# NM_000162.5(GCK):c.458C>A (p.Pro153His)

https://sugi.bio/variant/gck-p-pro153his

## Summary

**GCK p.Pro153His (c.458C>A)** is classified **Pathogenic** in GCK (ClinVar, Expert panel, 2 submitters; last evaluated 2026-06-24). AlphaMissense: likely pathogenic (0.9868); Absent from gnomAD v4.1; Associated with monogenic diabetes.

**At a glance:** Pathogenic · review: Expert panel · rsID rs2484529426 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GCK gene that is considered disease-causing, submitted by 2 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.Pro153His |
| Coding change (HGVS c.) | c.458C>A |
| MANE Select transcript | [NM_000162](https://www.ncbi.nlm.nih.gov/nuccore/NM_000162) |
| dbSNP | [rs2484529426](https://www.ncbi.nlm.nih.gov/snp/rs2484529426/) |
| Variant type | single nucleotide variant |
| Location | chr7:44150981-44150981 (GRCh38) |
| ClinVar | [VCV2567920](https://www.ncbi.nlm.nih.gov/clinvar/variation/2567920/) |

**All HGVS expressions:** `LRG_1074:g.52190C>A`, `LRG_1074t1:c.458C>A`, `LRG_1074t2:c.461C>A`, `NC_000007.13:g.44190580G>T`, `NC_000007.14:g.44150981G>T`, `NG_008847.2:g.52190C>A`, `NM_000162.5:c.458C>A`, `NM_001354800.1:c.458C>A`, `NM_033507.3:c.461C>A`, `NM_033508.3:c.455C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9868) — concordant with the pathogenic call
- REVEL 0.985 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.93 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.53) — consistent with the pathogenic call
- Conservation: phyloP 11.801, GERP 1.84, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 35.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.53**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.53**.
- 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.Pro153His 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 2026-06-24.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Pathogenic).

**Submission history:** 2 submissions (2023–2026); 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):** `PP1_Strong`, `PM2_Supporting`, `PS4_Moderate`, `PM1`, `PP2`, `PP3`, `PM5`.
*Considered but not met:* `PP4`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.458C>A variant in the glucokinase gene, GCK, causes an amino acid change of proline to histidine at codon 153 (p.(Pro153His)) 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 0.985, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD 4.1.0 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia; however PP4 was unable to be evaluated due to insufficient clinical information (PS4_Moderate;  internal lab contributors). This variant was segregated with hyperglycemia, with seven informative meioses in five families (PP1_Strong; internal lab contributors). Another missense variant at the same residue, c.457C>T (p.Pro153Ser), has been interpreted as pathogenic by the ClinGen MDEP, and p.Pro153His has a greater Grantham distance (PM5). In summary, c.458C>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): PP1_Strong, PS4_Moderate, PM1, PM5, PM2_Supporting, PP2, PP3.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50016 · approved 2026-06-24 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/dc0a8035-6e5a-4c6f-9c2e-bdda0a027ad3).*
*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 |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-18 |
| ClinGen Monogenic Diabetes Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2026-06-24 |

## Associated conditions {#conditions}

[monogenic diabetes](https://sugi.bio/atlas/disease/monogenic-diabetes/), [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, Maturity onset diabetes mellitus in young.

## Same-residue context {#hotspot}

Residue **153** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [GCK p.Pro153Ser](/variant/gck-p-pro153ser), [GCK p.Pro153=](/variant/gck-p-pro153). *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.Pro153=](/variant/gck-p-pro153), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2567920). 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.*