Is GCK p.Phe330Val (c.988T>G) pathogenic?

GCK p.Phe330Val (c.988T>G) is classified Uncertain significance in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). AlphaMissense: likely pathogenic (0.8112); Very rare (popmax 0.00133%, afr); Associated with type 2 diabetes mellitus.

What condition is associated with GCK p.Phe330Val (c.988T>G)?

GCK p.Phe330Val (c.988T>G) is associated with type 2 diabetes mellitus, maturity-onset diabetes of the young type 2, hyperinsulinemic hypoglycemia, familial, 3 (ClinVar).

How common is GCK p.Phe330Val (c.988T>G) in the general population?

GCK p.Phe330Val (c.988T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about GCK p.Phe330Val (c.988T>G)?

AlphaMissense predicts likely pathogenic (score 0.8112) — an in-silico prediction, not a clinical call.

GCK p.Phe330Val

c.988T>G · VCV3594713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.8112	likely pathogenic
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -11.87	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 9.1	GERP 0.89, 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

Grpmax group 0.00133% African / African-American · 1/74,908 alleles

Overall 0.000657% 1/152,166 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.Phe330Val
Coding: c.988T>G
MANE Select: NM_000162
Type: single nucleotide variant
Location: chr7:44146494 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 330: the hexokinase domain; the 'hexokinase large subdomain' region; a UniProt-annotated variant site (in mody2); 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

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: maturity-onset diabetes of the young type 2 hyperinsulinemic hypoglycemia, familial, 3 permanent neonatal diabetes mellitus 1

Similar variants

GCK p.Phe330Ser Likely pathogenic ★ same residue
GCK p.Phe330= Uncertain significance ★ 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-phe330val (accessed [today's date]).

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