Is GCK p.Arg369Pro (c.1106G>C) pathogenic?

GCK p.Arg369Pro (c.1106G>C) is classified Pathogenic/Likely pathogenic in GCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-17). AlphaMissense: likely pathogenic (0.9554); Absent from gnomAD v4.1; Associated with GCK-related disorder.

What condition is associated with GCK p.Arg369Pro (c.1106G>C)?

GCK p.Arg369Pro (c.1106G>C) is associated with GCK-related disorder (ClinVar).

How common is GCK p.Arg369Pro (c.1106G>C) in the general population?

GCK p.Arg369Pro (c.1106G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCK p.Arg369Pro (c.1106G>C)?

AlphaMissense predicts likely pathogenic (score 0.9554) — an in-silico prediction, not a clinical call.

GCK p.Arg369Pro

c.1106G>C · rs1372420759 · VCV2632567

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9554 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GCK-related disorder

Computational evidence

Protein change
AlphaMissense	0.9554	likely pathogenic ✓ concordant with ClinVar
REVEL	0.699	pathogenic-leaning
SaProt	LLR -13.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.77	GERP -0.6, phastCons 0.19
Regional constraint	o/e 0.71	unconstrained · MANE · 7,224 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GCK
Protein: p.Arg369Pro
Coding: c.1106G>C
MANE Select: NM_000162
dbSNP: rs1372420759
Type: single nucleotide variant
Location: chr7:44145644 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 369: the hexokinase domain; a UniProt-annotated variant site (in mody2); an α-helix; the 'hexokinase large subdomain' region; 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

GCK-related disorder

Similar variants

GCK p.Arg369Gly Uncertain significance ★★★ ⚠ same residue
GCK p.Arg369Cys Likely pathogenic ★ ⚠ same residue
GCK c.208+2T>C Pathogenic/Likely pathogenic ★★ same condition
GCK c.209-1G>A Pathogenic/Likely pathogenic ★★ same condition
GCK p.Arg186Ter Pathogenic ★★ same condition
GCK p.Asp205His Pathogenic ★★ same condition
GCK p.Cys129Tyr Likely pathogenic ★★ same condition
GCK p.Gln106Ter Pathogenic/Likely 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-arg369pro (accessed [today's date]).

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