Is CTRC p.Leu124Phe (c.370C>T) pathogenic?

CTRC p.Leu124Phe (c.370C>T) is classified Uncertain significance in CTRC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-24). AlphaMissense: likely pathogenic (0.7216); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary chronic pancreatitis.

What condition is associated with CTRC p.Leu124Phe (c.370C>T)?

CTRC p.Leu124Phe (c.370C>T) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CTRC p.Leu124Phe (c.370C>T) in the general population?

CTRC p.Leu124Phe (c.370C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CTRC p.Leu124Phe (c.370C>T)?

AlphaMissense predicts likely pathogenic (score 0.7216) — an in-silico prediction, not a clinical call.

CTRC p.Leu124Phe

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.370C>T · rs755318289 · VCV1734182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.7216	likely pathogenic
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -13.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP -0.83, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,121 bp · p 0.049 · regional, not allelic
Overall
CADD	22.2	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 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 0.000805% 13/1,614,106 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0187%	5,337
European (non-Finnish)grpmax	8.47e-05%	1,180,044

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu124Phe
Coding: c.370C>T
MANE Select: NM_007272
dbSNP: rs755318289
Type: single nucleotide variant
Location: chr1:15443432 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.03 · 1 PDB
Residue 124: a disulfide bond; the peptidase s1 domain; a β-strand

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.Leu124= Uncertain significance ★ same residue
CTRC p.Leu124Arg Uncertain significance ★ ⚠ same residue
CTRC p.Leu124His Uncertain significance ★ ⚠ same residue
CTRC p.Leu124Val 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

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-leu124phe (accessed [today's date]).

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