Is GCK p.Ser131= (c.393C>T) pathogenic?

GCK p.Ser131= (c.393C>T) is classified Conflicting classifications of pathogenicity in GCK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-12-23). Ultra-rare (popmax 0.0165%, mid); Associated with maturity-onset diabetes of the young type 2.

What condition is associated with GCK p.Ser131= (c.393C>T)?

GCK p.Ser131= (c.393C>T) is associated with maturity-onset diabetes of the young type 2, hyperinsulinemic hypoglycemia, familial, 3, maturity-onset diabetes of the young (ClinVar).

How common is GCK p.Ser131= (c.393C>T) in the general population?

GCK p.Ser131= (c.393C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

GCK p.Ser131=

c.393C>T · rs139139350 · VCV360299

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

maturity-onset diabetes of the young type 2

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 -6.4	GERP -3.7
Overall
CADD	0.887	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00477% 77/1,614,120 alleles · ultra-rare exomes 64/1,461,810 · genomes 13/152,310 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.0154%	6,506
African / African-American	0.00666%	15,009
East Asian	0.00446%	22,442
European (non-Finnish)	0.00432%	23,137
Admixed American	0.00333%	30,017
Remaining individualsnot grpmax-eligible	0.0032%	31,248

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.Ser131=
Coding: c.393C>T
MANE Select: NM_000162
dbSNP: rs139139350
Type: single nucleotide variant
Location: chr7:44151046 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 131: the hexokinase domain; an α-helix; the 'hexokinase small subdomain' region; a UniProt-annotated variant site (in mody2); a UniProt-annotated variant site (in mody2; decreased affinity for glucose)

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

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

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

GCK p.Ser131Pro Likely pathogenic ★★ same residue
GCK c.1019+2T>G Pathogenic ★★★ same condition
GCK c.1020-10C>A Likely pathogenic ★★★ same condition
GCK c.1020-1G>A Pathogenic ★★★ same condition
GCK c.1020-1G>C Pathogenic ★★★ same condition
GCK c.1253+1G>C Pathogenic ★★★ same condition
GCK c.46-2A>G Pathogenic ★★★ same condition
GCK c.580-9T>G 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-ser131 (accessed [today's date]).

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