# NM_000162.5(GCK):c.787T>C (p.Ser263Pro)

https://sugi.bio/variant/gck-p-ser263pro

## Summary

**GCK p.Ser263Pro (c.787T>C)** is classified **Pathogenic** in GCK (ClinVar, Expert panel, 12 submitters; last evaluated 2025-06-27). AlphaMissense: likely pathogenic (0.5986); Very rare (popmax 0.000169%, nfe); Associated with monogenic diabetes.

**At a glance:** Pathogenic · review: Expert panel · rsID rs193922331 · 12 submitters · 5 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the GCK gene that is considered disease-causing, submitted by 12 submitters, and is linked to monogenic diabetes.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GCK](https://sugi.bio/atlas/gene/GCK/) |
| Protein change (HGVS p.) | p.Ser263Pro |
| Coding change (HGVS c.) | c.787T>C |
| MANE Select transcript | [NM_000162](https://www.ncbi.nlm.nih.gov/nuccore/NM_000162) |
| dbSNP | [rs193922331](https://www.ncbi.nlm.nih.gov/snp/rs193922331/) |
| Variant type | single nucleotide variant |
| Location | chr7:44147726-44147726 (GRCh38) |
| ClinVar | [VCV36258](https://www.ncbi.nlm.nih.gov/clinvar/variation/36258/) |

**All HGVS expressions:** `LRG_1074:g.55445T>C`, `LRG_1074t1:c.787T>C`, `LRG_1074t2:c.790T>C`, `NC_000007.13:g.44187325A>G`, `NC_000007.14:g.44147726A>G`, `NG_008847.2:g.55445T>C`, `NM_000162.5:c.787T>C`, `NM_001354800.1:c.787T>C`, `NM_033507.3:c.790T>C`, `NM_033508.3:c.784T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.5986) — concordant with the pathogenic call
- REVEL 0.689 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.513 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 2.79, GERP -3.69, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 22.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.71** across the covering region of the MANE Select transcript (44,145,139–44,152,363), spanning 7,224 bp. Chi-square p 1.1e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,996 in the highest group · 2/1,613,370 alleles overall — very rare (popmax 0.000169%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GCK** population constraint: LOEUF 0.866, pLI 7.7468e-07, missense-Z 2.7902; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **monogenic diabetes** — Definitive (SD)
- **hyperinsulinism due to glucokinase deficiency** — Definitive (AD)

## Protein context {#protein}

Residue **263** lies in the hexokinase domain; a turn; the 'hexokinase large subdomain' region; a UniProt-annotated variant site (in mody2); a UniProt-annotated variant site (in mody2 and t2d).

AlphaFold model confidence (whole protein): pLDDT 93.87, 85% of residues very-high.

**35 experimental structure(s)** (PDB): [1V4S](https://www.rcsb.org/structure/1V4S), [1V4T](https://www.rcsb.org/structure/1V4T), [3A0I](https://www.rcsb.org/structure/3A0I), [3F9M](https://www.rcsb.org/structure/3F9M), [3FGU](https://www.rcsb.org/structure/3FGU), [3FR0](https://www.rcsb.org/structure/3FR0).

## What this gene does {#gene-function}

*Describes the biological roles of GCK (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GCK's established molecular role includes glucokinase activity. p.Ser263Pro falls in the hexokinase domain. In Reactome, GCK is annotated in disease pathway(s) including **Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)**, **Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)**.

**Disease mechanism (Reactome):** GCK loss or alteration is curated in [Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)](https://reactome.org/content/detail/R-HSA-5619073), [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107).

### Pathways affected {#pathways}

GCK participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective GCK causes maturity-onset diabetes of the young 2 (MODY2)](https://reactome.org/content/detail/R-HSA-5619073) | curated |
| ⚕ [Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)](https://reactome.org/content/detail/R-HSA-5619107) | curated |
| [Glycolysis](https://reactome.org/content/detail/R-HSA-70171) | curated |
| [Regulation of Glucokinase by Glucokinase Regulatory Protein](https://reactome.org/content/detail/R-HSA-170822) | curated |
| [FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes](https://reactome.org/content/detail/R-HSA-9615017) | electronic |
| [Regulation of gene expression in beta cells](https://reactome.org/content/detail/R-HSA-210745) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** glucokinase activity, ATP binding, D-glucose binding.

