Is GCK p.Phe84Ser (c.251T>C) pathogenic?

GCK p.Phe84Ser (c.251T>C) is classified Uncertain significance in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-12). AlphaMissense: likely pathogenic (0.9921); Absent from gnomAD v4.1.

How common is GCK p.Phe84Ser (c.251T>C) in the general population?

GCK p.Phe84Ser (c.251T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCK p.Phe84Ser (c.251T>C)?

AlphaMissense predicts likely pathogenic (score 0.9921) — an in-silico prediction, not a clinical call.

GCK p.Phe84Ser

c.251T>C · rs2128822702 · VCV1352737

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9921 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9921	likely pathogenic · top 7% in GCK
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -15.24	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 0.13	constrained · MANE · 949 bp · p 2.4e-06 · regional, not allelic
Overall
CADD	32.0	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.Phe84Ser
Coding: c.251T>C
MANE Select: NM_000162
dbSNP: rs2128822702
Type: single nucleotide variant
Location: chr7:44152383 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 84: 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

Similar variants

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
GCK c.1020-1G>A Pathogenic ★★★ same type
GCK c.1020-1G>C Pathogenic ★★★ same type
GCK c.1253+1G>A 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-phe84ser (accessed [today's date]).

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