# NM_000162.5(GCK):c.393C>T (p.Ser131=)

https://sugi.bio/variant/gck-p-ser131

## Summary

**GCK p.Ser131= (c.393C>T)** is classified **Conflicting classifications of pathogenicity** in GCK (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2022-12-23). Ultra-rare (popmax 0.0165%, mid); Associated with maturity-onset diabetes of the young type 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139139350 · 4 submitters · 4 linked conditions · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the GCK gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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.Ser131= |
| Coding change (HGVS c.) | c.393C>T |
| MANE Select transcript | [NM_000162](https://www.ncbi.nlm.nih.gov/nuccore/NM_000162) |
| dbSNP | [rs139139350](https://www.ncbi.nlm.nih.gov/snp/rs139139350/) |
| Variant type | single nucleotide variant |
| Location | chr7:44151046-44151046 (GRCh38) |
| ClinVar | [VCV360299](https://www.ncbi.nlm.nih.gov/clinvar/variation/360299/) |

**All HGVS expressions:** `LRG_1074:g.52125C>T`, `LRG_1074t1:c.393C>T`, `LRG_1074t2:c.396C>T`, `NC_000007.13:g.44190645G>A`, `NC_000007.14:g.44151046G>A`, `NG_008847.2:g.52125C>T`, `NM_000162.5:c.393C>T`, `NM_001354800.1:c.393C>T`, `NM_033507.3:c.396C>T`, `NM_033508.3:c.390C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -6.351, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 0.887**. 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: **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 **0.0165%** (mid) · FAF95 0.00919% · FAF99 0.00735% · 1/6,060 in the highest group · 77/1,614,120 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| South Asian | 0.0154% | 6,506 |
| African / African-American | 0.00666% | 15,009 |
| East Asian | 0.00446% | 22,442 |
| European (non-Finnish) | 0.00432% | 23,137 |
| Admixed American | 0.00333% | 30,017 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,248 |

*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 **131** lies in 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; decreased affinity for glucose).

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.Ser131= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-12-23.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 7 submissions (2018–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | Benign | criteria provided, single submitter | research |  |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-12-23 |

## Associated conditions {#conditions}

[maturity-onset diabetes of the young type 2](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young-type-2/), [hyperinsulinemic hypoglycemia, familial, 3](https://sugi.bio/atlas/disease/hyperinsulinemic-hypoglycemia-familial-3/), [maturity-onset diabetes of the young](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young/), [permanent neonatal diabetes mellitus](https://sugi.bio/atlas/disease/permanent-neonatal-diabetes-mellitus/).

**Reported phenotype names (ClinVar):** Maturity-onset diabetes of the young type 2, Transient Neonatal Diabetes, Recessive, Permanent neonatal diabetes mellitus, Hyperinsulinemic hypoglycemia, familial, 3, Maturity-onset diabetes of the young, not provided, none provided, MODY type 2, Diabetes mellitus MODY type 2, MODY glucokinase-related.

## Same-residue context {#hotspot}

Residue **131** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GCK p.Ser131Pro](/variant/gck-p-ser131pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GCK variant pages (same residue, condition, or type): [GCK p.Ser131Pro](/variant/gck-p-ser131pro), [GCK c.1019+2T>G](/variant/gck-c-1019-plus-2t-g), [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>C](/variant/gck-c-1253-plus-1g-c), [GCK c.46-2A>G](/variant/gck-c-46-minus-2a-g), [GCK c.580-9T>G](/variant/gck-c-580-minus-9t-g).

### 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 360299). 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.*