Is CTRC p.Thr199Ser (c.595A>T) pathogenic?

CTRC p.Thr199Ser (c.595A>T) is classified Conflicting classifications of pathogenicity in CTRC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.1404); Ultra-rare (popmax 0.0567%, amr); Associated with hereditary chronic pancreatitis.

What condition is associated with CTRC p.Thr199Ser (c.595A>T)?

CTRC p.Thr199Ser (c.595A>T) is associated with hereditary chronic pancreatitis (ClinVar).

How common is CTRC p.Thr199Ser (c.595A>T) in the general population?

CTRC p.Thr199Ser (c.595A>T) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about CTRC p.Thr199Ser (c.595A>T)?

AlphaMissense predicts likely benign (score 0.1404) — an in-silico prediction, not a clinical call.

CTRC p.Thr199Ser

Q: How is Autosomal dominant hereditary chronic pancreatitis inherited?

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

c.595A>T · rs751977111 · VCV826079

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1404 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary chronic pancreatitis

Computational evidence

Protein change
AlphaMissense	0.1404	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.48
Regional constraint	o/e 0.90	unconstrained · MANE · 8,121 bp · p 0.049 · regional, not allelic
Overall
CADD	10.25	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 0.0567% Admixed American · 34/59,996 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00235% 38/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Thr199Ser
Coding: c.595A>T
MANE Select: NM_007272
dbSNP: rs751977111
Type: single nucleotide variant
Location: chr1:15444707 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.03 · 1 PDB
Residue 199: 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.Thr199Ala Uncertain significance ★ ⚠ same residue
CTRC p.Thr199Asn Uncertain significance ★ ⚠ same residue
CTRC p.Thr199Ile Uncertain significance ★ ⚠ same residue
CTRC p.Thr199Pro 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-thr199ser (accessed [today's date]).

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