Is GCK p.Arg303= (c.907C>A) pathogenic?

GCK p.Arg303= (c.907C>A) is classified Uncertain significance in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). Very rare (popmax 0.00333%, amr); Associated with type 2 diabetes mellitus.

What condition is associated with GCK p.Arg303= (c.907C>A)?

GCK p.Arg303= (c.907C>A) is associated with type 2 diabetes mellitus, maturity-onset diabetes of the young type 2, hyperinsulinemic hypoglycemia, familial, 3 (ClinVar).

How common is GCK p.Arg303= (c.907C>A) in the general population?

GCK p.Arg303= (c.907C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

GCK p.Arg303=

c.907C>A · VCV3594715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

type 2 diabetes mellitus

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 3	GERP -0.64, phastCons 1
Overall
CADD	13.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,032 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000137% 2/1,460,018 alleles · very rare

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.Arg303=
Coding: c.907C>A
MANE Select: NM_000162
Type: single nucleotide variant
Location: chr7:44146575 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 303: the hexokinase domain; an α-helix; the 'hexokinase large subdomain' region; a UniProt-annotated variant site (in mody2); 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

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: maturity-onset diabetes of the young type 2 hyperinsulinemic hypoglycemia, familial, 3 permanent neonatal diabetes mellitus 1

Similar variants

GCK p.Arg303Gln Likely pathogenic ★★ same residue
GCK p.Arg303Leu Pathogenic/Likely pathogenic ★★ same residue
GCK p.Arg303Trp Likely pathogenic ★★ same residue
GCK c.1020-10C>A Likely pathogenic ★★★ same condition
GCK c.1020-1G>C Pathogenic ★★★ same condition
GCK c.679+1G>C Pathogenic ★★★ same condition
GCK c.680-2A>G Pathogenic ★★★ same condition
GCK c.863+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-arg303 (accessed [today's date]).

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