Is GCK p.Pro145= (c.435C>G) pathogenic?

GCK p.Pro145= (c.435C>G) is classified Conflicting classifications of pathogenicity in GCK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-23). Rare (popmax 0.43%, eas); Associated with Transient Neonatal Diabetes, Recessive.

What condition is associated with GCK p.Pro145= (c.435C>G)?

GCK p.Pro145= (c.435C>G) is associated with Transient Neonatal Diabetes, Recessive, maturity-onset diabetes of the young type 2, hyperinsulinemic hypoglycemia, familial, 3 (ClinVar).

How common is GCK p.Pro145= (c.435C>G) in the general population?

GCK p.Pro145= (c.435C>G) is rare (popmax 0.43%, eas) (gnomAD).

GCK p.Pro145=

c.435C>G · rs773281783 · VCV909540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.43%, eas)

Conditions

Transient Neonatal Diabetes, Recessive

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 0.27	GERP -3.7, phastCons 0.5
Overall
CADD	7.377	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.43% East Asian · 193/44,884 alleles

Filtering AF 0.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.361%

Overall 0.0122% 197/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.43%	233
Remaining individualsnot grpmax-eligible	0.0064%	15,625

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.Pro145=
Coding: c.435C>G
MANE Select: NM_000162
dbSNP: rs773281783
Type: single nucleotide variant
Location: chr7:44151004 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 145: the hexokinase domain; a β-strand; the 'hexokinase small subdomain' region; a UniProt-annotated variant site (in mody2)

Full GCK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Transient Neonatal Diabetes, Recessive

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

Similar variants

GCK p.Pro145Leu Uncertain significance ★ ⚠ same residue
GCK c.1019+2T>G Pathogenic ★★★ same condition
GCK c.1020-10C>A Likely pathogenic ★★★ same condition
GCK c.1020-1G>A Pathogenic ★★★ same condition
GCK c.1020-1G>C 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

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-pro145 (accessed [today's date]).

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