser453= (c.1359G>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is MODY inherited?

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

GCK p.Ser453=

c.1359G>T · rs761968548 · VCV1938767

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.9	GERP -3.7
Overall
CADD	0.138	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/90,704 alleles

Filtering AF 0.00754% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00595%

Overall 0.0031% 50/1,610,342 alleles · ultra-rare exomes 44/1,458,114 · genomes 6/152,228 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,559
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,550
European (non-Finnish)	0.00288%	34,686
Admixed American	0.00167%	59,844
Finnishnot grpmax-eligible	0.00162%	61,854
Remaining individualsnot grpmax-eligible	0.0016%	62,352

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.Ser453=
Coding: c.1359G>T
MANE Select: NM_000162
dbSNP: rs761968548
Type: single nucleotide variant
Location: chr7:44145175 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 453: 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

maturity-onset diabetes of the young — 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.Ser453Ter Likely pathogenic ★★★ same residue
GCK p.Ser453Leu Pathogenic/Likely pathogenic ★★ same residue
GCK p.Ser453Trp Pathogenic/Likely pathogenic ★★ same residue
GCK c.1020-1G>A 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

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-ser453 (accessed [today's date]).

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