Is CTRC p.Ile209Phe (c.625A>T) pathogenic?

CTRC p.Ile209Phe (c.625A>T) is classified Uncertain significance in CTRC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-16). AlphaMissense: ambiguous (0.3673); Very rare (popmax 0.000508%, nfe); Associated with hereditary chronic pancreatitis.

What condition is associated with CTRC p.Ile209Phe (c.625A>T)?

CTRC p.Ile209Phe (c.625A>T) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CTRC p.Ile209Phe (c.625A>T) in the general population?

CTRC p.Ile209Phe (c.625A>T) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about CTRC p.Ile209Phe (c.625A>T)?

AlphaMissense predicts ambiguous (score 0.3673) — an in-silico prediction, not a clinical call.

CTRC p.Ile209Phe

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.625A>T · rs778850385 · VCV1752479

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.3673	ambiguous
REVEL	0.526	indeterminate
SaProt	LLR -8.42	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -0.86, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 8,121 bp · p 0.049 · regional, not allelic
Overall
CADD	22.6	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 0.000508% European (non-Finnish) · 6/1,180,036 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000479% 7/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)grpmax	0.000508%	196,673

Remaining individuals 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.Ile209Phe
Coding: c.625A>T
MANE Select: NM_007272
dbSNP: rs778850385
Type: single nucleotide variant
Location: chr1:15444737 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.03 · 1 PDB
Residue 209: a disulfide bond; the peptidase s1 domain; a UniProt-annotated variant site (sequence variant); 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.Ile209Val 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
CTRC p.Ala12Val 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-ile209phe (accessed [today's date]).

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