# NM_001807.6(CEL):c.1539G>A (p.Thr513=)

https://sugi.bio/variant/cel-p-thr513

## Summary

**CEL p.Thr513= (c.1539G>A)** is classified **Conflicting classifications of pathogenicity** in CEL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-02-12). Very rare (popmax 0.0017%, nfe); Associated with maturity-onset diabetes of the young type 8.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 1 linked condition · very rare (popmax 0.0017%, nfe)

## For patients & families {#patients}

This is a change in the CEL gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to maturity-onset diabetes of the young type 8.

*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) |
| Diagnostic panels | CEL is a diagnostic-grade gene on 2 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/0010662/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CEL](https://sugi.bio/atlas/gene/CEL/) |
| Protein change (HGVS p.) | p.Thr513= |
| Coding change (HGVS c.) | c.1539G>A |
| MANE Select transcript | [NM_001807](https://www.ncbi.nlm.nih.gov/nuccore/NM_001807) |
| Variant type | single nucleotide variant |
| Location | chr9:133071041-133071041 (GRCh38) |
| ClinVar | [VCV3596576](https://www.ncbi.nlm.nih.gov/clinvar/variation/3596576/) |

**All HGVS expressions:** `NC_000009.11:g.135946428G>A`, `NC_000009.12:g.133071041G>A`, `NG_016394.1:g.14064G>A`, `NM_001807.6:c.1539G>A`

## 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 **acceptor gain** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.089, GERP -2.29 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 12.21**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.29**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.0017%** (nfe) · FAF95 0.00111% · FAF99 0.0009% · 20/1,179,826 in the highest group · 21/1,461,376 alleles overall — very rare (popmax 0.0017%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0017% | 58,991 |
| South Asian | 0.0011% | 91,070 |

*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}

**CEL** population constraint: LOEUF 0.972, pLI 3.4493e-10, missense-Z 1.4207. *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):

- **maturity-onset diabetes of the young type 8** — Moderate (AD)

## Protein context {#protein}

Residue **513** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 84.10, 69% of residues very-high.

**7 experimental structure(s)** (PDB): [1F6W](https://www.rcsb.org/structure/1F6W), [1JMY](https://www.rcsb.org/structure/1JMY), [6H0T](https://www.rcsb.org/structure/6H0T), [6H0V](https://www.rcsb.org/structure/6H0V), [6H18](https://www.rcsb.org/structure/6H18), [6H19](https://www.rcsb.org/structure/6H19).

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

*Describes the biological roles of CEL (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.*


### Pathways affected {#pathways}

CEL participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Developmental Lineage of Pancreatic Acinar Cells](https://reactome.org/content/detail/R-HSA-9925561) | curated |
| [Digestion of dietary lipid](https://reactome.org/content/detail/R-HSA-192456) | curated |

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

**Biological process:** pancreatic juice secretion, intestinal cholesterol absorption.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-02-12.

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

**Submission history:** 2 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-12 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2019-12-13 |

## Associated conditions {#conditions}

[maturity-onset diabetes of the young type 8](https://sugi.bio/atlas/disease/maturity-onset-diabetes-of-the-young-type-8/).

**Reported phenotype names (ClinVar):** Maturity-onset diabetes of the young type 8, not specified, AllHighlyPenetrant, DIABETES AND PANCREATIC EXOCRINE DYSFUNCTION, DIABETES-PANCREATIC EXOCRINE DYSFUNCTION SYNDROME.

## Similar variants {#similar}

Related CEL variant pages (same residue, condition, or type): [CEL p.Thr513Ala](/variant/cel-p-thr513ala), [CEL p.Thr513Met](/variant/cel-p-thr513met), [CEL c.67-3C>A](/variant/cel-c-67-minus-3c-a), [CEL p.Ala295Ser](/variant/cel-p-ala295ser), [CEL p.Ala548Glu](/variant/cel-p-ala548glu), [CEL p.Ala722Val](/variant/cel-p-ala722val), [CEL p.Arg116Gln](/variant/cel-p-arg116gln), [CEL p.Arg185Trp](/variant/cel-p-arg185trp).

### 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 3596576). 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.*