Is CTRC p.Ser99Pro (c.295T>C) pathogenic?

CTRC p.Ser99Pro (c.295T>C) is classified Uncertain significance in CTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-05). AlphaMissense: likely pathogenic (0.8135); Very rare (popmax 0.00267%, afr); Associated with hereditary chronic pancreatitis.

What condition is associated with CTRC p.Ser99Pro (c.295T>C)?

CTRC p.Ser99Pro (c.295T>C) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CTRC p.Ser99Pro (c.295T>C) in the general population?

CTRC p.Ser99Pro (c.295T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CTRC p.Ser99Pro (c.295T>C)?

AlphaMissense predicts likely pathogenic (score 0.8135) — an in-silico prediction, not a clinical call.

CTRC p.Ser99Pro

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.295T>C · rs2526294543 · VCV3226063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8135 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.8135	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -14.58	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,121 bp · p 0.049 · regional, not allelic
Overall
CADD	21.5	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 0.00267% African / African-American · 2/75,004 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,872 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,502
European (non-Finnish)	8.47e-05%	1,180,012

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: CTRC
Protein: p.Ser99Pro
Coding: c.295T>C
MANE Select: NM_007272
dbSNP: rs2526294543
Type: single nucleotide variant
Location: chr1:15442511 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.03 · 1 PDB
Residue 99: a disulfide bond; the peptidase s1 domain

Full CTRC 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

CTRC p.Ser99Thr Uncertain significance ★★ ⚠ same residue
CTRC p.Ser99Phe Uncertain significance ★ same residue
CTRC p.Ser99Tyr Uncertain significance ★ same residue
CTRC p.Ser99= Likely benign ★ same residue
CTRC c.494-1G>C Pathogenic/Likely pathogenic ★★ same condition
CTRC p.Arg29Ter Pathogenic/Likely pathogenic ★★ same condition
CTRC p.Gln174Ter Pathogenic/Likely pathogenic ★★ same condition
CTRC c.356+1G>A 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/ctrc-p-ser99pro (accessed [today's date]).

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