Is CTRC p.Pro249Leu (c.746C>T) pathogenic?

CTRC p.Pro249Leu (c.746C>T) is classified Conflicting classifications of pathogenicity in CTRC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.905); Ultra-rare (popmax 0.0879%, afr); Associated with hereditary chronic pancreatitis.

What condition is associated with CTRC p.Pro249Leu (c.746C>T)?

CTRC p.Pro249Leu (c.746C>T) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CTRC p.Pro249Leu (c.746C>T) in the general population?

CTRC p.Pro249Leu (c.746C>T) is ultra-rare (popmax 0.0879%, afr) (gnomAD).

What do computational predictors say about CTRC p.Pro249Leu (c.746C>T)?

AlphaMissense predicts likely pathogenic (score 0.905) — an in-silico prediction, not a clinical call.

CTRC p.Pro249Leu

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.746C>T · rs142560329 · VCV566014

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0879%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.905	likely pathogenic
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -15.21	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 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,121 bp · p 0.049 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0879% African / African-American · 66/75,048 alleles

Filtering AF 0.0709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0647%

Overall 0.00558% 90/1,613,954 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0879%	1,137
Remaining individualsnot grpmax-eligible	0.008%	12,500
Admixed American	0.005%	20,008
South Asian	0.0022%	45,542
Finnishnot grpmax-eligible	0.00156%	64,022
European (non-Finnish)	0.0011%	90,756

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.Pro249Leu
Coding: c.746C>T
MANE Select: NM_007272
dbSNP: rs142560329
Type: single nucleotide variant
Location: chr1:15445703 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.03 · 1 PDB
Residue 249: the peptidase s1 domain; a UniProt-annotated variant site (in pctt; results in reduced protein secretion and loss of activity)

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.Pro249= Benign/Likely benign ★★ same residue
CTRC p.Pro249Ser Uncertain significance ★ ⚠ 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
CTRC c.40+4A>G Uncertain significance ★★ same condition
CTRC c.40+6C>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/ctrc-p-pro249leu (accessed [today's date]).

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