Is GCK p.Ser411= (c.1233C>G) pathogenic?

GCK p.Ser411= (c.1233C>G) is classified Benign/Likely benign in GCK (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-05-01). Very rare (popmax 0.00883%, nfe); Associated with maturity-onset diabetes of the young.

What condition is associated with GCK p.Ser411= (c.1233C>G)?

GCK p.Ser411= (c.1233C>G) is associated with maturity-onset diabetes of the young (ClinVar).

How common is GCK p.Ser411= (c.1233C>G) in the general population?

GCK p.Ser411= (c.1233C>G) is very rare (popmax 0.00883%, nfe) (gnomAD).

How is MODY inherited?

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

GCK p.Ser411=

c.1233C>G · rs755112715 · VCV736532

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00883%, nfe)

Conditions

maturity-onset diabetes of the young

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 -10	GERP -3.7
Overall
CADD	0.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00883% European (non-Finnish) · 104/1,177,920 alleles

Filtering AF 0.00742% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00693%

Overall 0.00715% 115/1,608,364 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,782
European (non-Finnish)grpmax	0.00883%	11,326
African / African-American	0.00267%	37,444
East Asian	0.00224%	44,732

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser411=
Coding: c.1233C>G
MANE Select: NM_000162
dbSNP: rs755112715
Type: single nucleotide variant
Location: chr7:44145517 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 411: the hexokinase domain; a UniProt-annotated variant site (in mody2); a binding site; an α-helix; the 'hexokinase large subdomain' region; 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

maturity-onset diabetes of the young — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MODY (Orphanet):

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

Similar variants

GCK p.Ser411Phe Likely pathogenic ★★ same residue
GCK p.Ser411Pro Likely pathogenic ★ same residue
GCK c.1020-1G>A 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
GCK c.679+1G>A Pathogenic ★★★ same condition
GCK c.679+5G>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-ser411 (accessed [today's date]).

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