Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

CA4239604

804849 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 24504115-2c42-4175-bedd-c3677f1a7b2e

Approved on: 2026-05-26

Published on: 2026-06-24

HGVS expressions

NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

NM_000162.5:c.562G>A

NC_000007.14:g.44149986C>T

CM000669.2:g.44149986C>T

NC_000007.13:g.44189585C>T

CM000669.1:g.44189585C>T

NC_000007.12:g.44156110C>T

NG_008847.1:g.44438G>A

NG_008847.2:g.53185G>A

ENST00000395796.8:c.*560G>A

ENST00000616242.5:c.562G>A

ENST00000682635.1:n.1048G>A

ENST00000345378.7:c.565G>A

ENST00000403799.8:c.562G>A

ENST00000671824.1:c.562G>A

ENST00000673284.1:c.562G>A

ENST00000345378.6:c.565G>A

ENST00000395796.7:c.559G>A

ENST00000403799.7:c.562G>A

ENST00000437084.1:c.511G>A

ENST00000616242.4:c.559G>A

NM_000162.3:c.562G>A

NM_033507.1:c.565G>A

NM_033508.1:c.559G>A

NM_000162.4:c.562G>A

NM_001354800.1:c.562G>A

NM_033507.2:c.565G>A

NM_033508.2:c.559G>A

NM_033507.3:c.565G>A

NM_033508.3:c.559G>A

Pathogenic

PP1_Strong PS3_Moderate PM3_Strong PS4 PM2_Supporting PP3 PP2 PP4_Moderate

PM1

Evidence Links 1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.562G>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to threonine at codon 188 (p.(Ala188Thr)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies meeting MDEP wild type quality control measures showed that the relative activity Index (RAI) of this variant was 0, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 41516031). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.81e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant was identified in at least 66 individuals with hyperglycemia (PS4; PMID: 29207974, 39859454, 38752501, 36227502, 36836406, 34556497, 36257325, 35472491, 35592779, 34440516, 30257192, 28170077, 22761713, 20337973, 16602010, 14517956, 12955723, 12050210, 8933019, 8314448, ClinVar, internal lab contributors). Furthermore, at least two individuals of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant has been detected in at least 7 individuals with neonatal diabetes. Of those individuals, 6 were homozygous, and one was compound heterozygous for this variant and another variant classified as pathogenic (c.667G>A, p.Gly223Ser) by ClinGen MDEP (PM3_Strong; PMID: 38752501, Madani et al. 2018, internal lab contributors). Additionally, this variant segregated with hyperglycemia with at least 36 informative meioses in multiple families (PP1_Strong, PMID: 30257192, 36257325, Madani et al., 2018; internal lab contributors). In summary, c.562G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PS4, PM3_Strong, PP1_Strong, PS3_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3.

PP1_Strong

This variant segregated with hyperglycemia with at least 36 informative meioses in multiple families (PP1_Strong, PMID: 30257192, 36257325, Madani et al., 2018; internal lab contributors).

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 41516031).

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0, which is below the MDEP cutoff (<0.5) PubMed:41516031

PM3_Strong

This variant has been detected in at least 7 individuals with neonatal diabetes. Of those individuals, 6 were homozygous, and one was compound heterozygous for this variant and another variant classified as pathogenic (c.667G>A, p.Gly223Ser) by ClinGen MDEP (PM3_Strong; PMID: 38752501, Madani et al. 2018, internal lab contributors).

PS4

This variant was identified in at least 66 individuals with hyperglycemia (PS4; PMID: 29207974, 39859454, 38752501, 36227502, 36836406, 34556497, 36257325, 35472491, 35592779, 34440516, 30257192, 28170077, 22761713, 20337973, 16602010, 14517956, 12955723, 12050210, 8933019, 8314448, ClinVar, internal lab contributors).

PM2_Supporting

This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.81e-7, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.933, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2).

PP4_Moderate

This variant was identified in at least two individuals with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors).

PM1

This variant does not reside in an amino acid that directly binds glucose or ATP, which are defined as critical for the GCK protein's function by the ClinGen MDEP.

Curation History

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