# NM_001379610.1(SPINK1):c.182del (p.Cys61fs)

https://sugi.bio/variant/spink1-p-cys61fs

## Summary

**SPINK1 p.Cys61fs (c.182del)** is classified **Conflicting classifications of pathogenicity** in SPINK1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-05-10). No gnomAD frequency available for this variant; Associated with hereditary chronic pancreatitis.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2480198849 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the SPINK1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to hereditary chronic pancreatitis.

*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 |
| Age of onset (of this condition) | Adolescent, Childhood |
| Prevalence | 1-9 / 1 000 000 (France) |
| Clinical trials | 8 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | SPINK1 is a diagnostic-grade gene on 1 Genomics England panel |

**Commonly reported features of Autosomal dominant hereditary chronic pancreatitis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Leukocytosis — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Elevated circulating C-reactive protein concentration — Very frequent (99-80%)
- Recurrent pancreatitis — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Frequent (79-30%)
- Diabetes mellitus — Occasional (29-5%)
- Jaundice — Occasional (29-5%)
- Pancreatic calcification — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006632/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SPINK1](https://sugi.bio/atlas/gene/SPINK1/) |
| Protein change (HGVS p.) | p.Cys61fs |
| Coding change (HGVS c.) | c.182del |
| MANE Select transcript | [NM_001379610](https://www.ncbi.nlm.nih.gov/nuccore/NM_001379610) |
| dbSNP | [rs2480198849](https://www.ncbi.nlm.nih.gov/snp/rs2480198849/) |
| Variant type | Deletion |
| Location | chr5:147828034-147828034 (GRCh38) |
| ClinVar | [VCV2414904](https://www.ncbi.nlm.nih.gov/clinvar/variation/2414904/) |

**All HGVS expressions:** `NC_000005.10:g.147828034del`, `NC_000005.9:g.147207597del`, `NG_008356.2:g.16198del`, `NM_001354966.2:c.182del`, `NM_001379610.1:c.182del`, `NM_003122.4:c.182del`, `NM_003122.5:c.182del`

## 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 0.362, phastCons 0.001 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (3 of 4, 12 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**SPINK1** population constraint: LOEUF 1.03, pLI 0.22443, missense-Z 0.17221; 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.*

## Protein context {#protein}

Residue **61** lies in the kazal-like domain; an α-helix; a disulfide bond.

AlphaFold model confidence (whole protein): pLDDT 88.70, 61% of residues very-high.

**5 experimental structure(s)** (PDB): [1CGI](https://www.rcsb.org/structure/1CGI), [1CGJ](https://www.rcsb.org/structure/1CGJ), [1HPT](https://www.rcsb.org/structure/1HPT), [7QE8](https://www.rcsb.org/structure/7QE8), [7QE9](https://www.rcsb.org/structure/7QE9) — incl. mutant structure 1CGI.

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

*Describes the biological roles of SPINK1 (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}

SPINK1 participates in **1 Reactome pathway** (⚕ = disease pathway):

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

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-05-10.

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

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-19 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-10 |

## Associated conditions {#conditions}

[hereditary chronic pancreatitis](https://sugi.bio/atlas/disease/hereditary-chronic-pancreatitis/).

**Reported phenotype names (ClinVar):** Hereditary pancreatitis, not provided, none provided, Hereditary chronic pancreatitis, PRSS1-Related Hereditary Pancreatitis.

## Similar variants {#similar}

Related SPINK1 variant pages (same residue, condition, or type): [SPINK1 p.Cys61Arg](/variant/spink1-p-cys61arg), [SPINK1 p.Cys61=](/variant/spink1-p-cys61), [SPINK1 p.Ser10fs](/variant/spink1-p-ser10fs), [SPINK1 p.Asn56fs](/variant/spink1-p-asn56fs), [SPINK1 p.Lys31_Tyr33del](/variant/spink1-p-lys31-tyr33del), [SPINK1 c.-191-129_56-932del](/variant/spink1-c-minus-191-minus-129-56-minus-932del), [SPINK1 c.194+2T>C](/variant/spink1-c-194-plus-2t-c), [SPINK1 p.Glu35Ter](/variant/spink1-p-glu35ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2414904). 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.*