Is GCK p.Arg186= (c.556C>A) pathogenic?

GCK p.Arg186= (c.556C>A) is classified Likely benign in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-30). Ultra-rare (popmax 0.011%, sas); Associated with maturity-onset diabetes of the young.

What condition is associated with GCK p.Arg186= (c.556C>A)?

GCK p.Arg186= (c.556C>A) is associated with maturity-onset diabetes of the young (ClinVar).

How common is GCK p.Arg186= (c.556C>A) in the general population?

GCK p.Arg186= (c.556C>A) is ultra-rare (popmax 0.011%, sas) (gnomAD).

How is MODY inherited?

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

GCK p.Arg186=

c.556C>A · rs104894006 · VCV1748348

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

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	<0.2	all four deltas below 0.2 · G>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.88	GERP -3.7, phastCons 0.39
Overall
CADD	3.927	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,090 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00062% 10/1,613,790 alleles · ultra-rare exomes 9/1,461,656 · genomes 1/152,134 · joint denominator

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.Arg186=
Coding: c.556C>A
MANE Select: NM_000162
dbSNP: rs104894006
Type: single nucleotide variant
Location: chr7:44149992 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 93.87 · 35 PDB
Residue 186: 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 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.Arg186Ter Pathogenic ★★ same residue
GCK p.Arg186Leu Likely pathogenic ★ same residue
GCK p.Arg186Gln Uncertain significance ★ ⚠ 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

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-arg186 (accessed [today's date]).

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