Is GCK p.Arg43= (c.129C>T) pathogenic?

GCK p.Arg43= (c.129C>T) is classified Benign/Likely benign in GCK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-30). Very rare (popmax 0.00223%, eas); Associated with maturity-onset diabetes of the young.

What condition is associated with GCK p.Arg43= (c.129C>T)?

GCK p.Arg43= (c.129C>T) is associated with maturity-onset diabetes of the young (ClinVar).

How common is GCK p.Arg43= (c.129C>T) in the general population?

GCK p.Arg43= (c.129C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

How is MODY inherited?

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

GCK p.Arg43=

c.129C>T · rs760912915 · VCV255400

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -8.5	GERP -3.7
Overall
CADD	2.706	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,894 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000805% 13/1,614,044 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
South Asian	0.0011%	91,084
European (non-Finnish)	0.000932%	107,275

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.Arg43=
Coding: c.129C>T
MANE Select: NM_000162
dbSNP: rs760912915
Type: single nucleotide variant
Location: chr7:44153380 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 43: the hexokinase domain; an α-helix; a UniProt-annotated variant site (in pndm1; decreased stability; decreased glucokinase activity; no effect on affinity for glucose); a UniProt-annotated variant site (in mody2; decreased enzyme stability shown by thermostability assays; no effect on kinetic parameters for glucokinase activity in vitro); 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

For MODY (Orphanet):

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

Similar variants

GCK p.Arg43His Pathogenic ★★★ ⚠ same residue
GCK p.Arg43Cys Pathogenic ★★★ ⚠ same residue
GCK p.Arg43Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
GCK p.Arg43Pro Likely pathogenic ★ same residue
GCK p.Arg43Leu Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg43 (accessed [today's date]).

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