# NM_000162.5(GCK):c.459T>G (p.Pro153=)

https://sugi.bio/variant/gck-p-pro153

## Summary

**GCK p.Pro153= (c.459T>G)** is classified **Likely pathogenic** in GCK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-01). Absent from gnomAD v4.1; Associated with maturity-onset diabetes of the young type 2.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GCK gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to maturity-onset diabetes of the young type 2.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GCK is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of MODY** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Glucose intolerance — Frequent (79-30%)
- Hyperglycemia — Frequent (79-30%)
- Glycosuria — Frequent (79-30%)
- Abnormal oral glucose tolerance — Frequent (79-30%)
- Abnormal C-peptide level — Frequent (79-30%)
- Abnormal circulating insulin concentration — Frequent (79-30%)
- Hypoinsulinemia — Frequent (79-30%)
- Elevated hemoglobin A1c — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010657/index) · [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.Pro153= |
| Coding change (HGVS c.) | c.459T>G |
| MANE Select transcript | [NM_000162](https://www.ncbi.nlm.nih.gov/nuccore/NM_000162) |
| Variant type | single nucleotide variant |
| Location | chr7:44150980-44150980 (GRCh38) |
| ClinVar | [VCV4813357](https://www.ncbi.nlm.nih.gov/clinvar/variation/4813357/) |

**All HGVS expressions:** `LRG_1074:g.52191T>G`, `LRG_1074t1:c.459T>G`, `LRG_1074t2:c.462T>G`, `NC_000007.13:g.44190579A>C`, `NC_000007.14:g.44150980A>C`, `NG_008847.2:g.52191T>G`, `NM_000162.5:c.459T>G`, `NM_001354800.1:c.459T>G`, `NM_033507.3:c.462T>G`, `NM_033508.3:c.456T>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.90) — consistent with the pathogenic call
- Conservation: phyloP -6.896, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 18.47**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.09**, acceptor gain **0.00**, donor gain **0.90**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.90**.
- Pangolin: Δ**0.70** (gain), gain 0.70 / loss 0.12. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 3/3, triplosensitivity 0/3. *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 **153** lies in the hexokinase domain; the 'hexokinase small subdomain' region; a UniProt-annotated variant site (in mody2).

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.Pro153= 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-01.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Groupe Hospitalier Pitie Salpetriere, Uf Genomique Du Developpement, Assistance Publique Hopitaux de Paris Sorbonne Université | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-06-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Maturity-onset diabetes of the young type 2, Diabetes mellitus, type II, autosomal dominant, MODY type 2, Diabetes mellitus MODY type 2, MODY glucokinase-related.

## Same-residue context {#hotspot}

Residue **153** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [GCK p.Pro153His](/variant/gck-p-pro153his), [GCK p.Pro153Ser](/variant/gck-p-pro153ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GCK variant pages (same residue, condition, or type): [GCK p.Pro153Ser](/variant/gck-p-pro153ser), [GCK p.Pro153His](/variant/gck-p-pro153his), [GCK c.1020-10C>A](/variant/gck-c-1020-minus-10c-a), [GCK c.1020-1G>C](/variant/gck-c-1020-minus-1g-c), [GCK c.679+1G>C](/variant/gck-c-679-plus-1g-c), [GCK c.680-2A>G](/variant/gck-c-680-minus-2a-g), [GCK c.863+1G>A](/variant/gck-c-863-plus-1g-a), [GCK c.864-1G>A](/variant/gck-c-864-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 4813357). 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.*