**Biological process:** glucose catabolic process, positive regulation of insulin secretion, glucose homeostasis, negative regulation of gluconeogenesis, positive regulation of glycogen biosynthetic process, regulation of insulin secretion.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-06-27.

**Submitter consensus:** conflicting (6 Likely pathogenic, 5 Pathogenic, 1 likely pathogenic).

**Submission history:** 12 submissions (2017–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Monogenic Diabetes VCEP (monogenic diabetes). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP4_Moderate`, `PP1_Strong`, `PM2_Supporting`, `PS4`, `PP2`.
*Considered but not met:* `PS3_Supporting`, `PP3`, `BP4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.787T>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to proline at codon 263 (p.(Ser263Pro)) of NM_000162.5. This variant was identified in at least 14 unrelated individuals with hyperglycemia (PS4; PMID: 32074423, internal lab contributors). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 2.80e-7, which is below the threshold for PM2_Supporting (Grpmax FAF <= 0.000003) (PM2_Supporting). This variant segregated with diabetes/hyperglycemia, with at least 21 informative meioses in 9 families (PP1_Strong; PMID: 32074423, internal lab contributors). 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 was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; internal lab contributors). This variant has a REVEL score of 0.689, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. The relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and while the variant appears to result in thermal instability, the relative stability index was not calculated, therefore PS3_Supporting will not be applied (PMID: 16731834). In summary, c.787T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 2/17/2025): PS4, PM2_Supporting, PP1_Strong, PP2, PP4_Moderate.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50016 · approved 2025-06-27 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/9af40b37-5fda-4648-8252-561ce853763e).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-05-15 |
| Translational Genomics Laboratory, University of Maryland School of Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-06-09 |
| Genetic Services Laboratory, University of Chicago | Likely pathogenic | no assertion criteria provided | clinical testing | 2021-11-18 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-06 |
| New York Genome Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-05 |
| Athena Diagnostics | likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-29 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-03-11 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-20 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-01-18 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-12-20 |
| ClinGen Monogenic Diabetes Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2025-06-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-16 |

## Associated conditions {#conditions}

[monogenic diabetes](https://sugi.bio/atlas/disease/monogenic-diabetes/), [type 2 diabetes mellitus](https://sugi.bio/atlas/disease/type-2-diabetes-mellitus/), [gestational diabetes](https://sugi.bio/atlas/disease/gestational-diabetes/), [maturity-onset diabetes of the young type 2](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young-type-2/), [maturity-onset diabetes of the young](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young/).

**Reported phenotype names (ClinVar):** Monogenic diabetes, Maturity-onset diabetes of the young type 2, Gestational diabetes, not provided, Maturity-onset diabetes of the young, Type 2 diabetes mellitus, GCK-related disorder, GCK-related condition, MODY type 2, Diabetes mellitus MODY type 2.

## Same-residue context {#hotspot}

Residue **263** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GCK p.Ser263fs](/variant/gck-p-ser263fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GCK variant pages (same residue, condition, or type): [GCK c.1019+1G>A](/variant/gck-c-1019-plus-1g-a), [GCK c.1019+1G>T](/variant/gck-c-1019-plus-1g-t), [GCK c.1019+2T>G](/variant/gck-c-1019-plus-2t-g), [GCK c.1019+5G>A](/variant/gck-c-1019-plus-5g-a), [GCK c.1020-10C>A](/variant/gck-c-1020-minus-10c-a), [GCK c.1020-1G>A](/variant/gck-c-1020-minus-1g-a), [GCK c.1020-1G>C](/variant/gck-c-1020-minus-1g-c), [GCK c.1253+1G>A](/variant/gck-c-1253-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 36258). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*