Is GCK p.Arg43Pro (c.128G>C) pathogenic?

GCK p.Arg43Pro (c.128G>C) is classified Likely pathogenic in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-12). AlphaMissense: likely pathogenic (0.9787); Absent from gnomAD v4.1.

How common is GCK p.Arg43Pro (c.128G>C) in the general population?

GCK p.Arg43Pro (c.128G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCK p.Arg43Pro (c.128G>C)?

AlphaMissense predicts likely pathogenic (score 0.9787) — an in-silico prediction, not a clinical call.

GCK p.Arg43Pro

c.128G>C · rs764232985 · VCV585913

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9787 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9787	likely pathogenic ✓ concordant with ClinVar
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -12.62	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 5.9	GERP -0.56, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 36 kb · p 0.056 · regional, not allelic
Overall
CADD	29.6	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.Arg43Pro
Coding: c.128G>C
MANE Select: NM_000162
dbSNP: rs764232985
Type: single nucleotide variant
Location: chr7:44153381 (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

Similar variants

GCK p.Arg43Cys Pathogenic ★★★ ⚠ same residue
GCK p.Arg43His Pathogenic ★★★ ⚠ same residue
GCK p.Arg43Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
GCK p.Arg43= Benign/Likely benign ★★ same residue
GCK p.Arg43Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GCK c.1019+1G>A Pathogenic ★★★ same type
GCK c.1019+1G>T Pathogenic ★★★ same type
GCK c.1019+2T>G Pathogenic ★★★ same type

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-arg43pro (accessed [today's date]).

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