Is GCK p.Arg36= (c.108G>A) pathogenic?

GCK p.Arg36= (c.108G>A) is classified Benign/Likely benign in GCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-10-23). Very rare (popmax 0.0011%, sas); Associated with maturity-onset diabetes of the young.

What condition is associated with GCK p.Arg36= (c.108G>A)?

GCK p.Arg36= (c.108G>A) is associated with maturity-onset diabetes of the young (ClinVar).

How common is GCK p.Arg36= (c.108G>A) in the general population?

GCK p.Arg36= (c.108G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is MODY inherited?

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

GCK p.Arg36=

c.108G>A · rs754169218 · VCV984522

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.43	GERP -0.56, phastCons 0.99
Overall
CADD	9.187	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,090 alleles

Overall 6.2e-05% 1/1,614,140 alleles · very rare exomes 1/1,461,852 · genomes 0/152,288 · joint denominator

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.Arg36=
Coding: c.108G>A
MANE Select: NM_000162
dbSNP: rs754169218
Type: single nucleotide variant
Location: chr7:44153401 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 36: the hexokinase domain; an α-helix; 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.Arg36Trp Pathogenic ★★★ same residue
GCK p.Arg36Gln Uncertain significance ★★★ ⚠ same residue
GCK p.Arg36Pro 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
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-arg36 (accessed [today's date]).

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