Is GCK p.Pro59Ser (c.175C>T) pathogenic?

GCK p.Pro59Ser (c.175C>T) is classified Pathogenic/Likely pathogenic in GCK (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-01). AlphaMissense: likely pathogenic (0.9214); Very rare (popmax 8.47e-05%, nfe); Associated with maturity-onset diabetes of the young type 2.

What condition is associated with GCK p.Pro59Ser (c.175C>T)?

GCK p.Pro59Ser (c.175C>T) is associated with maturity-onset diabetes of the young type 2 (ClinVar).

How common is GCK p.Pro59Ser (c.175C>T) in the general population?

GCK p.Pro59Ser (c.175C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GCK p.Pro59Ser (c.175C>T)?

AlphaMissense predicts likely pathogenic (score 0.9214) — an in-silico prediction, not a clinical call.

GCK p.Pro59Ser

c.175C>T · rs193922287 · VCV36205

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maturity-onset diabetes of the young type 2

Computational evidence

Protein change
AlphaMissense	0.9214	likely pathogenic ✓ concordant with ClinVar
REVEL	0.956	strongly pathogenic-leaning
SaProt	LLR -12.94	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 36 kb · p 0.056 · regional, not allelic
Overall
CADD	29.1	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.84e-05% 1/1,461,840 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.Pro59Ser
Coding: c.175C>T
MANE Select: NM_000162
dbSNP: rs193922287
Type: single nucleotide variant
Location: chr7:44153334 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 59: the hexokinase domain; a β-strand

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

Disease context

maturity-onset diabetes of the young type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

GCK p.Pro59Ala Conflicting classifications of pathogenicity ★ ⚠ 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
GCK c.864-1G>A Pathogenic ★★★ same condition
GCK c.864-1G>C 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-pro59ser (accessed [today's date]).

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