Is GCK p.Ser151Phe (c.452C>T) pathogenic?

GCK p.Ser151Phe (c.452C>T) is classified Uncertain significance in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely pathogenic (0.9969); Absent from gnomAD v4.1.

How common is GCK p.Ser151Phe (c.452C>T) in the general population?

GCK p.Ser151Phe (c.452C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCK p.Ser151Phe (c.452C>T)?

AlphaMissense predicts likely pathogenic (score 0.9969) — an in-silico prediction, not a clinical call.

GCK p.Ser151Phe

c.452C>T · VCV3665750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9969 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9969	likely pathogenic · top 3% in GCK
REVEL	0.987	strongly pathogenic-leaning
SaProt	LLR -13.81	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 0.71	unconstrained · MANE · 7,224 bp · p 1.1e-11 · regional, not allelic
Overall
CADD	33.0	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.Ser151Phe
Coding: c.452C>T
MANE Select: NM_000162
Type: single nucleotide variant
Location: chr7:44150987 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 151: the hexokinase domain; the 'hexokinase small subdomain' region; a UniProt-annotated variant site (in mody2); a binding site; a UniProt-annotated variant site (in pndm1)

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

Similar variants

GCK p.Ser151Pro Likely pathogenic ★★★ same residue
GCK p.Ser151Tyr Likely pathogenic ★ same residue
GCK p.Ser151del Pathogenic ★★★ 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
GCK c.1019+5G>A Likely pathogenic ★★★ same type
GCK c.1020-10C>A Likely 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-ser151phe (accessed [today's date]).

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