Is GCK p.Arg447Pro (c.1340G>C) pathogenic?

GCK p.Arg447Pro (c.1340G>C) is classified Likely pathogenic in GCK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-10). AlphaMissense: likely pathogenic (0.9759); Absent from gnomAD v4.1; Associated with hyperinsulinemic hypoglycemia, familial, 3.

What condition is associated with GCK p.Arg447Pro (c.1340G>C)?

GCK p.Arg447Pro (c.1340G>C) is associated with hyperinsulinemic hypoglycemia, familial, 3, type 2 diabetes mellitus, maturity-onset diabetes of the young type 2 (ClinVar).

How common is GCK p.Arg447Pro (c.1340G>C) in the general population?

GCK p.Arg447Pro (c.1340G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCK p.Arg447Pro (c.1340G>C)?

AlphaMissense predicts likely pathogenic (score 0.9759) — an in-silico prediction, not a clinical call.

GCK p.Arg447Pro

Q: How is Congenital glucokinase-related hyperinsulinism inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1340G>C · rs1131691416 · VCV804842

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9759 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperinsulinemic hypoglycemia, familial, 3

Computational evidence

Protein change
AlphaMissense	0.9759	likely pathogenic ✓ concordant with ClinVar
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -10.23	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 7.6	GERP 0.68, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 7,224 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	31.0	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.Arg447Pro
Coding: c.1340G>C
MANE Select: NM_000162
dbSNP: rs1131691416
Type: single nucleotide variant
Location: chr7:44145194 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 447: 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

hyperinsulinemic hypoglycemia, familial, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus maturity-onset diabetes of the young type 2 permanent neonatal diabetes mellitus 1

For Congenital glucokinase-related hyperinsulinism (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

GCK p.Arg447Gln Pathogenic/Likely pathogenic ★★ ⚠ same residue
GCK p.Arg447Gly Pathogenic/Likely pathogenic ★★ ⚠ same residue
GCK p.Arg447fs 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-arg447pro (accessed [today's date]).

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