Is GCK p.Phe123= (c.369C>T) pathogenic?

GCK p.Phe123= (c.369C>T) is classified Likely benign in GCK (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-04-20). Very rare (popmax 0.00333%, amr); Associated with GCK-related disorder.

What condition is associated with GCK p.Phe123= (c.369C>T)?

GCK p.Phe123= (c.369C>T) is associated with GCK-related disorder (ClinVar).

How common is GCK p.Phe123= (c.369C>T) in the general population?

GCK p.Phe123= (c.369C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

GCK p.Phe123=

c.369C>T · rs1470961138 · VCV3054186

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

GCK-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -3.7
Overall
CADD	1.502	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,008 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000958% 14/1,461,630 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,004
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000932%	107,268

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.Phe123=
Coding: c.369C>T
MANE Select: NM_000162
dbSNP: rs1470961138
Type: single nucleotide variant
Location: chr7:44151070 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 123: 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

GCK-related disorder

Similar variants

GCK p.Phe123Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GCK p.Phe123Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
GCK c.208+2T>C Pathogenic/Likely pathogenic ★★ same condition
GCK c.209-1G>A Pathogenic/Likely pathogenic ★★ same condition
GCK p.Arg186Ter Pathogenic ★★ same condition
GCK p.Arg369Pro Pathogenic/Likely pathogenic ★★ same condition
GCK p.Asp205His Pathogenic ★★ same condition
GCK p.Cys129Tyr Likely 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-phe123 (accessed [today's date]).

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