Is SPINK1 p.Cys61Arg (c.181T>C) pathogenic?

SPINK1 p.Cys61Arg (c.181T>C) is classified Uncertain significance in SPINK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.9724); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary chronic pancreatitis.

What condition is associated with SPINK1 p.Cys61Arg (c.181T>C)?

SPINK1 p.Cys61Arg (c.181T>C) is associated with hereditary chronic pancreatitis (ClinVar).

How common is SPINK1 p.Cys61Arg (c.181T>C) in the general population?

SPINK1 p.Cys61Arg (c.181T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SPINK1 p.Cys61Arg (c.181T>C)?

AlphaMissense predicts likely pathogenic (score 0.9724) — an in-silico prediction, not a clinical call.

SPINK1 p.Cys61Arg

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.181T>C · rs1756440825 · VCV3223133

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.9724	likely pathogenic · top 4% in SPINK1
REVEL	0.722	pathogenic-leaning
SaProt	LLR -13.00	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 6,913 bp · p 0.62 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,544 alleles

Overall 6.85e-05% 1/1,460,664 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SPINK1
Protein: p.Cys61Arg
Coding: c.181T>C
MANE Select: NM_001379610
dbSNP: rs1756440825
Type: single nucleotide variant
Location: chr5:147828035 (GRCh38)
Gene constraint: LOEUF 1.03 · pLI 0.22 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 88.70 · 5 PDB
Residue 61: the kazal-like domain; an α-helix; a disulfide bond

Full SPINK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary chronic pancreatitis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant hereditary chronic pancreatitis (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Childhood
Prevalence: 1-9 / 1 000 000 (France)

Similar variants

SPINK1 p.Cys61= Likely benign ★ same residue
SPINK1 p.Cys61fs Conflicting classifications of pathogenicity ★ ⚠ same residue
SPINK1 c.194+2T>C Pathogenic/Likely pathogenic ★★ same condition
SPINK1 p.Glu35Ter Pathogenic ★★ same condition
SPINK1 c.194+5G>A Uncertain significance ★★ same condition
SPINK1 c.55+5G>A Uncertain significance ★★ same condition
SPINK1 c.-142T>C Uncertain significance ★★ same condition
SPINK1 c.-53C>T Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/spink1-p-cys61arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown