Is GCK p.Phe133Val (c.397T>G) pathogenic?

GCK p.Phe133Val (c.397T>G) is classified Uncertain significance in GCK (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-15). AlphaMissense: likely pathogenic (0.9574); Absent from gnomAD v4.1; Associated with maturity-onset diabetes of the young type 2.

What condition is associated with GCK p.Phe133Val (c.397T>G)?

GCK p.Phe133Val (c.397T>G) is associated with maturity-onset diabetes of the young type 2 (ClinVar).

How common is GCK p.Phe133Val (c.397T>G) in the general population?

GCK p.Phe133Val (c.397T>G) is absent from gnomAD v4.1 (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.Phe133Val (c.397T>G)?

AlphaMissense predicts likely pathogenic (score 0.9574) — an in-silico prediction, not a clinical call.

GCK p.Phe133Val

c.397T>G · rs2128822093 · VCV1803244

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9574 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maturity-onset diabetes of the young type 2

Computational evidence

Protein change
AlphaMissense	0.9574	likely pathogenic
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -13.45	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 7,224 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Phe133Val
Coding: c.397T>G
MANE Select: NM_000162
dbSNP: rs2128822093
Type: single nucleotide variant
Location: chr7:44151042 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 133: the hexokinase domain; an α-helix; 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

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.Phe133Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
GCK p.Phe133Leu 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

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-phe133val (accessed [today's date]).

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